WorldWideScience

Sample records for target factor analysis

  1. Genome-wide identification of the regulatory targets of a transcription factor using biochemical characterization and computational genomic analysis

    Directory of Open Access Journals (Sweden)

    Jolly Emmitt R

    2005-11-01

    Full Text Available Abstract Background A major challenge in computational genomics is the development of methodologies that allow accurate genome-wide prediction of the regulatory targets of a transcription factor. We present a method for target identification that combines experimental characterization of binding requirements with computational genomic analysis. Results Our method identified potential target genes of the transcription factor Ndt80, a key transcriptional regulator involved in yeast sporulation, using the combined information of binding affinity, positional distribution, and conservation of the binding sites across multiple species. We have also developed a mathematical approach to compute the false positive rate and the total number of targets in the genome based on the multiple selection criteria. Conclusion We have shown that combining biochemical characterization and computational genomic analysis leads to accurate identification of the genome-wide targets of a transcription factor. The method can be extended to other transcription factors and can complement other genomic approaches to transcriptional regulation.

  2. Factor Analysis of Therapist-Identified Treatment Targets in Community-Based Children's Mental Health.

    Science.gov (United States)

    Love, Allison R; Okado, Izumi; Orimoto, Trina E; Mueller, Charles W

    2018-01-01

    The present study used exploratory and confirmatory factor analyses to identify underlying latent factors affecting variation in community therapists' endorsement of treatment targets. As part of a statewide practice management program, therapist completed monthly reports of treatment targets (up to 10 per month) for a sample of youth (n = 790) receiving intensive in-home therapy. Nearly 75 % of youth were diagnosed with multiple co-occurring disorders. Five factors emerged: Disinhibition, Societal Rules Evasion, Social Engagement Deficits, Emotional Distress, and Management of Biodevelopmental Outcomes. Using logistic regression, primary diagnosis predicted therapist selection of Disinhibition and Emotional Distress targets. Client age predicted endorsement of Societal Rules Evasion targets. Practice-to-research implications are discussed.

  3. SUPERPIXEL BASED FACTOR ANALYSIS AND TARGET TRANSFORMATION METHOD FOR MARTIAN MINERALS DETECTION

    Directory of Open Access Journals (Sweden)

    X. Wu

    2018-04-01

    Full Text Available The Factor analysis and target transformation (FATT is an effective method to test for the presence of particular mineral on Martian surface. It has been used both in thermal infrared (Thermal Emission Spectrometer, TES and near-infrared (Compact Reconnaissance Imaging Spectrometer for Mars, CRISM hyperspectral data. FATT derived a set of orthogonal eigenvectors from a mixed system and typically selected first 10 eigenvectors to least square fit the library mineral spectra. However, minerals present only in a limited pixels will be ignored because its weak spectral features compared with full image signatures. Here, we proposed a superpixel based FATT method to detect the mineral distributions on Mars. The simple linear iterative clustering (SLIC algorithm was used to partition the CRISM image into multiple connected image regions with spectral homogeneous to enhance the weak signatures by increasing their proportion in a mixed system. A least square fitting was used in target transformation and performed to each region iteratively. Finally, the distribution of the specific minerals in image was obtained, where fitting residual less than a threshold represent presence and otherwise absence. We validate our method by identifying carbonates in a well analysed CRISM image in Nili Fossae on Mars. Our experimental results indicate that the proposed method work well both in simulated and real data sets.

  4. Theory of error for target factor analysis with applications to mass spectrometry and nuclear magnetic resonance spectrometry

    International Nuclear Information System (INIS)

    Malinowski, E.R.

    1978-01-01

    Based on the theory of error for abstract factor analysis described earlier, a theory of error for target factor analysis is developed. The theory shows how the error in the data matrix mixes with the error in the target test vector. The apparent error in a target test is found to be a vector sum of the real error in the target vector and the real error in the predicted vector. The theory predicts the magnitudes of these errors without requiring any a priori knowledge of the error in the data matrix or the target vector. A reliability function and a spoil function are developed for the purpose of assessing the validity and the worthiness of a target vector. Examples from model data, mass spectrometry and nuclear magnetic resonance spectrometry are presented. (Auth.)

  5. Analysis of miRNAs targeting transcription factors in Persicaria minor induced by Fusarium oxysporum

    Science.gov (United States)

    Samad, Abdul Fatah A.; Ali, Nazaruddin Muhammad; Ismail, Ismanizan; Murad, Abdul Munir Abdul

    2016-11-01

    A recent discovery showed small non-coding RNA known as microRNA has a crucial role in plant development and plant survival in extreme condition. In the past few years, researchers have managed to identify the various families of transcription factors that play a crucial role in regulating plant development and plant responses to stresses. This study focuses on the expression pattern of miRNA targeted transcription factor under biotic stress in a plant rich with secondary metabolite, Persicaria minor. A pathogenic fungus, Fusarium oxysporum was used in the biotic stress treatment since the previous study revealed this fungus could trigger plant defense system. Two small RNA libraries were constructed which consist of control and treated samples. In order to identify the potential target, psRobot target prediction software was used for each miRNA that shows significant change due to the infection. The result showed miR156b/c, miR172a, miR319, miR858, and miR894 were found to be targeting a wide range of transcription factors that involve in plant development and plant response towards stresses. The expression of miR156b/c and miR172 were up-regulated while the expression of miR319, miR858, and miR894 was found to be down-regulated. These results may provide a certain level of networking between those two regulatory molecules in plant genetic system under biotic stress.

  6. Reduction of interferences in the analysis of Children's Dimetapp using ultraviolet spectroscopy data and target factor analysis

    Science.gov (United States)

    Msimanga, Huggins Z.; Lam, Truong Thach Ho; Latinwo, Nathaniel; Song, Mihyang Kristy; Tavakoli, Newsha

    2018-03-01

    A calibration matrix has been developed and successfully applied to quantify actives in Children's Dimetapp®, a cough mixture whose active components suffer from heavy spectral interference. High-performance liquid chromatography/photodiode array instrument was used to identify the actives and any other UV-detectable excipients that might contribute to interferences. The instrument was also used to obtain reference data on the actives, instead of relying on the manufacturer's claims. Principal component analysis was used during the developmental stages of the calibration matrix to highlight any mismatch between the calibration and sample spectra, making certain that "apples" were not compared with "oranges". The prediction model was finally calculated using target factor analysis and partial least squares regression. In addition to the actives in Children's Dimetapp® (brompheniramine maleate, phenylephrine hydrogen chloride, and dextromethorphan hydrogen bromide), sodium benzoate was identified as the major and FD&C Blue #1, FD&C Red #40, and methyl anthranilate as minor spectral interferences. Model predictions were compared before and after the interferences were included into the calibration matrix. Before including interferences, the following results were obtained: brompheniramine maleate = 481.3 mg L- 1 ± 134% RE; phenylephrine hydrogen chloride = 1041 mg L- 1 ± 107% RE; dextromethorphan hydrogen bromide = 1571 mg L- 1 ± 107% RE, where % RE = percent relative error based on the reference HPLC data. After including interferences, the results were as follows: brompheniramine maleate = 196.3 mg L- 1 ± 4.4% RE; phenylephrine hydrogen chloride = 501.3 mg L- 1 ± 0.10% RE; dextromethorphan hydrogen bromide = 998.7 mg L- 1 ± 1.6% RE as detailed in Table 6.

  7. Determination of the valence-band offset of CdS/CIS solar cell devices by target factor analysis

    Energy Technology Data Exchange (ETDEWEB)

    Niles, D.W.; Contreras, M.; Ramanathan, K.; Noufi, R. [National Renewable Energy Lab., Golden, CO (United States)

    1996-05-01

    X-ray photoemission spectroscopy (XPS) is used to determine and compare the valence-band offsets ({Delta}E{sub v}) for CdS grown by chemical bath deposition on single-crystal and thin-film CuInSe{sub 2} (CIS). The thin-film CIS device was suitable for photovoltaic energy production. By sputtering through the CdS/CIS interface and reducing the depth profile with target factor analysis, the magnitude of {Delta}E{sub v} was determined to be {Delta}E{sub v} = 1.06 {+-} 0.15 eV for both the single-crystal and thin-film interfaces. This determination of {Delta}E{sub v} is about 0.25 eV larger than many previously reported estimations CdS grown by physical vapor deposition on CIS and helps explain the record performance of CdS/CIS photovoltaic devices.

  8. Factor analysis

    CERN Document Server

    Gorsuch, Richard L

    2013-01-01

    Comprehensive and comprehensible, this classic covers the basic and advanced topics essential for using factor analysis as a scientific tool in psychology, education, sociology, and related areas. Emphasizing the usefulness of the techniques, it presents sufficient mathematical background for understanding and sufficient discussion of applications for effective use. This includes not only theory but also the empirical evaluations of the importance of mathematical distinctions for applied scientific analysis.

  9. Phosphoproteomic analysis for the identification of predictive molecular factors and new molecular targets in breast, colorectal, ovary, and lung cancer

    International Nuclear Information System (INIS)

    Belluco, C.; De Paoli, P.

    2009-01-01

    Neoadjuvant chemotherapy is a standard therapeutic approach for several types of locally advanced and metastatic tumors. Molecular factors predictive of response to therapy are highly needed for exploiting the potential benefit of properative chemotherapy. Moreover, neoadjuvant chemotherapy represents an ideal clinical model for studying predictive factors since it allows to obtain pre-treatment tissue biopsies which can be analyzed and the results compared to clinical and pathological response. Protein kinases represent some of the most important drug targets in medicine today and their aberrant activation are involved in many disease processes including cancer development and progression

  10. Analysis of Lung Tumor Motion in a Large Sample: Patterns and Factors Influencing Precise Delineation of Internal Target Volume

    Energy Technology Data Exchange (ETDEWEB)

    Knybel, Lukas [Department of Oncology, University Hospital Ostrava, Ostrava (Czech Republic); VŠB-Technical University of Ostrava, Ostrava (Czech Republic); Cvek, Jakub, E-mail: Jakub.cvek@fno.cz [Department of Oncology, University Hospital Ostrava, Ostrava (Czech Republic); Molenda, Lukas; Stieberova, Natalie; Feltl, David [Department of Oncology, University Hospital Ostrava, Ostrava (Czech Republic)

    2016-11-15

    Purpose/Objective: To evaluate lung tumor motion during respiration and to describe factors affecting the range and variability of motion in patients treated with stereotactic ablative radiation therapy. Methods and Materials: Log file analysis from online respiratory tumor tracking was performed in 145 patients. Geometric tumor location in the lungs, tumor volume and origin (primary or metastatic), sex, and tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were recorded. Tumor motion variability during treatment was described using intrafraction/interfraction amplitude variability and tumor motion baseline changes. Tumor movement dependent on the tumor volume, position and origin, and sex were evaluated using statistical regression and correlation analysis. Results: After analysis of >500 hours of data, the highest rates of motion amplitudes, intrafraction/interfraction variation, and tumor baseline changes were in the SI direction (6.0 ± 2.2 mm, 2.2 ± 1.8 mm, 1.1 ± 0.9 mm, and −0.1 ± 2.6 mm). The mean motion amplitudes in the lower/upper geometric halves of the lungs were significantly different (P<.001). Motion amplitudes >15 mm were observed only in the lower geometric quarter of the lungs. Higher tumor motion amplitudes generated higher intrafraction variations (R=.86, P<.001). Interfraction variations and baseline changes >3 mm indicated tumors contacting mediastinal structures or parietal pleura. On univariate analysis, neither sex nor tumor origin (primary vs metastatic) was an independent predictive factor of different movement patterns. Metastatic lesions in women, but not men, showed significantly higher mean amplitudes (P=.03) and variability (primary, 2.7 mm; metastatic, 4.9 mm; P=.002) than primary tumors. Conclusion: Online tracking showed significant irregularities in lung tumor movement during respiration. Motion amplitude was significantly lower in upper lobe

  11. Analysis of Lung Tumor Motion in a Large Sample: Patterns and Factors Influencing Precise Delineation of Internal Target Volume

    International Nuclear Information System (INIS)

    Knybel, Lukas; Cvek, Jakub; Molenda, Lukas; Stieberova, Natalie; Feltl, David

    2016-01-01

    Purpose/Objective: To evaluate lung tumor motion during respiration and to describe factors affecting the range and variability of motion in patients treated with stereotactic ablative radiation therapy. Methods and Materials: Log file analysis from online respiratory tumor tracking was performed in 145 patients. Geometric tumor location in the lungs, tumor volume and origin (primary or metastatic), sex, and tumor motion amplitudes in the superior-inferior (SI), latero-lateral (LL), and anterior-posterior (AP) directions were recorded. Tumor motion variability during treatment was described using intrafraction/interfraction amplitude variability and tumor motion baseline changes. Tumor movement dependent on the tumor volume, position and origin, and sex were evaluated using statistical regression and correlation analysis. Results: After analysis of >500 hours of data, the highest rates of motion amplitudes, intrafraction/interfraction variation, and tumor baseline changes were in the SI direction (6.0 ± 2.2 mm, 2.2 ± 1.8 mm, 1.1 ± 0.9 mm, and −0.1 ± 2.6 mm). The mean motion amplitudes in the lower/upper geometric halves of the lungs were significantly different (P 15 mm were observed only in the lower geometric quarter of the lungs. Higher tumor motion amplitudes generated higher intrafraction variations (R=.86, P 3 mm indicated tumors contacting mediastinal structures or parietal pleura. On univariate analysis, neither sex nor tumor origin (primary vs metastatic) was an independent predictive factor of different movement patterns. Metastatic lesions in women, but not men, showed significantly higher mean amplitudes (P=.03) and variability (primary, 2.7 mm; metastatic, 4.9 mm; P=.002) than primary tumors. Conclusion: Online tracking showed significant irregularities in lung tumor movement during respiration. Motion amplitude was significantly lower in upper lobe tumors; higher interfraction amplitude variability indicated tumors in contact

  12. Critical analysis of the potential for the therapeutic targeting of the Sp1 transcription factor in pancreatic cancer

    Directory of Open Access Journals (Sweden)

    Jutooru I

    2014-06-01

    Full Text Available Indira Jutooru,1 Gayathri Chadalapaka,1 Stephen Safe1,21Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX, USA; 2Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, USAAbstract: Pancreatic ductal adenocarcinoma (PDAC is a major cause of cancer-related deaths in developed countries and, in 2013, it is estimated that in excess of 45,220 new cases were diagnosed in the United States. PDAC is a highly aggressive disease that invariably evades early diagnosis. The mean survival time for patients with metastatic disease is only 3–6 months, and only 20%–30% of pancreatic cancer patients are alive after 12 months. Because pancreatic cancers are frequently detected at an advanced stage, treatments have provided very limited improvements in tumor regression and overall survival times after diagnosis. 5-Fluorouracil alone or in combination with other drugs has been extensively used for treatment of advanced pancreatic cancer, and gemcitabine has partially replaced 5-fluorouracil as a treatment for pancreatic cancer. Gemcitabine provides increased clinical benefits in terms of response rate; however, future studies need to focus on developing treatment modalities that will improve the survival rate for pancreatic cancer patients. Specificity protein 1 (Sp1 is overexpressed in PDAC patients, and high expression is associated with poor prognosis, lymph node metastasis, and low survival. Knockdown studies have shown that Sp1 plays an important role in cell growth, angiogenesis, inflammation, survival, and metastasis. Sp1 expression is low in normal tissue when compared to tumor tissue, which makes Sp1 a potential target for development of new mechanism-based drugs for treatment of pancreatic cancer. Several drugs such as tolfenamic acid, betulinic acid, and methyl-2-cyano3,12-dioxooleana-1,9(11-dien-28-oate are shown to downregulate Sp1 expression through various pathways

  13. ChIP-on-chip analysis identifies IL-22 as direct target gene of ectopically expressed FOXP3 transcription factor in human T cells

    Directory of Open Access Journals (Sweden)

    Jeron Andreas

    2012-12-01

    Full Text Available Abstract Background The transcription factor (TF forkhead box P3 (FOXP3 is constitutively expressed at high levels in naturally occurring CD4+CD25+ regulatory T cells (nTregs. It is not only the most accepted marker for that cell population but is also considered lineage determinative. Chromatin immunoprecipitation (ChIP of TFs in combination with genomic tiling microarray analysis (ChIP-on-chip has been shown to be an appropriate tool for identifying FOXP3 transcription factor binding sites (TFBSs on a genome-wide scale. In combination with microarray expression analysis, the ChIP-on-chip technique allows identification of direct FOXP3 target genes. Results ChIP-on-chip analysis of the human FOXP3 expressed in resting and PMA/ionomycin–stimulated Jurkat T cells revealed several thousand putative FOXP3 binding sites and demonstrated the importance of intronic regions for FOXP3 binding. The analysis of expression data showed that the stimulation-dependent down-regulation of IL-22 was correlated with direct FOXP3 binding in the IL-22 promoter region. This association was confirmed by real-time PCR analysis of ChIP-DNA. The corresponding ChIP-region also contained a matching FOXP3 consensus sequence. Conclusions Knowledge of the general distribution patterns of FOXP3 TFBSs in the human genome under resting and activated conditions will contribute to a better understanding of this TF and its influence on direct target genes, as well as its importance for the phenotype and function of Tregs. Moreover, FOXP3-dependent repression of Th17-related IL-22 may be relevant to an understanding of the phenomenon of Treg/Th17 cell plasticity.

  14. Analysis Of Performance Factors Of Construction Management Consultant Affecting The Failure In Achieving Time And Quality Targets On Construction Project Of Samarinda Baru Airport

    Directory of Open Access Journals (Sweden)

    Maryudi Utomo

    2017-11-01

    Full Text Available This research aims to determine the performance factors of construction management consultants affecting the failure in achieving time and quality targets on construction project of Samarinda Baru Airport. This research uses survey method by collecting respondents opinion experience and attitude by taking primary data from questionnaires and secondary data from related institutions. The results of the research are 1 Factors directly affecting the Time Target Y1 are the Understanding of Contract Document X1 Material Requirements X3 Worker Requirements X4 and Equipment Completeness X5 while factors indirectly affecting the Time Target Y1 are the Understanding of Technical Specifications X2 and Local Government Regulations X7 2 Factors directly affecting the Quality Target Y2 are the Understanding of Contract Document X1 the Understanding of Technical Specifications X2 Material Requirements X3 Worker Requirements X4 Equipment Completeness X5 and Time Target Y1 while factor indirectly affecting the Quality Target Y1 is Local Government Regulations X7 3 The most dominant factor affecting the unsuccessful Time Target Y1 is the Worker Requirements X4 with the path coefficient value of 0.431. While the most dominant factor affecting the unsuccessful Quality Target Y2 is Worker Requirements X4 with path coefficient value of 0.579 4.

  15. Factor XI and XII as antithrombotic targets.

    Science.gov (United States)

    Müller, Felicitas; Gailani, David; Renné, Thomas

    2011-09-01

    Arterial and venous thrombosis are major causes of morbidity and mortality, and the incidence of thromboembolic diseases increases as a population ages. Thrombi are formed by activated platelets and fibrin. The latter is a product of the plasma coagulation system. Currently available anticoagulants such as heparins, vitamin K antagonists and inhibitors of thrombin or factor Xa target enzymes of the coagulation cascade that are critical for fibrin formation. However, fibrin is also necessary for terminating blood loss at sites of vascular injury. As a result, anticoagulants currently in clinical use increase the risk of bleeding, partially offsetting the benefits of reduced thrombosis. This review focuses on new targets for anticoagulation that are associated with minimal or no therapy-associated increased bleeding. Data from experimental models using mice and clinical studies of patients with hereditary deficiencies of coagulation factors XI or XII have shown that both of these clotting factors are important for thrombosis, while having minor or no apparent roles in processes that terminate blood loss (hemostasis). Hereditary deficiency of factor XII (Hageman factor) or factor XI, plasma proteases that initiate the intrinsic pathway of coagulation, impairs thrombus formation and provides protection from vascular occlusive events, while having a minimal impact on hemostasis. As the factor XII-factor XI pathway contributes to thrombus formation to a greater extent than to normal hemostasis, pharmacological inhibition of these coagulation factors may offer the exciting possibility of anticoagulation therapies with minimal or no bleeding risk.

  16. Analysis Of Performance Factors Of Construction Management Consultant Affecting The Failure In Achieving Time And Quality Targets On Construction Project Of Samarinda Baru Airport

    OpenAIRE

    Maryudi Utomo; Kustamar; Bambang Wedyantadji

    2017-01-01

    This research aims to determine the performance factors of construction management consultants affecting the failure in achieving time and quality targets on construction project of Samarinda Baru Airport. This research uses survey method by collecting respondents opinion experience and attitude by taking primary data from questionnaires and secondary data from related institutions. The results of the research are 1 Factors directly affecting the Time Target Y1 are the Understanding of Contra...

  17. Integration analysis of quantitative proteomics and transcriptomics data identifies potential targets of frizzled-8 protein-related antiproliferative factor in vivo.

    Science.gov (United States)

    Yang, Wei; Kim, Yongsoo; Kim, Taek-Kyun; Keay, Susan K; Kim, Kwang Pyo; Steen, Hanno; Freeman, Michael R; Hwang, Daehee; Kim, Jayoung

    2012-12-01

    What's known on the subject? and What does the study add? Interstitial cystitis (IC) is a prevalent and debilitating pelvic disorder generally accompanied by chronic pain combined with chronic urinating problems. Over one million Americans are affected, especially middle-aged women. However, its aetiology or mechanism remains unclear. No efficient drug has been provided to patients. Several urinary biomarker candidates have been identified for IC; among the most promising is antiproliferative factor (APF), whose biological activity is detectable in urine specimens from >94% of patients with both ulcerative and non-ulcerative IC. The present study identified several important mediators of the effect of APF on bladder cell physiology, suggesting several candidate drug targets against IC. In an attempt to identify potential proteins and genes regulated by APF in vivo, and to possibly expand the APF-regulated network identified by stable isotope labelling by amino acids in cell culture (SILAC), we performed an integration analysis of our own SILAC data and the microarray data of Gamper et al. (2009) BMC Genomics 10: 199. Notably, two of the proteins (i.e. MAPKSP1 and GSPT1) that are down-regulated by APF are involved in the activation of mTORC1, suggesting that the mammalian target of rapamycin (mTOR) pathway is potentially a critical pathway regulated by APF in vivo. Several components of the mTOR pathway are currently being studied as potential therapeutic targets in other diseases. Our analysis suggests that this pathway might also be relevant in the design of diagnostic tools and medications targeting IC. • To enhance our understanding of the interstitial cystitis urine biomarker antiproliferative factor (APF), as well as interstitial cystitis biology more generally at the systems level, we reanalyzed recently published large-scale quantitative proteomics and in vivo transcriptomics data sets using an integration analysis tool that we have developed. • To

  18. Foundations of factor analysis

    CERN Document Server

    Mulaik, Stanley A

    2009-01-01

    Introduction Factor Analysis and Structural Theories Brief History of Factor Analysis as a Linear Model Example of Factor AnalysisMathematical Foundations for Factor Analysis Introduction Scalar AlgebraVectorsMatrix AlgebraDeterminants Treatment of Variables as Vectors Maxima and Minima of FunctionsComposite Variables and Linear Transformations Introduction Composite Variables Unweighted Composite VariablesDifferentially Weighted Composites Matrix EquationsMulti

  19. Combined serial analysis of gene expression and transcription factor binding site prediction identifies novel-candidate-target genes of Nr2e1 in neocortex development.

    Science.gov (United States)

    Schmouth, Jean-François; Arenillas, David; Corso-Díaz, Ximena; Xie, Yuan-Yun; Bohacec, Slavita; Banks, Kathleen G; Bonaguro, Russell J; Wong, Siaw H; Jones, Steven J M; Marra, Marco A; Simpson, Elizabeth M; Wasserman, Wyeth W

    2015-07-24

    Nr2e1 (nuclear receptor subfamily 2, group e, member 1) encodes a transcription factor important in neocortex development. Previous work has shown that nuclear receptors can have hundreds of target genes, and bind more than 300 co-interacting proteins. However, recognition of the critical role of Nr2e1 in neural stem cells and neocortex development is relatively recent, thus the molecular mechanisms involved for this nuclear receptor are only beginning to be understood. Serial analysis of gene expression (SAGE), has given researchers both qualitative and quantitative information pertaining to biological processes. Thus, in this work, six LongSAGE mouse libraries were generated from laser microdissected tissue samples of dorsal VZ/SVZ (ventricular zone and subventricular zone) from the telencephalon of wild-type (Wt) and Nr2e1-null embryos at the critical development ages E13.5, E15.5, and E17.5. We then used a novel approach, implementing multiple computational methods followed by biological validation to further our understanding of Nr2e1 in neocortex development. In this work, we have generated a list of 1279 genes that are differentially expressed in response to altered Nr2e1 expression during in vivo neocortex development. We have refined this list to 64 candidate direct-targets of NR2E1. Our data suggested distinct roles for Nr2e1 during different neocortex developmental stages. Most importantly, our results suggest a possible novel pathway by which Nr2e1 regulates neurogenesis, which includes Lhx2 as one of the candidate direct-target genes, and SOX9 as a co-interactor. In conclusion, we have provided new candidate interacting partners and numerous well-developed testable hypotheses for understanding the pathways by which Nr2e1 functions to regulate neocortex development.

  20. Microarray-Based Identification of Transcription Factor Target Genes

    NARCIS (Netherlands)

    Gorte, M.; Horstman, A.; Page, R.B.; Heidstra, R.; Stromberg, A.; Boutilier, K.A.

    2011-01-01

    Microarray analysis is widely used to identify transcriptional changes associated with genetic perturbation or signaling events. Here we describe its application in the identification of plant transcription factor target genes with emphasis on the design of suitable DNA constructs for controlling TF

  1. Ubiquitome Analysis Reveals PCNA-Associated Factor 15 (PAF15) as a Specific Ubiquitination Target of UHRF1 in Embryonic Stem Cells.

    Science.gov (United States)

    Karg, Elisabeth; Smets, Martha; Ryan, Joel; Forné, Ignasi; Qin, Weihua; Mulholland, Christopher B; Kalideris, Georgia; Imhof, Axel; Bultmann, Sebastian; Leonhardt, Heinrich

    2017-12-08

    Ubiquitination is a multifunctional posttranslational modification controlling the activity, subcellular localization and stability of proteins. The E3 ubiquitin ligase ubiquitin-like PHD and RING finger domain-containing protein 1 (UHRF1) is an essential epigenetic factor that recognizes repressive histone marks as well as hemi-methylated DNA and recruits DNA methyltransferase 1. To explore enzymatic functions of UHRF1 beyond epigenetic regulation, we conducted a comprehensive screen in mouse embryonic stem cells to identify novel ubiquitination targets of UHRF1 and its paralogue UHRF2. We found differentially ubiquitinated peptides associated with a variety of biological processes such as transcriptional regulation and DNA damage response. Most prominently, we identified PCNA-associated factor 15 (PAF15; also known as Pclaf, Ns5atp9, KIAA0101 and OEATC-1) as a specific ubiquitination target of UHRF1. Although the function of PAF15 ubiquitination in translesion DNA synthesis is well characterized, the respective E3 ligase had been unknown. We could show that UHRF1 ubiquitinates PAF15 at Lys 15 and Lys 24 and promotes its binding to PCNA during late S-phase. In summary, we identified novel ubiquitination targets that link UHRF1 to transcriptional regulation and DNA damage response. Copyright © 2017. Published by Elsevier Ltd.

  2. Preparation, crystallization and preliminary X-ray diffraction analysis of the DNA-binding domain of the Ets transcription factor in complex with target DNA

    International Nuclear Information System (INIS)

    Suwa, Yoshiaki; Nakamura, Teruya; Toma, Sachiko; Ikemizu, Shinji; Kai, Hirofumi; Yamagata, Yuriko

    2008-01-01

    The complex between the Ets domain of Ets2 and its target DNA has been crystallized. The crystals diffracted to 3.0 Å resolution. The Ets2 transcription factor is a member of the Ets transcription-factor family. Ets2 plays a role in the malignancy of cancer and in Down’s syndrome by regulating the transcription of various genes. The DNA-binding domain of Ets2 (Ets domain; ETSD), which contains residues that are highly conserved among Ets transcription-factor family members, was expressed as a GST-fusion protein. The aggregation of ETSD produced after thrombin cleavage could be prevented by treatment with NDSB-195 (nondetergent sulfobetaine 195). ETSD was crystallized in complex with DNA containing the Ets2 target sequence (GGAA) by the hanging-drop vapour-diffusion method. The best crystals were grown using 25% PEG 3350, 80 mM magnesium acetate, 50 mM sodium cacodylate pH 5.0/5.5 as the reservoir at 293 K. The crystals belonged to space group C2, with unit-cell parameters a = 85.89, b = 95.52, c = 71.89 Å, β = 101.7° and a V M value of 3.56 Å 3 Da −1 . Diffraction data were collected to a resolution of 3.0 Å

  3. Preparation, crystallization and preliminary X-ray diffraction analysis of the DNA-binding domain of the Ets transcription factor in complex with target DNA

    Energy Technology Data Exchange (ETDEWEB)

    Suwa, Yoshiaki; Nakamura, Teruya; Toma, Sachiko; Ikemizu, Shinji; Kai, Hirofumi; Yamagata, Yuriko, E-mail: yamagata@gpo.kumamoto-u.ac.jp [Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973 (Japan)

    2008-03-01

    The complex between the Ets domain of Ets2 and its target DNA has been crystallized. The crystals diffracted to 3.0 Å resolution. The Ets2 transcription factor is a member of the Ets transcription-factor family. Ets2 plays a role in the malignancy of cancer and in Down’s syndrome by regulating the transcription of various genes. The DNA-binding domain of Ets2 (Ets domain; ETSD), which contains residues that are highly conserved among Ets transcription-factor family members, was expressed as a GST-fusion protein. The aggregation of ETSD produced after thrombin cleavage could be prevented by treatment with NDSB-195 (nondetergent sulfobetaine 195). ETSD was crystallized in complex with DNA containing the Ets2 target sequence (GGAA) by the hanging-drop vapour-diffusion method. The best crystals were grown using 25% PEG 3350, 80 mM magnesium acetate, 50 mM sodium cacodylate pH 5.0/5.5 as the reservoir at 293 K. The crystals belonged to space group C2, with unit-cell parameters a = 85.89, b = 95.52, c = 71.89 Å, β = 101.7° and a V{sub M} value of 3.56 Å{sup 3} Da{sup −1}. Diffraction data were collected to a resolution of 3.0 Å.

  4. Factor analysis and scintigraphy

    International Nuclear Information System (INIS)

    Di Paola, R.; Penel, C.; Bazin, J.P.; Berche, C.

    1976-01-01

    The goal of factor analysis is usually to achieve reduction of a large set of data, extracting essential features without previous hypothesis. Due to the development of computerized systems, the use of largest sampling, the possibility of sequential data acquisition and the increase of dynamic studies, the problem of data compression can be encountered now in routine. Thus, results obtained for compression of scintigraphic images were first presented. Then possibilities given by factor analysis for scan processing were discussed. At last, use of this analysis for multidimensional studies and specially dynamic studies were considered for compression and processing [fr

  5. Uncertainties in thick-target PIXE analysis

    International Nuclear Information System (INIS)

    Campbell, J.L.; Cookson, J.A.; Paul, H.

    1983-01-01

    Thick-target PIXE analysis insolves uncertainties arising from the calculation of thick-target X-ray production in addition to the usual PIXE uncertainties. The calculation demands knowledge of ionization cross-sections, stopping powers and photon attenuation coefficients. Information on these is reviewed critically and a computational method is used to estimate the uncertainties transmitted from this data base into results of thick-target PIXE analyses with reference to particular specimen types using beams of 2-3 MeV protons. A detailed assessment of the accuracy of thick-target PIXE is presented. (orig.)

  6. The role of bevacizumab in targeted vascular endothelial growth factor therapy for epithelial ovarian cancer: an updated systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Ruan GY

    2018-01-01

    Full Text Available Guanyu Ruan,1,* Lixiang Ye,2,* Guifen Liu,3 Jian An,3 Jalid Sehouli,4 Pengming Sun1,3 1Laboratory of Gynecologic Oncology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, 2Fujian Center for Safety Evaluation of New Drugs, Fujian Medical University, 3Department of Gynecology, Fujian Provincial Maternity and Children’s Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou, People’s Republic of China; 4Department of Gynecologic Oncology and Gynecology, Charité Campus Virchow-Klinikum, European Competence Center for Ovarian Cancer, University of Berlin, Berlin, Germany *These authors contributed equally to this work Abstract: The impact of bevacizumab (an anti-vascular endothelial growth factor therapy remains uncertain, which has been the focus of studies on the management of epithelial ovarian cancer (EOC. To investigate the efficacy of bevacizumab combinations with different regimens in the treatment of patients with EOC, a meta-analysis of Phase III randomized controlled trials was conducted. The databases searched included PubMed, Embase, ClinicalTrials.gov, Chinese Knowledge Infrastructure, as well as the Cochrane Central Register of Controlled Trials. After evaluation of quality, a meta-analysis of valid extracted data was performed using Review Manager (RevMan software. Five studies with 4,369 patients were included. Bevacizumab plus chemotherapy improved progression-free survival (hazard ratio [HR] =0.63; 95% confidence interval [CI], 0.51–0.77; P<0.01 and overall survival (HR =0.91; 95% CI, 0.84–0.99; P<0.05. Interestingly, in patients with a high risk of progression, the subgroups that received bevacizumab combined with different regimens of chemotherapy showed a significant improvement with paclitaxel plus carboplatin-based chemotherapy (HR =0.86; 95% CI, 0.77–0.95; P<0.01, but not with non-paclitaxel plus carboplatin-based chemotherapy (HR =0.91; 95% CI, 0

  7. "Factor Analysis Using ""R"""

    Directory of Open Access Journals (Sweden)

    A. Alexander Beaujean

    2013-02-01

    Full Text Available R (R Development Core Team, 2011 is a very powerful tool to analyze data, that is gaining in popularity due to its costs (its free and flexibility (its open-source. This article gives a general introduction to using R (i.e., loading the program, using functions, importing data. Then, using data from Canivez, Konold, Collins, and Wilson (2009, this article walks the user through how to use the program to conduct factor analysis, from both an exploratory and confirmatory approach.

  8. Optimisation of high-performance liquid chromatography with diode array detection using an automatic peak tracking procedure based on augmented iterative target transformation factor analysis

    NARCIS (Netherlands)

    van Zomeren, Paul; Hoogvorst, A.; Coenegracht, P.M J; de Jong, G.J.

    2004-01-01

    An automated method for the optimisation of high-performance liquid chromatography is developed. First of all, the sample of interest is analysed with various eluent compositions. All obtained data are combined into one augmented data matrix. Subsequently, augmented iterative target transformation

  9. Preliminary analysis of a target factory for laser fusion

    International Nuclear Information System (INIS)

    Sherohman, J.W.; Hendricks, C.D.

    1980-01-01

    An analysis of a target factory leading to the determination of production expressions has provided for the basis of a parametric study. Parameters involving the input and output rate of a process system, processing yield factors, and multiple processing steps and production lines have been used to develop an understanding of their dependence on the rate of target injection for laser fusion. Preliminary results have indicated that a parametric study of this type will be important in the selection of processing methods to be used in the final production scheme of a target factory

  10. An evaluation of energy-environment-economic efficiency for EU, APEC and ASEAN countries: Design of a Target-Oriented DFM model with fixed factors in Data Envelopment Analysis

    International Nuclear Information System (INIS)

    Suzuki, Soushi; Nijkamp, Peter

    2016-01-01

    This paper aims to offer an advanced assessment methodology for sustainable national energy-environment-economic efficiency strategies, based on an extended Data Envelopment Analysis (DEA). The use of novel efficiency-improving approaches based on DEA originates from the so-called Distance Friction Minimisation (DFM) method. To design a feasible improvement strategy for low-efficiency DMUs, we develop here a Target-Oriented (TO) DFM model. However, in many real-world cases input factors may not be flexibly adjusted in the short run. In this study, we integrate the TO-DFM model with a fixed (inflexible) factor (FF) approach to cope with such more realistic circumstances. Super-efficiency DEA is next used in our comparative study on the efficiency assessment of energy-environment-economic targets for the EU, APEC and ASEAN (A&A) countries, employing appropriate data sets from the years 2003 to 2012. We consider two inputs (primary energy consumption and population) and two outputs (CO 2 and GDP), including a fixed input factor (viz. population). On the basis of our DEA analysis results, EU countries appear to exhibit generally a higher efficiency than A&A countries. The above-mentioned TO-DFM-FF projection model is able to address realistic circumstances and requirements in an operational sustainability strategy for efficiency improvement in inefficient countries in the A&A region. - Highlights: • We examine energy-environment-economic efficiency in European and A&A countries. • We present an operational efficiency improvement strategy using DEA. • European countries tend to have higher energy efficiency than A&A countries. • The study provides efficiency-enhancing strategic paths for inefficient countries.

  11. CFD analysis of the HYPER spallation target

    International Nuclear Information System (INIS)

    Cho, Chungho; Tak, Nam-il; Choi, Jae-Hyuk; Lee, Yong-Bum

    2008-01-01

    KAERI (Korea Atomic Energy Research Institute) is developing an accelerator driven system (ADS) named HYPER (HYbrid Power Extraction Reactor) for a transmutation of long-lived nuclear wastes. One of the challenging tasks for the HYPER system is to design a large spallation target with a beam power of 15-25 MW. The paper focuses on a thermal-hydraulic analysis of the active part of the HYPER target. Computational fluid dynamics (CFD) analysis was performed by using a commercial code CFX 5.7.1. Several advanced turbulence models with different grid structures were applied. The CFX results reveal a significant impact of the turbulence model on the window temperature. Particularly, the k-ε model predicts the lowest window temperature among the five investigated turbulence models

  12. Uncertainty Prediction in Passive Target Motion Analysis

    Science.gov (United States)

    2016-05-12

    Number 15/152,696 Filing Date 12 May 2016 Inventor John G. Baylog et al Address any questions concerning this matter to the Office of...300118 1 of 25 UNCERTAINTY PREDICTION IN PASSIVE TARGET MOTION ANALYSIS STATEMENT OF GOVERNMENT INTEREST [0001] The invention described herein...at an unknown location and following an unknown course relative to an observer 12. Observer 12 has a sensor array such as a passive sonar or radar

  13. Factors affecting construction performance: exploratory factor analysis

    Science.gov (United States)

    Soewin, E.; Chinda, T.

    2018-04-01

    The present work attempts to develop a multidimensional performance evaluation framework for a construction company by considering all relevant measures of performance. Based on the previous studies, this study hypothesizes nine key factors, with a total of 57 associated items. The hypothesized factors, with their associated items, are then used to develop questionnaire survey to gather data. The exploratory factor analysis (EFA) was applied to the collected data which gave rise 10 factors with 57 items affecting construction performance. The findings further reveal that the items constituting ten key performance factors (KPIs) namely; 1) Time, 2) Cost, 3) Quality, 4) Safety & Health, 5) Internal Stakeholder, 6) External Stakeholder, 7) Client Satisfaction, 8) Financial Performance, 9) Environment, and 10) Information, Technology & Innovation. The analysis helps to develop multi-dimensional performance evaluation framework for an effective measurement of the construction performance. The 10 key performance factors can be broadly categorized into economic aspect, social aspect, environmental aspect, and technology aspects. It is important to understand a multi-dimension performance evaluation framework by including all key factors affecting the construction performance of a company, so that the management level can effectively plan to implement an effective performance development plan to match with the mission and vision of the company.

  14. Signatures of DNA target selectivity by ETS transcription factors.

    Science.gov (United States)

    Poon, Gregory M K; Kim, Hye Mi

    2017-05-27

    The ETS family of transcription factors is a functionally heterogeneous group of gene regulators that share a structurally conserved, eponymous DNA-binding domain. DNA target specificity derives from combinatorial interactions with other proteins as well as intrinsic heterogeneity among ETS domains. Emerging evidence suggests molecular hydration as a fundamental feature that defines the intrinsic heterogeneity in DNA target selection and susceptibility to epigenetic DNA modification. This perspective invokes novel hypotheses in the regulation of ETS proteins in physiologic osmotic stress, their pioneering potential in heterochromatin, and the effects of passive and pharmacologic DNA demethylation on ETS regulation.

  15. Drug-Target Interaction Prediction with Graph Regularized Matrix Factorization.

    Science.gov (United States)

    Ezzat, Ali; Zhao, Peilin; Wu, Min; Li, Xiao-Li; Kwoh, Chee-Keong

    2017-01-01

    Experimental determination of drug-target interactions is expensive and time-consuming. Therefore, there is a continuous demand for more accurate predictions of interactions using computational techniques. Algorithms have been devised to infer novel interactions on a global scale where the input to these algorithms is a drug-target network (i.e., a bipartite graph where edges connect pairs of drugs and targets that are known to interact). However, these algorithms had difficulty predicting interactions involving new drugs or targets for which there are no known interactions (i.e., "orphan" nodes in the network). Since data usually lie on or near to low-dimensional non-linear manifolds, we propose two matrix factorization methods that use graph regularization in order to learn such manifolds. In addition, considering that many of the non-occurring edges in the network are actually unknown or missing cases, we developed a preprocessing step to enhance predictions in the "new drug" and "new target" cases by adding edges with intermediate interaction likelihood scores. In our cross validation experiments, our methods achieved better results than three other state-of-the-art methods in most cases. Finally, we simulated some "new drug" and "new target" cases and found that GRMF predicted the left-out interactions reasonably well.

  16. Molecular Composition Analysis of Distant Targets

    Science.gov (United States)

    Hughes, Gary B.; Lubin, Philip

    2017-01-01

    This document is the Final Report for NASA Innovative Advanced Concepts (NIAC) Phase I Grant 15-NIAC16A-0145, titled Molecular Composition Analysis of Distant Targets. The research was focused on developing a system concept for probing the molecular composition of cold solar system targets, such as Asteroids, Comets, Planets and Moons from a distant vantage, for example from a spacecraft that is orbiting the target (Hughes et al., 2015). The orbiting spacecraft is equipped with a high-power laser, which is run by electricity from photovoltaic panels. The laser is directed at a spot on the target. Materials on the surface of the target are heated by the laser beam, and begin to melt and then evaporate, forming a plume of asteroid molecules in front of the heated spot. The heated spot glows, producing blackbody illumination that is visible from the spacecraft, via a path through the evaporated plume. As the blackbody radiation from the heated spot passes through the plume of evaporated material, molecules in the plume absorb radiation in a manner that is specific to the rotational and vibrational characteristics of the specific molecules. A spectrometer aboard the spacecraft is used to observe absorption lines in the blackbody signal. The pattern of absorption can be used to estimate the molecular composition of materials in the plume, which originated on the target. Focusing on a single spot produces a borehole, and shallow subsurface profiling of the targets bulk composition is possible. At the beginning of the Phase I research, the estimated Technology Readiness Level (TRL) of the system was TRL-1. During the Phase I research, an end-to-end theoretical model of the sensor system was developed from first principles. The model includes laser energy and optical propagation, target heating, melting and evaporation of target material, plume density, thermal radiation from the heated spot, molecular cross section of likely asteroid materials, and estimation of the

  17. Factors leading to inflation targeting : The impact of adoption

    NARCIS (Netherlands)

    Samarina, Anna; Sturm, Jan-Egbert

    2013-01-01

    This paper examines how the analysis of inflation targeting (IT) adoption is affected by allowing for a structural change after adoption, using panel probit models for 60 countries over the period 1985-2008. Our findings suggest that there is a structural change after IT adoption. Including the

  18. Factors leading to inflation targeting - the impact of adoption

    NARCIS (Netherlands)

    Samarina, Anna; Sturm, Jan-Egbert

    2013-01-01

    This paper examines how the analysis of inflation targeting (IT) adoption is affected by the choice of the analyzed period. We test whether country characteristics influence the decision to apply IT differently before and after its adoption, using panel probit models for 60 countries over the period

  19. Analysis of directly driven ICF targets

    International Nuclear Information System (INIS)

    Velarde, G.; Aragones, J.M.; Gago, J.A.

    1986-01-01

    The current capabilities at DENIM for the analysis of directly driven targets are presented. These include theoretical, computational and applied physical studies and developments of detailed simulation models for the most relevant processes in ICF. The simulation of directly driven ICF targets is carried out with the one-dimensional NORCLA code developed at DENIM. This code contains two main segments: NORMA and CLARA, able to work fully coupled and in an iterative manner. NORMA solves the hydrodynamic equations in a lagrangian mesh. It has modular programs couple to it to treat the laser or particle beam interaction with matter. Equations of state, opacities and conductivities are taken from a DENIM atomic data library, generated externally with other codes that will also be explained in this work. CLARA solves the transport equation for neutrons, as well as for charged particles, and suprathermal electrons using discrete ordinates and finite element methods in the computational procedure. Parametric calculations of multilayered single-shell targets driven by heavy ion beams are also analyzed. Finally, conclusions are focused on the ongoing developments in the areas of interest such as: radiation transport, atomic physics, particle in cell method, charged particle transport, two-dimensional calculations and instabilities. (author)

  20. Failure probability analysis on mercury target vessel

    International Nuclear Information System (INIS)

    Ishikura, Syuichi; Futakawa, Masatoshi; Kogawa, Hiroyuki; Sato, Hiroshi; Haga, Katsuhiro; Ikeda, Yujiro

    2005-03-01

    Failure probability analysis was carried out to estimate the lifetime of the mercury target which will be installed into the JSNS (Japan spallation neutron source) in J-PARC (Japan Proton Accelerator Research Complex). The lifetime was estimated as taking loading condition and materials degradation into account. Considered loads imposed on the target vessel were the static stresses due to thermal expansion and static pre-pressure on He-gas and mercury and the dynamic stresses due to the thermally shocked pressure waves generated repeatedly at 25 Hz. Materials used in target vessel will be degraded by the fatigue, neutron and proton irradiation, mercury immersion and pitting damages, etc. The imposed stresses were evaluated through static and dynamic structural analyses. The material-degradations were deduced based on published experimental data. As a result, it was quantitatively confirmed that the failure probability for the lifetime expected in the design is very much lower, 10 -11 in the safety hull, meaning that it will be hardly failed during the design lifetime. On the other hand, the beam window of mercury vessel suffered with high-pressure waves exhibits the failure probability of 12%. It was concluded, therefore, that the leaked mercury from the failed area at the beam window is adequately kept in the space between the safety hull and the mercury vessel by using mercury-leakage sensors. (author)

  1. Human cellular restriction factors that target HIV-1 replication

    Directory of Open Access Journals (Sweden)

    Jeang Kuan-Teh

    2009-09-01

    Full Text Available Abstract Recent findings have highlighted roles played by innate cellular factors in restricting intracellular viral replication. In this review, we discuss in brief the activities of apolipoprotein B mRNA-editing enzyme 3G (APOBEC3G, bone marrow stromal cell antigen 2 (BST-2, cyclophilin A, tripartite motif protein 5 alpha (Trim5α, and cellular microRNAs as examples of host restriction factors that target HIV-1. We point to countermeasures encoded by HIV-1 for moderating the potency of these cellular restriction functions.

  2. Nuclear Security: Target Analysis-rev

    Energy Technology Data Exchange (ETDEWEB)

    Singh, Surinder Paul [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Gibbs, Philip W. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Bultz, Garl A. [Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

    2014-03-01

    The objectives of this presentation are to understand target identification, including roll-up and protracted theft; evaluate target identification in the SNRI; recognize the target characteristics and consequence levels; and understand graded safeguards.

  3. Hand function evaluation: a factor analysis study.

    Science.gov (United States)

    Jarus, T; Poremba, R

    1993-05-01

    The purpose of this study was to investigate hand function evaluations. Factor analysis with varimax rotation was used to assess the fundamental characteristics of the items included in the Jebsen Hand Function Test and the Smith Hand Function Evaluation. The study sample consisted of 144 subjects without disabilities and 22 subjects with Colles fracture. Results suggest a four factor solution: Factor I--pinch movement; Factor II--grasp; Factor III--target accuracy; and Factor IV--activities of daily living. These categories differentiated the subjects without Colles fracture from the subjects with Colles fracture. A hand function evaluation consisting of these four factors would be useful. Such an evaluation that can be used for current clinical purposes is provided.

  4. Factor analysis of multivariate data

    Digital Repository Service at National Institute of Oceanography (India)

    Fernandes, A.A.; Mahadevan, R.

    A brief introduction to factor analysis is presented. A FORTRAN program, which can perform the Q-mode and R-mode factor analysis and the singular value decomposition of a given data matrix is presented in Appendix B. This computer program, uses...

  5. Error Analysis of Fast Moving Target Geo-location in Wide Area Surveillance Ground Moving Target Indication Mode

    Directory of Open Access Journals (Sweden)

    Zheng Shi-chao

    2013-12-01

    Full Text Available As an important mode in airborne radar systems, Wide Area Surveillance Ground Moving Target Indication (WAS-GMTI mode has the ability of monitoring a large area in a short time, and then the detected moving targets can be located quickly. However, in real environment, many factors introduce considerable errors into the location of moving targets. In this paper, a fast location method based on the characteristics of the moving targets in WAS-GMTI mode is utilized. And in order to improve the location performance, those factors that introduce location errors are analyzed and moving targets are relocated. Finally, the analysis of those factors is proved to be reasonable by simulation and real data experiments.

  6. Targeting Interferon Regulatory Factor for Cardiometabolic Diseases: Opportunities and Challenges.

    Science.gov (United States)

    Zhang, Yaxing; Zhang, Xiao-Jing; Li, Hongliang

    2017-01-01

    The pathological activation of innate immune system may contribute to the development of cardiometabolic diseases. The interferon regulatory factor (IRF) family members, which are the major transcription factors in innate immune signaling, are implicated in cardiometabolic diseases. The aim of this review is to summary the current knowledge of the biological functions of IRFs in innate immune responses and immune cell development, and highlight our contemporary understanding of the functions and molecular mechanisms of IRFs in metabolic diseases, cardiovascular remodeling, and stroke. IRFs are the essential regulators of cardiometabolic diseases via immune-dependent and - independent manners. IRFs signaling is the promising target to manage the initiation and progression of cardiometabolic disorders. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  7. Shock ignition targets: gain and robustness vs ignition threshold factor

    Science.gov (United States)

    Atzeni, Stefano; Antonelli, Luca; Schiavi, Angelo; Picone, Silvia; Volponi, Gian Marco; Marocchino, Alberto

    2017-10-01

    Shock ignition is a laser direct-drive inertial confinement fusion scheme, in which the stages of compression and hot spot formation are partly separated. The hot spot is created at the end of the implosion by a converging shock driven by a final ``spike'' of the laser pulse. Several shock-ignition target concepts have been proposed and relevant gain curves computed (see, e.g.). Here, we consider both pure-DT targets and more facility-relevant targets with plastic ablator. The investigation is conducted with 1D and 2D hydrodynamic simulations. We determine ignition threshold factors ITF's (and their dependence on laser pulse parameters) by means of 1D simulations. 2D simulations indicate that robustness to long-scale perturbations increases with ITF. Gain curves (gain vs laser energy), for different ITF's, are generated using 1D simulations. Work partially supported by Sapienza Project C26A15YTMA, Sapienza 2016 (n. 257584), Eurofusion Project AWP17-ENR-IFE-CEA-01.

  8. Targeting cancer stem cells: emerging role of Nanog transcription factor

    Directory of Open Access Journals (Sweden)

    Wang ML

    2013-09-01

    Full Text Available Mong-Lien Wang,1 Shih-Hwa Chiou,2,3 Cheng-Wen Wu1,4–61Institute of Biochemistry and Molecular Biology, 2Institute of Pharmacology, National Yang Ming University, Taipei, Taiwan; 3Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan; 4Institute of Microbiology and Immunology, 5Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan; 6Institute of Biomedical Science, Academia Sinica, Taipei, TaiwanAbstract: The involvement of stemness factors in cancer initiation and progression has drawn much attention recently, especially after the finding that introducing four stemness factors in somatic cells is able to reprogram the cells back to an embryonic stem cell-like state. Following accumulating data revealing abnormal elevated expression levels of key stemness factors, like Nanog, Oct4, and Sox2, in several types of cancer stem cells; the importance and therapeutic potential of targeting these stemness regulators in cancers has turned to research focus. Nanog determines cell fate in both embryonic and cancer stem cells; activating Nanog at an inappropriate time would result in cancer stem cells rather than normal pluripotent stem cells or differentiated somatic cells. Upregulated Nanog is correlated with poor survival outcome of patients with various types of cancer. The discoveries of downstream regulatory pathways directly or indirectly mediated by Nanog indicate that Nanog regulates several aspects of cancer development such as tumor cell proliferation, self-renewal, motility, epithelial-mesenchymal transition, immune evasion, and drug-resistance, which are all defined features for cancer stem cells. The current review paper illustrates the central role of Nanog in the regulatory networks of cancer malignant development and stemness acquirement, as well as in the communication between cancer cells and the surrounding stroma. Though a more defined model is needed to test the

  9. Targeting HOX and PBX transcription factors in ovarian cancer

    International Nuclear Information System (INIS)

    Morgan, Richard; Plowright, Lynn; Harrington, Kevin J; Michael, Agnieszka; Pandha, Hardev S

    2010-01-01

    Ovarian cancer still has a relatively poor prognosis due to the frequent occurrence of drug resistance, making the identification of new therapeutic targets an important goal. We have studied the role of HOX genes in the survival and proliferation of ovarian cancer cells. These are a family of homeodomain-containing transcription factors that determine cell and tissue identity in the early embryo, and have an anti-apoptotic role in a number of malignancies including lung and renal cancer. We used QPCR to determine HOX gene expression in normal ovary and in the ovarian cancer cell lines SK-OV3 and OV-90. We used a short peptide, HXR9, to disrupt the formation of HOX/PBX dimers and alter transcriptional regulation by HOX proteins. In this study we show that the ovarian cancer derived line SK-OV3, but not OV-90, exhibits highly dysregulated expression of members of the HOX gene family. Disrupting the interaction between HOX proteins and their co-factor PBX induces apoptosis in SK-OV3 cells and retards tumour growth in vivo. HOX/PBX binding is a potential target in ovarian cancer

  10. First course in factor analysis

    CERN Document Server

    Comrey, Andrew L

    2013-01-01

    The goal of this book is to foster a basic understanding of factor analytic techniques so that readers can use them in their own research and critically evaluate their use by other researchers. Both the underlying theory and correct application are emphasized. The theory is presented through the mathematical basis of the most common factor analytic models and several methods used in factor analysis. On the application side, considerable attention is given to the extraction problem, the rotation problem, and the interpretation of factor analytic results. Hence, readers are given a background of

  11. Lithuanian Population Aging Factors Analysis

    Directory of Open Access Journals (Sweden)

    Agnė Garlauskaitė

    2015-05-01

    Full Text Available The aim of this article is to identify the factors that determine aging of Lithuania’s population and to assess the influence of these factors. The article shows Lithuanian population aging factors analysis, which consists of two main parts: the first describes the aging of the population and its characteristics in theoretical terms. Second part is dedicated to the assessment of trends that influence the aging population and demographic factors and also to analyse the determinants of the aging of the population of Lithuania. After analysis it is concluded in the article that the decline in the birth rate and increase in the number of emigrants compared to immigrants have the greatest impact on aging of the population, so in order to show the aging of the population, a lot of attention should be paid to management of these demographic processes.

  12. Neutron performance analysis for ESS target proposal

    International Nuclear Information System (INIS)

    Magán, M.; Terrón, S.; Thomsen, K.; Sordo, F.; Perlado, J.M.; Bermejo, F.J.

    2012-01-01

    In the course of discussing different target types for their suitability in the European Spallation Source (ESS) one main focus was on neutronics' performance. Diverse concepts have been assessed baselining some preliminary engineering and geometrical details and including some optimization. With the restrictions and resulting uncertainty imposed by the lack of detailed designs optimizations at the time of compiling this paper, the conclusion drawn is basically that there is a little difference in the neutronic yield of the investigated targets. Other criteria like safety, environmental compatibility, reliability and cost will thus dominate the choice of an ESS target.

  13. Molecular Composition Analysis of Distant Targets

    Data.gov (United States)

    National Aeronautics and Space Administration — We propose a system capable of probing the molecular composition of cold solar system targets such as asteroids, comets, planets and moons from a distant vantage....

  14. Factor Analysis for Clustered Observations.

    Science.gov (United States)

    Longford, N. T.; Muthen, B. O.

    1992-01-01

    A two-level model for factor analysis is defined, and formulas for a scoring algorithm for this model are derived. A simple noniterative method based on decomposition of total sums of the squares and cross-products is discussed and illustrated with simulated data and data from the Second International Mathematics Study. (SLD)

  15. Transforming Rubrics Using Factor Analysis

    Science.gov (United States)

    Baryla, Ed; Shelley, Gary; Trainor, William

    2012-01-01

    Student learning and program effectiveness is often assessed using rubrics. While much time and effort may go into their creation, it is equally important to assess how effective and efficient the rubrics actually are in terms of measuring competencies over a number of criteria. This study demonstrates the use of common factor analysis to identify…

  16. Analysis of mineral phases in coal utilizing factor analysis

    International Nuclear Information System (INIS)

    Roscoe, B.A.; Hopke, P.K.

    1982-01-01

    The mineral phase inclusions of coal are discussed. The contribution of these to a coal sample are determined utilizing several techniques. Neutron activation analysis in conjunction with coal washability studies have produced some information on the general trends of elemental variation in the mineral phases. These results have been enhanced by the use of various statistical techniques. The target transformation factor analysis is specifically discussed and shown to be able to produce elemental profiles of the mineral phases in coal. A data set consisting of physically fractionated coal samples was generated. These samples were analyzed by neutron activation analysis and then their elemental concentrations examined using TTFA. Information concerning the mineral phases in coal can thus be acquired from factor analysis even with limited data. Additional data may permit the resolution of additional mineral phases as well as refinement of theose already identified

  17. Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression.

    Science.gov (United States)

    Feng, Shu; Shao, Longjiang; Yu, Wendong; Gavine, Paul; Ittmann, Michael

    2012-07-15

    Extensive correlative studies in human prostate cancer as well as studies in vitro and in mouse models indicate that fibroblast growth factor receptor (FGFR) signaling plays an important role in prostate cancer progression. In this study, we used a probe compound for an FGFR inhibitor, which potently inhibits FGFR-1-3 and significantly inhibits FGFR-4. The purpose of this study is to determine whether targeting FGFR signaling from all four FGFRs will have in vitro activities consistent with inhibition of tumor progression and will inhibit tumor progression in vivo. Effects of AZ8010 on FGFR signaling and invasion were analyzed using immortalized normal prostate epithelial (PNT1a) cells and PNT1a overexpressing FGFR-1 or FGFR-4. The effect of AZ8010 on invasion and proliferation in vitro was also evaluated in prostate cancer cell lines. Finally, the impact of AZ8010 on tumor progression in vivo was evaluated using a VCaP xenograft model. AZ8010 completely inhibits FGFR-1 and significantly inhibits FGFR-4 signaling at 100 nmol/L, which is an achievable in vivo concentration. This results in marked inhibition of extracellular signal-regulated kinase (ERK) phosphorylation and invasion in PNT1a cells expressing FGFR-1 and FGFR-4 and all prostate cancer cell lines tested. Treatment in vivo completely inhibited VCaP tumor growth and significantly inhibited angiogenesis and proliferation and increased cell death in treated tumors. This was associated with marked inhibition of ERK phosphorylation in treated tumors. Targeting FGFR signaling is a promising new approach to treating aggressive prostate cancer.

  18. Epidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: An Evidence-Based Analysis.

    Science.gov (United States)

    2010-01-01

    In February 2010, the Medical Advisory Secretariat (MAS) began work on evidence-based reviews of the literature surrounding three pharmacogenomic tests. This project came about when Cancer Care Ontario (CCO) asked MAS to provide evidence-based analyses on the effectiveness and cost-effectiveness of three oncology pharmacogenomic tests currently in use in Ontario.Evidence-based analyses have been prepared for each of these technologies. These have been completed in conjunction with internal and external stakeholders, including a Provincial Expert Panel on Pharmacogenetics (PEPP). Within the PEPP, subgroup committees were developed for each disease area. For each technology, an economic analysis was also completed by the Toronto Health Economics and Technology Assessment Collaborative (THETA) and is summarized within the reports.THE FOLLOWING REPORTS CAN BE PUBLICLY ACCESSED AT THE MAS WEBSITE AT: http://www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlGENE EXPRESSION PROFILING FOR GUIDING ADJUVANT CHEMOTHERAPY DECISIONS IN WOMEN WITH EARLY BREAST CANCER: An Evidence-Based AnalysisEpidermal Growth Factor Receptor Mutation (EGFR) Testing for Prediction of Response to EGFR-Targeting Tyrosine Kinase Inhibitor (TKI) Drugs in Patients with Advanced Non-Small-Cell Lung Cancer: an Evidence-Based AnalysisK-RAS testing in Treatment Decisions for Advanced Colorectal Cancer: an Evidence-Based Analysis The Medical Advisory Secretariat undertook a systematic review of the evidence on the clinical effectiveness and cost-effectiveness of epidermal growth factor receptor (EGFR) mutation testing compared with no EGFR mutation testing to predict response to tyrosine kinase inhibitors (TKIs), gefitinib (Iressa(®)) or erlotinib (Tarceva(®)) in patients with advanced non-small cell lung cancer (NSCLC). TARGET POPULATION AND CONDITION With an estimated 7,800 new cases and 7,000 deaths last year, lung cancer is the leading cause of cancer

  19. Targeting TBP-associated factors in ovarian cancer

    Directory of Open Access Journals (Sweden)

    Jennifer R Ribeiro

    2014-03-01

    Full Text Available As ovarian tumors progress, they undergo a process of dedifferentiation, allowing adaptive changes in growth and morphology that promote metastasis and chemoresistance. Herein, we outline a hypothesis that TATA-box binding protein (TBP associated factors (TAFs, which compose the RNA Polymerase II initiation factor, TFIID, contribute to regulation of dedifferentiation states in ovarian cancer. Numerous studies demonstrate that TAFs regulate differentiation and proliferation states; their expression is typically high in pluripotent cells and reduced upon differentiation. Strikingly, TAF2 exhibits copy number increases or mRNA overexpression in 73% of high grade serous ovarian cancers (HGSC. At the biochemical level, TAF2 directs TFIID to TATA-less promoters by contact with an Initiator element, which may lead to the deregulation of the transcriptional output of these tumor cells. TAF4, which is altered in 66% of HGSC, is crucial for the stability of the TFIID complex and helps drive dedifferentiation of mouse embryonic fibroblasts to induced pluripotent stem cells. Its ovary-enriched paralog, TAF4B, is altered in 26% of HGSC. Here, we show that Taf4b mRNA correlates with Cyclin D2 mRNA expression in human granulosa cell tumors. TAF4B may also contribute to regulation of tumor microenvironment due to its estrogen-responsiveness and ability to act as a cofactor for NFκB. Conversely, TAF9, a cofactor for p53 in regulating apoptosis, may act as a tumor suppressor in ovarian cancer, since it is downregulated or deleted in 98% of HGSC. We conclude that a greater understanding of mechanisms of transcriptional regulation that execute signals from oncogenic signaling cascades is needed in order to expand our understanding of the etiology and progression of ovarian cancer, and most importantly to identify novel targets for therapeutic intervention.

  20. Identification of target genes of transcription factor activator protein 2 gamma in breast cancer cells

    International Nuclear Information System (INIS)

    Ailan, He; Shuanglin, Xiang; Xiangwen, Xiao; Daolong, Ren; Lu, Gan; Xiaofeng, Ding; Xi, Qiao; Xingwang, Hu; Rushi, Liu; Jian, Zhang

    2009-01-01

    Activator protein 2 gamma (AP-2γ) is a member of the transcription factor activator protein-2 (AP-2) family, which is developmentally regulated and plays a role in human neoplasia. AP-2γ has been found to be overexpressed in most breast cancers, and have a dual role to inhibit tumor initiation and promote tumor progression afterwards during mammary tumorigensis. To identify the gene targets that mediate its effects, we performed chromatin immunoprecipitation (ChIP) to isolate AP-2γ binding sites on genomic DNA from human breast cancer cell line MDA-MB-453. 20 novel DNA fragments proximal to potential AP-2γ targets were obtained. They are categorized into functional groups of carcinogenesis, metabolism and others. A combination of sequence analysis, reporter gene assays, quantitative real-time PCR, electrophoretic gel mobility shift assays and immunoblot analysis further confirmed the four AP-2γ target genes in carcinogenesis group: ErbB2, CDH2, HPSE and IGSF11. Our results were consistent with the previous reports that ErbB2 was the target gene of AP-2γ. Decreased expression and overexpression of AP-2γ in human breast cancer cells significantly altered the expression of these four genes, indicating that AP-2γ directly regulates them. This suggested that AP-2γ can coordinate the expression of a network of genes, involving in carcinogenesis, especially in breast cancer. They could serve as therapeutic targets against breast cancers in the future

  1. Monetary targeting and financial system characteristics : An empirical analysis

    NARCIS (Netherlands)

    Samarina, A..

    2012-01-01

    This paper investigates how reforms and characteristics of the financial system affect the likelihood of countries to abandon their strategy of monetary targeting. Apart from financial system characteristics, we include macroeconomic, fiscal, and institutional factors potentially associated with

  2. Transmutation technology development; thermal hydraulic power analysis and structure analysis of the HYPER target beam window

    Energy Technology Data Exchange (ETDEWEB)

    Choi, J. H.; Ju, E. S.; Song, M. K.; Jeon, Y. Z. [Gyeongsang National University, Jinju (Korea)

    2002-03-01

    A thermal hydraulic power analysis, a structure analysis and optimization computation for some design factor for the design of spallation target suitable for HYPER with 1000 MW thermal power in this study was performed. Heat generation formula was used which was evaluated recently based on the LAHET code, mainly to find the maximum beam current under given computation conditions. Thermal hydraulic power of HYPER target system was calculated using FLUENT code, structure conducted by inputting the data into ANSYS. On the temp of beam windows and the pressure distribution calculated using FLUENT. Data transformation program was composed apply the data calculated using FLUENT being commercial CFD code and ANSYS being FEM code for CFX structure analysis. A basic study was conducted on various singular target to obtain fundamental data on the shape for optimum target design. A thermal hydraulic power analysis and structure analysis were conducted on the shapes of parabolic, uniform, scanning beams to choose the optimum shape of beam current analysis was done according to some turbulent model to simulate the real flow. To evaluate the reliability of numerical analysis result, benchmarking of FLUENT code reformed at SNU and Korea Advanced Institute of Science and Technology and it was compared to CFX in the possession of Korea Atomic Energy Research Institute and evaluated. Reliable deviation was observed in the results calculated using FLUENT code, but temperature deviation of about 200 .deg. C was observed in the result from CFX analysis at optimum design condition. Several benchmarking were performed on the basis of numerical analysis concerning conventional HYPER. It was possible to allow a beam arrests of 17.3 mA in the case of the {phi} 350 mm parabolic beam suggested to the optimum in nuclear transmutation when stress equivalent to VON-MISES was calculated to be 140 MPa. 29 refs., 109 figs. (Author)

  3. Transcription Factors in Heart: Promising Therapeutic Targets in Cardiac Hypertrophy

    OpenAIRE

    Kohli, Shrey; Ahuja, Suchit; Rani, Vibha

    2011-01-01

    Regulation of gene expression is central to cell growth, differentiation and diseases. Context specific and signal dependent regulation of gene expression is achieved to a large part by transcription factors. Cardiac transcription factors regulate heart development and are also involved in stress regulation of the adult heart, which may lead to cardiac hypertrophy. Hypertrophy of cardiac myocytes is an outcome of the imbalance between prohypertrophic factors and anti-hypertrophic factors. Thi...

  4. Targeting the epidermal growth factor receptor in solid tumor malignancies

    DEFF Research Database (Denmark)

    Nedergaard, Mette K; Hedegaard, Chris J; Poulsen, Hans S

    2012-01-01

    been proposed as valid targets in many cancer therapy settings. Different strategies have been developed in order to either inhibit EGFR/EGFRvIII activity or to ablate EGFR/EGFRvIII-positive tumor cells. Drugs that inhibit these receptors include monoclonal antibodies (mAbs) that bind...... to the extracellular part of EGFR, blocking the binding sites for the EGFR ligands, and intracellular tyrosine kinase inhibitors (TKIs) that block the ATP binding site of the tyrosine kinase domain. Besides an EGFRvIII-targeted vaccine, conjugated anti-EGFR mAbs have been used in different settings to deliver lethal...... agents to the EGFR/EGFRvIII-positive cells; among these are radio-labelled mAbs and immunotoxins. This article reviews the current status and efficacy of EGFR/EGFRvIII-targeted therapies....

  5. Identification of regulatory targets for the bacterial Nus factor complex.

    Science.gov (United States)

    Baniulyte, Gabriele; Singh, Navjot; Benoit, Courtney; Johnson, Richard; Ferguson, Robert; Paramo, Mauricio; Stringer, Anne M; Scott, Ashley; Lapierre, Pascal; Wade, Joseph T

    2017-12-11

    Nus factors are broadly conserved across bacterial species, and are often essential for viability. A complex of five Nus factors (NusB, NusE, NusA, NusG and SuhB) is considered to be a dedicated regulator of ribosomal RNA folding, and has been shown to prevent Rho-dependent transcription termination. Here, we identify an additional cellular function for the Nus factor complex in Escherichia coli: repression of the Nus factor-encoding gene, suhB. This repression occurs primarily by translation inhibition, followed by Rho-dependent transcription termination. Thus, the Nus factor complex can prevent or promote Rho activity depending on the gene context. Conservation of putative NusB/E binding sites upstream of Nus factor genes suggests that Nus factor autoregulation occurs in many bacterial species. Additionally, many putative NusB/E binding sites are also found upstream of other genes in diverse species, and we demonstrate Nus factor regulation of one such gene in Citrobacter koseri. We conclude that Nus factors have an evolutionarily widespread regulatory function beyond ribosomal RNA, and that they are often autoregulatory.

  6. Integrative Analysis of CRISPR/Cas9 Target Sites in the Human HBB Gene

    Directory of Open Access Journals (Sweden)

    Yumei Luo

    2015-01-01

    Full Text Available Recently, the clustered regularly interspaced short palindromic repeats (CRISPR system has emerged as a powerful customizable artificial nuclease to facilitate precise genetic correction for tissue regeneration and isogenic disease modeling. However, previous studies reported substantial off-target activities of CRISPR system in human cells, and the enormous putative off-target sites are labor-intensive to be validated experimentally, thus motivating bioinformatics methods for rational design of CRISPR system and prediction of its potential off-target effects. Here, we describe an integrative analytical process to identify specific CRISPR target sites in the human β-globin gene (HBB and predict their off-target effects. Our method includes off-target analysis in both coding and noncoding regions, which was neglected by previous studies. It was found that the CRISPR target sites in the introns have fewer off-target sites in the coding regions than those in the exons. Remarkably, target sites containing certain transcriptional factor motif have enriched binding sites of relevant transcriptional factor in their off-target sets. We also found that the intron sites have fewer SNPs, which leads to less variation of CRISPR efficiency in different individuals during clinical applications. Our studies provide a standard analytical procedure to select specific CRISPR targets for genetic correction.

  7. An easy guide to factor analysis

    CERN Document Server

    Kline, Paul

    2014-01-01

    Factor analysis is a statistical technique widely used in psychology and the social sciences. With the advent of powerful computers, factor analysis and other multivariate methods are now available to many more people. An Easy Guide to Factor Analysis presents and explains factor analysis as clearly and simply as possible. The author, Paul Kline, carefully defines all statistical terms and demonstrates step-by-step how to work out a simple example of principal components analysis and rotation. He further explains other methods of factor analysis, including confirmatory and path analysis, a

  8. Towards understanding the lifespan extension by reduced insulin signaling: bioinformatics analysis of DAF-16/FOXO direct targets in Caenorhabditis elegans.

    Science.gov (United States)

    Li, Yan-Hui; Zhang, Gai-Gai

    2016-04-12

    DAF-16, the C. elegans FOXO transcription factor, is an important determinant in aging and longevity. In this work, we manually curated FOXODB http://lyh.pkmu.cn/foxodb/, a database of FOXO direct targets. It now covers 208 genes. Bioinformatics analysis on 109 DAF-16 direct targets in C. elegans found interesting results. (i) DAF-16 and transcription factor PQM-1 co-regulate some targets. (ii) Seventeen targets directly regulate lifespan. (iii) Four targets are involved in lifespan extension induced by dietary restriction. And (iv) DAF-16 direct targets might play global roles in lifespan regulation.

  9. Vascular Risk Factors as Treatment Target to Prevent Cognitive Decline

    NARCIS (Netherlands)

    Richard, Edo; Moll van Charante, Eric P.; van Gool, Willem A.

    2012-01-01

    Epidemiological studies have consistently shown that vascular risk factors including hypertension, diabetes, obesity, hypercholesterolemia, smoking, and lack of physical exercise are associated with an increased risk of cognitive decline and dementia. Neuroradiological and neuropathological studies

  10. Kinetic analysis of the effects of target structure on siRNA efficiency

    Science.gov (United States)

    Chen, Jiawen; Zhang, Wenbing

    2012-12-01

    RNAi efficiency for target cleavage and protein expression is related to the target structure. Considering the RNA-induced silencing complex (RISC) as a multiple turnover enzyme, we investigated the effect of target mRNA structure on siRNA efficiency with kinetic analysis. The 4-step model was used to study the target cleavage kinetic process: hybridization nucleation at an accessible target site, RISC-mRNA hybrid elongation along with mRNA target structure melting, target cleavage, and enzyme reactivation. At this model, the terms accounting for the target accessibility, stability, and the seed and the nucleation site effects are all included. The results are in good agreement with that of experiments which show different arguments about the structure effects on siRNA efficiency. It shows that the siRNA efficiency is influenced by the integrated factors of target's accessibility, stability, and the seed effects. To study the off-target effects, a simple model of one siRNA binding to two mRNA targets was designed. By using this model, the possibility for diminishing the off-target effects by the concentration of siRNA was discussed.

  11. Factors associated with high probability of target blood pressure non-achievement in hypertensive patients

    Directory of Open Access Journals (Sweden)

    S. P. Zhemanyuk

    2017-12-01

    Full Text Available One of the topic issue of modern cardiology is factors of target blood pressure level non-achievement clarifying due to a better understanding how we can reduce cardiovascular complications. The aim of the study is to determine the factors of poor blood pressure control using the ambulatory blood pressure monitoring parameters and adenosine 5'-diphosphate-induced platelet aggregation parameters in patients with arterial hypertension. Material and methods. The study involved 153 patients with essential hypertension (EH stage II, II degree. The ambulatory blood pressure monitoring (ABPM was performed in patients during at least two of first-line antihypertensive drugs in optimal daily doses usage by the ABPM bifunctional device (Incart, S.-P., R.F.. Platelet aggregation was carried out using light transmittance aggregation by optical analyzer (Solar, R.B. with adenosine 5'-diphosphate (Sigma-Aldrich at final concentration of 10.0 × 10-6 mol / L. The first group were inadequately controlled essential hypertensive individuals with high systolic or/and diastolic BP level according to the ABPM results, and the second one were patients with adequately controlled EH. Groups of patients were comparable in age (60.39 ± 10.74 years vs. 62.80 ± 9.63; p = 0.181, respectively. In the group of EH patients who reached the target level of blood pressure, women predominated (60% vs. 39.81%; p = 0.021, respectively. We used the binary logistic regression analysis to determine the predictors of target blood pressure level poor reaching using ABPM and platelet aggregation parameters. Results According to the univariate logistic regression analysis, the dependent factors influencing the target blood pressure level poor reaching are the average diurnal diastolic blood pressure (DBP (OR = 44.8; diurnal variability of systolic blood pressure (SBP (OR = 4.4; square index of hypertension for diurnal periods SBP (OR = 318.9; square index of hypertension for diurnal

  12. Integrative analysis of RUNX1 downstream pathways and target genes

    Directory of Open Access Journals (Sweden)

    Liu Marjorie

    2008-07-01

    Full Text Available Abstract Background The RUNX1 transcription factor gene is frequently mutated in sporadic myeloid and lymphoid leukemia through translocation, point mutation or amplification. It is also responsible for a familial platelet disorder with predisposition to acute myeloid leukemia (FPD-AML. The disruption of the largely unknown biological pathways controlled by RUNX1 is likely to be responsible for the development of leukemia. We have used multiple microarray platforms and bioinformatic techniques to help identify these biological pathways to aid in the understanding of why RUNX1 mutations lead to leukemia. Results Here we report genes regulated either directly or indirectly by RUNX1 based on the study of gene expression profiles generated from 3 different human and mouse platforms. The platforms used were global gene expression profiling of: 1 cell lines with RUNX1 mutations from FPD-AML patients, 2 over-expression of RUNX1 and CBFβ, and 3 Runx1 knockout mouse embryos using either cDNA or Affymetrix microarrays. We observe that our datasets (lists of differentially expressed genes significantly correlate with published microarray data from sporadic AML patients with mutations in either RUNX1 or its cofactor, CBFβ. A number of biological processes were identified among the differentially expressed genes and functional assays suggest that heterozygous RUNX1 point mutations in patients with FPD-AML impair cell proliferation, microtubule dynamics and possibly genetic stability. In addition, analysis of the regulatory regions of the differentially expressed genes has for the first time systematically identified numerous potential novel RUNX1 target genes. Conclusion This work is the first large-scale study attempting to identify the genetic networks regulated by RUNX1, a master regulator in the development of the hematopoietic system and leukemia. The biological pathways and target genes controlled by RUNX1 will have considerable importance in disease

  13. [Segment analysis of the target market of physiotherapeutic services].

    Science.gov (United States)

    Babaskin, D V

    2010-01-01

    The objective of the present study was to demonstrate the possibilities to analyse selected segments of the target market of physiotherapeutic services provided by medical and preventive-facilities of two major types. The main features of a target segment, such as provision of therapeutic massage, are illustrated in terms of two characteristics, namely attractiveness to the users and the ability of a given medical facility to satisfy their requirements. Based on the analysis of portfolio of the available target segments the most promising ones (winner segments) were selected for further marketing studies. This choice does not exclude the possibility of involvement of other segments of medical services in marketing activities.

  14. Cellular Antiviral Factors that Target Particle Infectivity of HIV-1.

    Science.gov (United States)

    Goffinet, Christine

    2016-01-01

    In the past decade, the identification and characterization of antiviral genes with the ability to interfere with virus replication has established cell-intrinsic innate immunity as a third line of antiviral defense in addition to adaptive and classical innate immunity. Understanding how cellular factors have evolved to inhibit HIV-1 reveals particularly vulnerable points of the viral replication cycle. Many, but not all, antiviral proteins share type I interferon-upregulated expression and sensitivity to viral counteraction or evasion measures. Whereas well-established restriction factors interfere with early post-entry steps and release of HIV-1, recent research has revealed a diverse set of proteins that reduce the infectious quality of released particles using individual, to date poorly understood modes of action. These include induction of paucity of mature glycoproteins in nascent virions or self-incorporation into the virus particle, resulting in poor infectiousness of the virion and impaired spread of the infection. A better understanding of these newly discovered antiviral factors may open new avenues towards the design of drugs that repress the spread of viruses whose genomes have already integrated.

  15. RISK FACTORS FOR PANCREATIC CANCER: UNDERLYING MECHANISMS AND POTENTIAL TARGETS

    Directory of Open Access Journals (Sweden)

    Thomas eKolodecik

    2014-01-01

    Full Text Available Purpose of the review:Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer.Recent Findings:Intracellular activation of both pancreatic enzymes and the transcription factor NF-kB are important mechanisms that induce acute pancreatitis. Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogneic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16 can ultimately lead to development of pancreatic cancer. Summary:Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions.

  16. A factor analysis to detect factors influencing building national brand

    Directory of Open Access Journals (Sweden)

    Naser Azad

    Full Text Available Developing a national brand is one of the most important issues for development of a brand. In this study, we present factor analysis to detect the most important factors in building a national brand. The proposed study uses factor analysis to extract the most influencing factors and the sample size has been chosen from two major auto makers in Iran called Iran Khodro and Saipa. The questionnaire was designed in Likert scale and distributed among 235 experts. Cronbach alpha is calculated as 84%, which is well above the minimum desirable limit of 0.70. The implementation of factor analysis provides six factors including “cultural image of customers”, “exciting characteristics”, “competitive pricing strategies”, “perception image” and “previous perceptions”.

  17. A novel small peptide as an epidermal growth factor receptor targeting ligand for nanodelivery in vitro

    Directory of Open Access Journals (Sweden)

    Han CY

    2013-04-01

    Full Text Available Cui-yan Han,1,2 Li-ling Yue,2 Ling-yu Tai,1 Li Zhou,2 Xue-yan Li,2 Gui-hua Xing,2 Xing-gang Yang,1 Ming-shuang Sun,1 Wei-san Pan1 1School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, People’s Republic of China; 2Qiqihar Medical University, Qiqihar, People’s Republic of China Abstract: The epidermal growth factor receptor (EGFR serves an important function in the proliferation of tumors in humans and is an effective target for the treatment of cancer. In this paper, we studied the targeting characteristics of small peptides (AEYLR, EYINQ, and PDYQQD that were derived from three major autophosphorylation sites of the EGFR C-terminus domain in vitro. These small peptides were labeled with fluorescein isothiocyanate (FITC and used the peptide LARLLT as a positive control, which bound to putative EGFR selected from a virtual peptide library by computer-aided design, and the independent peptide RALEL as a negative control. Analyses with flow cytometry and an internalization assay using NCI-H1299 and K562 with high EGFR and no EGFR expression, respectively, indicated that FITC-AEYLR had high EGFR targeting activity. Biotin-AEYLR that was specifically bound to human EGFR proteins demonstrated a high affinity for human non-small-cell lung tumors. We found that AEYLR peptide-conjugated, nanostructured lipid carriers enhanced specific cellular uptake in vitro during a process that was apparently mediated by tumor cells with high-expression EGFR. Analysis of the MTT assay indicated that the AEYLR peptide did not significantly stimulate or inhibit the growth activity of the cells. These findings suggest that, when mediated by EGFR, AEYLR may be a potentially safe and efficient delivery ligand for targeted chemotherapy, radiotherapy, and gene therapy. Keywords: EGFR, small peptide, tumor targeting, lung cancer, NLC

  18. Facility factors dominate the ability to achieve target haemoglobin levels in haemodialysis patients.

    Science.gov (United States)

    Chan, Kevin E; Lafayette, Richard A; Whittemore, Alice S; Hlatky, Mark A; Moran, John

    2008-09-01

    Our objective was to determine whether patient factors, processes of care and measures of erythropoietin (EPO) responsiveness were associated with successful anemia management at the individual patient level. We retrospectively reviewed laboratory and demographic data from 1499 patients receiving hemodialysis in 15 units operated by the same dialysis provider. We performed univariate and multivariate logistic regression analysis to determine predictors of an average 3-month hemoglobin level below or above the target interval of 11.0-12.5 g/dL. To explain the effect of facility on anemia performance, we calculated correlations between measures of EPO responsiveness and the probability of achieving the target interval by facility. Patients above the target hemoglobin range demonstrated an association with parathyroid hormone (PTH) (OR = 0.96 per 100 pg/mL increase), female gender (OR = 0.68), EPO protocol use (OR = 0.94 per 10% increase in use) and facility (range of OR = 0.26-2.59 for 15 participating sites). Patients below the target hemoglobin range demonstrated an association with CRP (OR = 1.10 per mg/L increase), PTH (OR = 1.07 per 100 pg/mL increase), iron deficiency (OR = 1.07 per 10% increase), EPO protocol use (OR = 0.89 per 10% increase in use), iron protocol use (OR = 0.93 per 10% increase in use) and facility (range of OR = 0.58-3.41 over 15 units). EPO index (r = 0.71), EPO dose (r = 0.73), hemoglobin (r = -0.60) and EPO per unit weight (r = 0.76) were significantly correlated with the probability of achieving the target hemoglobin by facility. The facility significantly influences the outcome of anemia management in patients with ESRD. In part, this is due to the patients' EPO responsiveness, which may be influenced by facility care patterns.

  19. The Infinitesimal Jackknife with Exploratory Factor Analysis

    Science.gov (United States)

    Zhang, Guangjian; Preacher, Kristopher J.; Jennrich, Robert I.

    2012-01-01

    The infinitesimal jackknife, a nonparametric method for estimating standard errors, has been used to obtain standard error estimates in covariance structure analysis. In this article, we adapt it for obtaining standard errors for rotated factor loadings and factor correlations in exploratory factor analysis with sample correlation matrices. Both…

  20. Analysis of target implosion irradiated by proton beam, (1)

    International Nuclear Information System (INIS)

    Tamba, Moritake; Nagata, Norimasa; Kawata, Shigeo; Niu, Keishiro.

    1982-10-01

    Numerical simulation and analysis were performed for the implosion of a hollow shell target driven by proton beam. The target consists of three layers of Pb, Al and DT. As the Al layer is heated by proton beam, the layer expands and pushes the DT layer toward the target center. To obtain the optimal velocity of DT implosion, the optimal target size and optimal layer thickness were determined. The target size is determined by, for example, the instability of the implosion or beam focusing on the target surface. The Rayleigh-Taylor instability and the unstable implosion due to the inhomogeneity were investigated. Dissipation, nonlinear effects and density gradient at the boundary were expected to reduce the growth rate of the Rayleigh-Taylor instability during the implosion. In order that the deviation of the boundary surface during the implosion is less than the thickness of fuel, the inhomogeneity of the temperature and the density of the target should be less than ten percent. The amplitude of the boundary surface roughness is required to be less than 4 micrometer. (Kato, T.)

  1. Co-factors necessary for PPAR mediated transactivation of endogenous target genes

    DEFF Research Database (Denmark)

    Grøntved, Lars; Nielsen, Ronni; Stunnenberg, Henk

    of endogenous target gene in different cell types are elusive. To mutually compare the ability of the PPAR subtypes to activate endogenous target genes in a given cell, PPARa, PPARb/d and PPARg2 were HA tagged and rapidly, equally and synchronously expressed using adenoviral delivery. Within a few hours after...... subtype specific activation of target genes. Accumulating evidence suggests that transcriptional co-factors can function as master regulators for nuclear receptors and impose promoter selectivity. To study co-factor necessity for PPAR mediated transactivation of endogenous target genes, specific co...

  2. Introduction to charm decay analysis in fixed target experiments

    Energy Technology Data Exchange (ETDEWEB)

    Bediaga, Ignacio; Goebel, Carla

    1996-01-01

    We present an introduction to data analysis in Experimental High Energy Physics, and some concepts and useful tools are discussed. To illustrate, we use the data of E-791, a fixed target experiment recently realized at Fermilab. In particular, we analyse decay modes of D{sup +} meson with three charged particles in the final state. (author). 8 refs., 22 figs., 1 tab.

  3. Introduction to charm decay analysis in fixed target experiments

    International Nuclear Information System (INIS)

    Bediaga, Ignacio; Goebel, Carla.

    1996-01-01

    We present an introduction to data analysis in Experimental High Energy Physics, and some concepts and useful tools are discussed. To illustrate, we use the data of E-791, a fixed target experiment recently realized at Fermilab. In particular, we analyse decay modes of D + meson with three charged particles in the final state. (author). 8 refs., 22 figs., 1 tab

  4. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target.

    Science.gov (United States)

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo J A; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-06-03

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients' clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression.

  5. c-Met in esophageal squamous cell carcinoma: an independent prognostic factor and potential therapeutic target

    International Nuclear Information System (INIS)

    Ozawa, Yohei; Nakamura, Yasuhiro; Fujishima, Fumiyoshi; Felizola, Saulo JA; Takeda, Kenichiro; Okamoto, Hiroshi; Ito, Ken; Ishida, Hirotaka; Konno, Takuro; Kamei, Takashi; Miyata, Go; Ohuchi, Noriaki; Sasano, Hironobu

    2015-01-01

    c-Met is widely known as a poor prognostic factor in various human malignancies. Previous studies have suggested the involvement of c-Met and/or its ligand, hepatocyte growth factor (HGF), in esophageal squamous cell carcinoma (ESCC), but the correlation between c-Met status and clinical outcome remains unclear. Furthermore, the identification of a novel molecular therapeutic target might potentially help improve the clinical outcome of ESCC patients. The expression of c-Met and HGF was immunohistochemically assessed in 104 surgically obtained tissue specimens. The correlation between c-Met/HGF expression and patients’ clinicopathological features, including survival, was evaluated. We also investigated changes in cell functions and protein expression of c-Met and its downstream signaling pathway components under treatments with HGF and/or c-Met inhibitor in ESCC cell lines. Elevated expression of c-Met was significantly correlated with tumor depth and pathological stage. Patients with high c-Met expression had significantly worse survival. In addition, multivariate analysis identified the high expression of c-Met as an independent prognostic factor. Treatment with c-Met inhibitor under HGF stimulation significantly inhibited the invasive capacity of an ESCC cell line with elevated c-Met mRNA expression. Moreover, c-Met and its downstream signaling inactivation was also detected after treatment with c-Met inhibitor. The results of our study identified c-Met expression as an independent prognostic factor in ESCC patients and demonstrated that c-Met could be a potential molecular therapeutic target for the treatment of ESCC with elevated c-Met expression. The online version of this article (doi:10.1186/s12885-015-1450-3) contains supplementary material, which is available to authorized users

  6. Genome-wide analysis of Polycomb targets in Drosophila

    Energy Technology Data Exchange (ETDEWEB)

    Schwartz, Yuri B.; Kahn, Tatyana G.; Nix, David A.; Li,Xiao-Yong; Bourgon, Richard; Biggin, Mark; Pirrotta, Vincenzo

    2006-04-01

    Polycomb Group (PcG) complexes are multiprotein assemblages that bind to chromatin and establish chromatin states leading to epigenetic silencing. PcG proteins regulate homeotic genes in flies and vertebrates but little is known about other PcG targets and the role of the PcG in development, differentiation and disease. We have determined the distribution of the PcG proteins PC, E(Z) and PSC and of histone H3K27 trimethylation in the Drosophila genome. At more than 200 PcG target genes, binding sites for the three PcG proteins colocalize to presumptive Polycomb Response Elements (PREs). In contrast, H3 me3K27 forms broad domains including the entire transcription unit and regulatory regions. PcG targets are highly enriched in genes encoding transcription factors but receptors, signaling proteins, morphogens and regulators representing all major developmental pathways are also included.

  7. Targets for bulk hydrogen analysis using thermal neutrons

    CERN Document Server

    Csikai, J; Buczko, C M

    2002-01-01

    The reflection property of substances can be characterized by the reflection cross-section of thermal neutrons, sigma subbeta. A combination of the targets with thin polyethylene foils allowed an estimation of the flux depression of thermal neutrons caused by a bulk sample containing highly absorbing elements or compounds. Some new and more accurate sigma subbeta values were determined by using the combined target arrangement. For the ratio, R of the reflection and the elastic scattering cross-sections of thermal neutrons, R=sigma subbeta/sigma sub E sub L a value of 0.60+-0.02 was found on the basis of the data obtained for a number of elements from H to Pb. Using this correlation factor, and the sigma sub E sub L values, the unknown sigma subbeta data can be deduced. The equivalent thicknesses, to polyethylene or hydrogen, of the different target materials were determined from the sigma subbeta values.

  8. A mathematical analysis of multiple-target SELEX.

    Science.gov (United States)

    Seo, Yeon-Jung; Chen, Shiliang; Nilsen-Hamilton, Marit; Levine, Howard A

    2010-10-01

    SELEX (Systematic Evolution of Ligands by Exponential Enrichment) is a procedure by which a mixture of nucleic acids can be fractionated with the goal of identifying those with specific biochemical activities. One combines the mixture with a specific target molecule and then separates the target-NA complex from the resulting reactions. The target-NA complex is separated from the unbound NA by mechanical means (such as by filtration), the NA is eluted from the complex, amplified by PCR (polymerase chain reaction), and the process repeated. After several rounds, one should be left with the nucleic acids that best bind to the target. The problem was first formulated mathematically in Irvine et al. (J. Mol. Biol. 222:739-761, 1991). In Levine and Nilsen-Hamilton (Comput. Biol. Chem. 31:11-25, 2007), a mathematical analysis of the process was given. In Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998), multiple target SELEX was considered. It was assumed that each target has a single nucleic acid binding site that permits occupation by no more than one nucleic acid. Here, we revisit Vant-Hull et al. (J. Mol. Biol. 278:579-597, 1998) using the same assumptions. The iteration scheme is shown to be convergent and a simplified algorithm is given. Our interest here is in the behavior of the multiple target SELEX process as a discrete "time" dynamical system. Our goal is to characterize the limiting states and their dependence on the initial distribution of nucleic acid and target fraction components. (In multiple target SELEX, we vary the target component fractions, but not their concentrations, as fixed and the initial pool of nucleic acids as a variable starting condition). Given N nucleic acids and a target consisting of M subtarget component species, there is an M × N matrix of affinities, the (i,j) entry corresponding to the affinity of the jth nucleic acid for the ith subtarget. We give a structure condition on this matrix that is equivalent to the following

  9. Tissue factor is an angiogenic-specific receptor for factor VII-targeted immunotherapy and photodynamic therapy.

    Science.gov (United States)

    Hu, Zhiwei; Cheng, Jijun; Xu, Jie; Ruf, Wolfram; Lockwood, Charles J

    2017-02-01

    Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role. Using VEGF-stimulated vascular endothelial cells (VECs) isolated from microvessels, venous and arterial blood vessels as in vitro angiogenic models and unstimulated VECs as a quiescent VEC model, we examined the expression of tissue factor (TF), a membrane-bound receptor on the angiogenic VEC models compared with quiescent VEC controls. We found that TF is specifically expressed on angiogenic VECs in a time-dependent manner in microvessels, venous and arterial vessels. TF-targeted therapeutic agents, including factor VII (fVII)-IgG1 Fc and fVII-conjugated photosensitizer, can selectively bind angiogenic VECs, but not the quiescent VECs. Moreover, fVII-targeted photodynamic therapy can selectively and completely eradicate angiogenic VECs. We conclude that TF is an angiogenic-specific receptor and the target molecule for fVII-targeted therapeutics. This study supports clinical trials of TF-targeted therapeutics for the treatment of angiogenesis-dependent diseases such as cancer, macular degeneration and endometriosis.

  10. Computer-aided target tracking in motion analysis studies

    Science.gov (United States)

    Burdick, Dominic C.; Marcuse, M. L.; Mislan, J. D.

    1990-08-01

    Motion analysis studies require the precise tracking of reference objects in sequential scenes. In a typical situation, events of interest are captured at high frame rates using special cameras, and selected objects or targets are tracked on a frame by frame basis to provide necessary data for motion reconstruction. Tracking is usually done using manual methods which are slow and prone to error. A computer based image analysis system has been developed that performs tracking automatically. The objective of this work was to eliminate the bottleneck due to manual methods in high volume tracking applications such as the analysis of crash test films for the automotive industry. The system has proven to be successful in tracking standard fiducial targets and other objects in crash test scenes. Over 95 percent of target positions which could be located using manual methods can be tracked by the system, with a significant improvement in throughput over manual methods. Future work will focus on the tracking of clusters of targets and on tracking deformable objects such as airbags.

  11. Analysis of Bernstein's factorization circuit

    NARCIS (Netherlands)

    Lenstra, A.K.; Shamir, A.; Tomlinson, J.; Tromer, E.; Zheng, Y.

    2002-01-01

    In [1], Bernstein proposed a circuit-based implementation of the matrix step of the number field sieve factorization algorithm. These circuits offer an asymptotic cost reduction under the measure "construction cost x run time". We evaluate the cost of these circuits, in agreement with [1], but argue

  12. Penetration analysis of projectile with inclined concrete target

    Directory of Open Access Journals (Sweden)

    Kim S.B.

    2015-01-01

    Full Text Available This paper presents numerical analysis result of projectile penetration with concrete target. We applied dynamic material properties of 4340 steels, aluminium and explosive for projectile body. Dynamic material properties were measured with static tensile testing machine and Hopkinson pressure bar tests. Moreover, we used three concrete damage models included in LS-DYNA 3D, such as SOIL_CONCRETE, CSCM (cap model with smooth interaction and CONCRETE_DAMAGE (K&C concrete models. Strain rate effect for concrete material is important to predict the fracture deformation and shape of concrete, and penetration depth for projectiles. CONCRETE_DAMAGE model with strain rate effect also applied to penetration analysis. Analysis result with CSCM model shows good agreement with penetration experimental data. The projectile trace and fracture shapes of concrete target were compared with experimental data.

  13. Penetration analysis of projectile with inclined concrete target

    Science.gov (United States)

    Kim, S. B.; Kim, H. W.; Yoo, Y. H.

    2015-09-01

    This paper presents numerical analysis result of projectile penetration with concrete target. We applied dynamic material properties of 4340 steels, aluminium and explosive for projectile body. Dynamic material properties were measured with static tensile testing machine and Hopkinson pressure bar tests. Moreover, we used three concrete damage models included in LS-DYNA 3D, such as SOIL_CONCRETE, CSCM (cap model with smooth interaction) and CONCRETE_DAMAGE (K&C concrete) models. Strain rate effect for concrete material is important to predict the fracture deformation and shape of concrete, and penetration depth for projectiles. CONCRETE_DAMAGE model with strain rate effect also applied to penetration analysis. Analysis result with CSCM model shows good agreement with penetration experimental data. The projectile trace and fracture shapes of concrete target were compared with experimental data.

  14. Epidermal Growth Factor Receptor targeting in non-small cell lung cancer: revisiting different strategies against the same target.

    Science.gov (United States)

    Castañón, Eduardo; Martín, Patricia; Rolfo, Christian; Fusco, Juan P; Ceniceros, Lucía; Legaspi, Jairo; Santisteban, Marta; Gil-Bazo, Ignacio

    2014-01-01

    Epidermal Growth Factor Receptor (EGFR) tyrosine kinase inhibitors (TKIs) have changed the paradigm of treatment in non-small cell lung cancer (NSCLC). The molecular biology study of EGFR has led to clinical trials that select patients more accurately, regarding the presence of EGFR activating mutations. Nonetheless, a lack of response or a temporary condition of the response has been detected in patients on EGFR TKIs. This has urged to study potential resistance mechanisms underneath. The most important ones are the presence of secondary mutations in EGFR, such as T790M, or the overexpression of mesenchymal-epithelial transition factor (MET) that may explain why patients who initially respond to EGFR TKIs, may ultimately become refractory. Several approaches have been taken and new drugs both targeting EGFR resistance-mutation or MET are currently being developed. Here we review and update the EGFR biological pathway as well as the clinical data leading to approval of the EGFR TKIs currently in the market. New compounds under investigation targeting resistance mutations or dually targeting EGFR and other relevant receptors are also reviewed and discussed.

  15. Integrative analysis to select cancer candidate biomarkers to targeted validation

    Science.gov (United States)

    Heberle, Henry; Domingues, Romênia R.; Granato, Daniela C.; Yokoo, Sami; Canevarolo, Rafael R.; Winck, Flavia V.; Ribeiro, Ana Carolina P.; Brandão, Thaís Bianca; Filgueiras, Paulo R.; Cruz, Karen S. P.; Barbuto, José Alexandre; Poppi, Ronei J.; Minghim, Rosane; Telles, Guilherme P.; Fonseca, Felipe Paiva; Fox, Jay W.; Santos-Silva, Alan R.; Coletta, Ricardo D.; Sherman, Nicholas E.; Paes Leme, Adriana F.

    2015-01-01

    Targeted proteomics has flourished as the method of choice for prospecting for and validating potential candidate biomarkers in many diseases. However, challenges still remain due to the lack of standardized routines that can prioritize a limited number of proteins to be further validated in human samples. To help researchers identify candidate biomarkers that best characterize their samples under study, a well-designed integrative analysis pipeline, comprising MS-based discovery, feature selection methods, clustering techniques, bioinformatic analyses and targeted approaches was performed using discovery-based proteomic data from the secretomes of three classes of human cell lines (carcinoma, melanoma and non-cancerous). Three feature selection algorithms, namely, Beta-binomial, Nearest Shrunken Centroids (NSC), and Support Vector Machine-Recursive Features Elimination (SVM-RFE), indicated a panel of 137 candidate biomarkers for carcinoma and 271 for melanoma, which were differentially abundant between the tumor classes. We further tested the strength of the pipeline in selecting candidate biomarkers by immunoblotting, human tissue microarrays, label-free targeted MS and functional experiments. In conclusion, the proposed integrative analysis was able to pre-qualify and prioritize candidate biomarkers from discovery-based proteomics to targeted MS. PMID:26540631

  16. Single-Molecule Analysis for RISC Assembly and Target Cleavage.

    Science.gov (United States)

    Sasaki, Hiroshi M; Tadakuma, Hisashi; Tomari, Yukihide

    2018-01-01

    RNA-induced silencing complex (RISC) is a small RNA-protein complex that mediates silencing of complementary target RNAs. Biochemistry has been successfully used to characterize the molecular mechanism of RISC assembly and function for nearly two decades. However, further dissection of intermediate states during the reactions has been warranted to fill in the gaps in our understanding of RNA silencing mechanisms. Single-molecule analysis with total internal reflection fluorescence (TIRF) microscopy is a powerful imaging-based approach to interrogate complex formation and dynamics at the individual molecule level with high sensitivity. Combining this technique with our recently established in vitro reconstitution system of fly Ago2-RISC, we have developed a single-molecule observation system for RISC assembly. In this chapter, we summarize the detailed protocol for single-molecule analysis of chaperone-assisted assembly of fly Ago2-RISC as well as its target cleavage reaction.

  17. Neighborhood Regularized Logistic Matrix Factorization for Drug-Target Interaction Prediction.

    Science.gov (United States)

    Liu, Yong; Wu, Min; Miao, Chunyan; Zhao, Peilin; Li, Xiao-Li

    2016-02-01

    In pharmaceutical sciences, a crucial step of the drug discovery process is the identification of drug-target interactions. However, only a small portion of the drug-target interactions have been experimentally validated, as the experimental validation is laborious and costly. To improve the drug discovery efficiency, there is a great need for the development of accurate computational approaches that can predict potential drug-target interactions to direct the experimental verification. In this paper, we propose a novel drug-target interaction prediction algorithm, namely neighborhood regularized logistic matrix factorization (NRLMF). Specifically, the proposed NRLMF method focuses on modeling the probability that a drug would interact with a target by logistic matrix factorization, where the properties of drugs and targets are represented by drug-specific and target-specific latent vectors, respectively. Moreover, NRLMF assigns higher importance levels to positive observations (i.e., the observed interacting drug-target pairs) than negative observations (i.e., the unknown pairs). Because the positive observations are already experimentally verified, they are usually more trustworthy. Furthermore, the local structure of the drug-target interaction data has also been exploited via neighborhood regularization to achieve better prediction accuracy. We conducted extensive experiments over four benchmark datasets, and NRLMF demonstrated its effectiveness compared with five state-of-the-art approaches.

  18. EBF factors drive expression of multiple classes of target genes governing neuronal development.

    Science.gov (United States)

    Green, Yangsook S; Vetter, Monica L

    2011-04-30

    Early B cell factor (EBF) family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

  19. EBF factors drive expression of multiple classes of target genes governing neuronal development

    Directory of Open Access Journals (Sweden)

    Vetter Monica L

    2011-04-01

    Full Text Available Abstract Background Early B cell factor (EBF family members are transcription factors known to have important roles in several aspects of vertebrate neurogenesis, including commitment, migration and differentiation. Knowledge of how EBF family members contribute to neurogenesis is limited by a lack of detailed understanding of genes that are transcriptionally regulated by these factors. Results We performed a microarray screen in Xenopus animal caps to search for targets of EBF transcriptional activity, and identified candidate targets with multiple roles, including transcription factors of several classes. We determined that, among the most upregulated candidate genes with expected neuronal functions, most require EBF activity for some or all of their expression, and most have overlapping expression with ebf genes. We also found that the candidate target genes that had the most strongly overlapping expression patterns with ebf genes were predicted to be direct transcriptional targets of EBF transcriptional activity. Conclusions The identification of candidate targets that are transcription factor genes, including nscl-1, emx1 and aml1, improves our understanding of how EBF proteins participate in the hierarchy of transcription control during neuronal development, and suggests novel mechanisms by which EBF activity promotes migration and differentiation. Other candidate targets, including pcdh8 and kcnk5, expand our knowledge of the types of terminal differentiated neuronal functions that EBF proteins regulate.

  20. Multiple factor analysis by example using R

    CERN Document Server

    Pagès, Jérôme

    2014-01-01

    Multiple factor analysis (MFA) enables users to analyze tables of individuals and variables in which the variables are structured into quantitative, qualitative, or mixed groups. Written by the co-developer of this methodology, Multiple Factor Analysis by Example Using R brings together the theoretical and methodological aspects of MFA. It also includes examples of applications and details of how to implement MFA using an R package (FactoMineR).The first two chapters cover the basic factorial analysis methods of principal component analysis (PCA) and multiple correspondence analysis (MCA). The

  1. A mechanistic overview of herbal medicine and botanical compounds to target transcriptional factors in Breast cancer.

    Science.gov (United States)

    Zhao, Yingke; Liu, Yue

    2018-04-01

    The abnormalities of transcription factors, such as NF-κB, STAT, estrogen receptor, play a critical role in the initiation and progression of breast cancer. Due to the limitation of current treatment, transcription factors could be promising therapeutic targets, which have received close attention. In this review, we introduced herbal medicines, as well as botanical compounds that had been verified with anti-tumor properties via regulating transcription factors. Herbs, compounds, as well as formulae reported with various transcriptional targets, were summarized thoroughly, to provide implication for the future research on basic experiment and clinical application. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Transcription factor HBP1 is a direct anti-cancer target of transcription factor FOXO1 in invasive oral cancer.

    Science.gov (United States)

    Chan, Chien-Yi; Huang, Shih-Yi; Sheu, Jim Jinn-Chyuan; Roth, Mendel M; Chou, I-Tai; Lien, Chia-Hsien; Lee, Ming-Fen; Huang, Chun-Yin

    2017-02-28

    Either FOXO1 or HBP1 transcription factor is a downstream effector of the PI3K/Akt pathway and associated with tumorigenesis. However, the relationship between FOXO1 and HBP1 in oral cancer remains unclear. Analysis of 30 oral tumor specimens revealed that mean mRNA levels of both FOXO1 and HBP1 in non-invasive and invasive oral tumors were found to be significantly lower than that of the control tissues, and the status of low FOXO1 and HBP1 (oral tumors. To investigate if HBP1 is a direct transcription target of FOXO1, we searched potential FOXO1 binding sites in the HBP1 promoter using the MAPPER Search Engine, and two putative FOXO1 binding sites located in the HBP1 promoter -132 to -125 bp and -343 to -336 bp were predicted. These binding sites were then confirmed by both reporter gene assays and the in cellulo ChIP assay. In addition, Akt activity manipulated by PI3K inhibitor LY294002 or Akt mutants was shown to negatively affect FOXO1-mediated HBP1 promoter activation and gene expression. Last, the biological significance of the FOXO1-HBP1 axis in oral cancer malignancy was evaluated in cell growth, colony formation, and invasiveness. The results indicated that HBP1 knockdown potently promoted malignant phenotypes of oral cancer and the suppressive effect of FOXO1 on cell growth, colony formation, and invasion was alleviated upon HBP1 knockdown in invasive oral cancer cells. Taken together, our data provide evidence for HBP1 as a direct downstream target of FOXO1 in oral cancer malignancy.

  3. Bioinformatics analysis of Brucella vaccines and vaccine targets using VIOLIN.

    Science.gov (United States)

    He, Yongqun; Xiang, Zuoshuang

    2010-09-27

    Brucella spp. are Gram-negative, facultative intracellular bacteria that cause brucellosis, one of the commonest zoonotic diseases found worldwide in humans and a variety of animal species. While several animal vaccines are available, there is no effective and safe vaccine for prevention of brucellosis in humans. VIOLIN (http://www.violinet.org) is a web-based vaccine database and analysis system that curates, stores, and analyzes published data of commercialized vaccines, and vaccines in clinical trials or in research. VIOLIN contains information for 454 vaccines or vaccine candidates for 73 pathogens. VIOLIN also contains many bioinformatics tools for vaccine data analysis, data integration, and vaccine target prediction. To demonstrate the applicability of VIOLIN for vaccine research, VIOLIN was used for bioinformatics analysis of existing Brucella vaccines and prediction of new Brucella vaccine targets. VIOLIN contains many literature mining programs (e.g., Vaxmesh) that provide in-depth analysis of Brucella vaccine literature. As a result of manual literature curation, VIOLIN contains information for 38 Brucella vaccines or vaccine candidates, 14 protective Brucella antigens, and 68 host response studies to Brucella vaccines from 97 peer-reviewed articles. These Brucella vaccines are classified in the Vaccine Ontology (VO) system and used for different ontological applications. The web-based VIOLIN vaccine target prediction program Vaxign was used to predict new Brucella vaccine targets. Vaxign identified 14 outer membrane proteins that are conserved in six virulent strains from B. abortus, B. melitensis, and B. suis that are pathogenic in humans. Of the 14 membrane proteins, two proteins (Omp2b and Omp31-1) are not present in B. ovis, a Brucella species that is not pathogenic in humans. Brucella vaccine data stored in VIOLIN were compared and analyzed using the VIOLIN query system. Bioinformatics curation and ontological representation of Brucella vaccines

  4. Genome-wide identification of Bcl11b gene targets reveals role in brain-derived neurotrophic factor signaling.

    Directory of Open Access Journals (Sweden)

    Bin Tang

    Full Text Available B-cell leukemia/lymphoma 11B (Bcl11b is a transcription factor showing predominant expression in the striatum. To date, there are no known gene targets of Bcl11b in the nervous system. Here, we define targets for Bcl11b in striatal cells by performing chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq in combination with genome-wide expression profiling. Transcriptome-wide analysis revealed that 694 genes were significantly altered in striatal cells over-expressing Bcl11b, including genes showing striatal-enriched expression similar to Bcl11b. ChIP-seq analysis demonstrated that Bcl11b bound a mixture of coding and non-coding sequences that were within 10 kb of the transcription start site of an annotated gene. Integrating all ChIP-seq hits with the microarray expression data, 248 direct targets of Bcl11b were identified. Functional analysis on the integrated gene target list identified several zinc-finger encoding genes as Bcl11b targets, and further revealed a significant association of Bcl11b to brain-derived neurotrophic factor/neurotrophin signaling. Analysis of ChIP-seq binding regions revealed significant consensus DNA binding motifs for Bcl11b. These data implicate Bcl11b as a novel regulator of the BDNF signaling pathway, which is disrupted in many neurological disorders. Specific targeting of the Bcl11b-DNA interaction could represent a novel therapeutic approach to lowering BDNF signaling specifically in striatal cells.

  5. Analysis of Myc-induced histone modifications on target chromatin.

    Directory of Open Access Journals (Sweden)

    Francesca Martinato

    Full Text Available The c-myc proto-oncogene is induced by mitogens and is a central regulator of cell growth and differentiation. The c-myc product, Myc, is a transcription factor that binds a multitude of genomic sites, estimated to be over 10-15% of all promoter regions. Target promoters generally pre-exist in an active or poised chromatin state that is further modified by Myc, contributing to fine transcriptional regulation (activation or repression of the afferent gene. Among other mechanisms, Myc recruits histone acetyl-transferases to target chromatin and locally promotes hyper-acetylation of multiple lysines on histones H3 and H4, although the identity and combination of the modified lysines is unknown. Whether Myc dynamically regulates other histone modifications (or marks at its binding sites also remains to be addressed. Here, we used quantitative chromatin immunoprecipitation (qChIP to profile a total of 24 lysine-acetylation and -methylation marks modulated by Myc at target promoters in a human B-cell line with a regulatable c-myc transgene. Myc binding promoted acetylation of multiple lysines, primarily of H3K9, H3K14, H3K18, H4K5 and H4K12, but significantly also of H4K8, H4K91 and H2AK5. Dimethylation of H3K79 was also selectively induced at target promoters. A majority of target promoters showed co-induction of multiple marks - in various combinations - correlating with recruitment of the two HATs tested (Tip60 and HBO1, incorporation of the histone variant H2A.Z and transcriptional activation. Based on this and previous findings, we surmise that Myc recruits the Tip60/p400 complex to achieve a coordinated histone acetylation/exchange reaction at activated promoters. Our data are also consistent with the additive and redundant role of multiple acetylation events in transcriptional activation.

  6. Thermal Analysis of Fission Moly Target Solid Waste Storage

    Energy Technology Data Exchange (ETDEWEB)

    Son, Hyung Min; Park, Jonghark [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2016-10-15

    There are various ways to produce Mo-99. Among them, nuclear transmutation of uranium target became the major one owing to its superior specific activity. After the fission molybdenum (FM) target is irradiated, it is transported to treatment facility to extract wanted isotope. During the process, various forms of wastes are produced including filter cake and other solid wastes. The filter cake is mostly consisted of decaying uranium compounds. The solid wastes are then packaged and moved to storage facility which will stay there for considerable amount of time. Being the continuous source of heat, the solid wastes are required to be cooled for the certain amount of time before transported to the storage area. In this study, temperature evaluation of the storage facility is carried out with pre-cooling time sensitivity to check its thermal integrity. In this study, thermal analysis on the FM target solid waste storage is performed. Finite volume method is utilized to numerically discretize and solve the geometry of interest. Analysis shows that the developed method can simulate temperature behavior during storage process, but needs to be checked against other code to see calculation accuracy. Highest temperature distribution is observed when every hole is filled with waste containers. Sensitivity results on pre-cooling time shows that at least 13 months of cooling is necessary to keep the structure integrity.

  7. SPATIAL ANALYSIS TO SUPPORT GEOGRAPHIC TARGETING OF GENOTYPES TO ENVIRONMENTS

    Directory of Open Access Journals (Sweden)

    Glenn eHyman

    2013-03-01

    Full Text Available Crop improvement efforts have benefited greatly from advances in available data, computing technology and methods for targeting genotypes to environments. These advances support the analysis of genotype by environment interactions to understand how well a genotype adapts to environmental conditions. This paper reviews the use of spatial analysis to support crop improvement research aimed at matching genotypes to their most appropriate environmental niches. Better data sets are now available on soils, weather and climate, elevation, vegetation, crop distribution and local conditions where genotypes are tested in experimental trial sites. The improved data are now combined with spatial analysis methods to compare environmental conditions across sites, create agro-ecological region maps and assess environment change. Climate, elevation and vegetation data sets are now widely available, supporting analyses that were much more difficult even five or ten years ago. While detailed soil data for many parts of the world remains difficult to acquire for crop improvement studies, new advances in digital soil mapping are likely to improve our capacity. Site analysis and matching and regional targeting methods have advanced in parallel to data and technology improvements. All these developments have increased our capacity to link genotype to phenotype and point to a vast potential to improve crop adaptation efforts.

  8. [Prevalence of target organ damage and factors associated with cardiovascular events in subjects with refractory hypertension].

    Science.gov (United States)

    Armario, Pedro; Oliveras, Anna; Hernández Del Rey, Raquel; Poch, Esteban; Larrouse, María; Roca-Cusachs, Alex; de la Sierra, Alejandro

    2009-06-27

    To asses the prevalence of target organ damage (TOD) and factors associated with cardiovascular events in subjects with refractory hypertension. Cross-sectional study of 146 patients with clinical diagnosis of refractory hypertension. TOD was defined as the presence of microalbuminuria (MA), renal failure (RF), left ventricular hypertrophy (LVH) or left atrial enlargement (LAE). Cardiovascular events were defined as the antecedent of stroke, coronary heart disease, heart failure or peripheral arterial disease. 24-h ambulatory blood pressure monitoring was (ABPM) performed with a validated Spacelabs 90207. The prevalence of LVH was 62.3%, and LAE was observed in 27.7% of the subjects. The prevalence of RF was 28.1% and MA was found in 41,4%. An association between MA and LVH was observed. After adjusting by age, the urinary albumin excretion (UAE) correlated with clinical blood pressure (BP) and BP during 24-h ABPM, whereas LVMI correlated with ambulatory BP but not with clinical BP. The prevalence of previous cardiovascular events was 22% and in the multivariate regression analysis, UAE was the only independent factor associated with the antecedent of cardiovascular events. In subjects with refractory hypertension, the prevalence of TOD was high, and an association between heart and renal organ damage was observed. UAE was independently associated with the antecedent of cardiovascular disease.

  9. Tritium inventory of a target factor in an ICF power plant

    International Nuclear Information System (INIS)

    Sherohman, J.W.

    1981-01-01

    A preliminary parametric study has been performed to estimate the tritium inventory of a conjectured Target Factory. The inventory of a proposed tritiated fuel processing system was determined as a function of production efficiency, storage factor, and time interval for the slowest processing step. Results indicated that a study of this type will be beneficial in evaluating possible processing schemes for the production of tritiated laser fusion targets

  10. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    International Nuclear Information System (INIS)

    Ragnum, Harald Bull; Røe, Kathrine; Holm, Ruth; Vlatkovic, Ljiljana; Nesland, Jahn Marthin; Aarnes, Eva-Katrine; Ree, Anne Hansen; Flatmark, Kjersti; Seierstad, Therese; Lilleby, Wolfgang; Lyng, Heidi

    2013-01-01

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  11. Hypoxia-Independent Downregulation of Hypoxia-Inducible Factor 1 Targets by Androgen Deprivation Therapy in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ragnum, Harald Bull [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Røe, Kathrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Holm, Ruth; Vlatkovic, Ljiljana [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Nesland, Jahn Marthin [Department of Pathology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Aarnes, Eva-Katrine [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Ree, Anne Hansen [Division of Medicine, Department of Oncology, Akershus University Hospital, Lørenskog (Norway); Medical Faculty, University of Oslo, Oslo (Norway); Flatmark, Kjersti [Department of Tumor Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Department of Gastrointestinal Surgery, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Seierstad, Therese [Department of Radiology and Nuclear Medicine, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Faculty of Health Sciences, Buskerud University College, Drammen (Norway); Lilleby, Wolfgang [Department of Oncology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway); Lyng, Heidi, E-mail: heidi.lyng@rr-research.no [Department of Radiation Biology, The Norwegian Radium Hospital, Oslo University Hospital, Oslo (Norway)

    2013-11-15

    Purpose: We explored changes in hypoxia-inducible factor 1 (HIF1) signaling during androgen deprivation therapy (ADT) of androgen-sensitive prostate cancer xenografts under conditions in which no significant change in immunostaining of the hypoxia marker pimonidazole had occurred. Methods and Materials: Gene expression profiles of volume-matched androgen-exposed and androgen-deprived CWR22 xenografts, with similar pimonidazole-positive fractions, were compared. Direct targets of androgen receptor (AR) and HIF1 transcription factors were identified among the differentially expressed genes by using published lists. Biological processes affected by ADT were determined by gene ontology analysis. HIF1α protein expression in xenografts and biopsy samples from 35 patients receiving neoadjuvant ADT was assessed by immunohistochemistry. Results: A total of 1344 genes showed more than 2-fold change in expression by ADT, including 35 downregulated and 5 upregulated HIF1 targets. Six genes were shared HIF1 and AR targets, and their downregulation was confirmed with quantitative RT-PCR. Significant suppression of the biological processes proliferation, metabolism, and stress response in androgen-deprived xenografts was found, consistent with tumor regression. Nineteen downregulated HIF1 targets were involved in those significant biological processes, most of them in metabolism. Four of these were shared AR and HIF1 targets, including genes encoding the regulatory glycolytic proteins HK2, PFKFB3, and SLC2A1. Most of the downregulated HIF1 targets were induced by hypoxia in androgen-responsive prostate cancer cell lines, confirming their role as hypoxia-responsive HIF1 targets in prostate cancer. Downregulation of HIF1 targets was consistent with the absence of HIF1α protein in xenografts and downregulation in patients by ADT (P<.001). Conclusions: AR repression by ADT may lead to downregulation of HIF1 signaling independently of hypoxic fraction, and this may contribute to

  12. Analysis of technological, institutional and socioeconomic factors ...

    African Journals Online (AJOL)

    Analysis of technological, institutional and socioeconomic factors that influences poor reading culture among secondary school students in Nigeria. ... Proliferation and availability of smart phones, chatting culture and social media were identified as technological factors influencing poor reading culture among secondary ...

  13. TAL effectors: highly adaptable phytobacterial virulence factors and readily engineered DNA targeting proteins

    Science.gov (United States)

    Doyle, Erin L.; Stoddard, Barry L.; Voytas, Daniel F.; Bogdanove, Adam J.

    2013-01-01

    Transcription activator-like (TAL) effectors are transcription factors injected into plant cells by pathogenic bacteria in the genus Xanthomonas. They function as virulence factors by activating host genes important for disease, or as avirulence factors by turning on genes that provide resistance. DNA binding specificity is encoded by polymorphic repeats in each protein that correspond one-to-one with different nucleotides. This code has facilitated target identification and opened new avenues for engineering disease resistance. It has also enabled TAL effector customization for targeted gene control, genome editing, and other applications. This article reviews the structural basis for TAL effector-DNA specificity, the impact of the TAL effector-DNA code on plant pathology and engineered resistance, and recent accomplishments and future challenges in TAL effector-based DNA targeting. PMID:23707478

  14. Bioinformatic analysis of xenobiotic reactive metabolite target proteins and their interacting partners

    Directory of Open Access Journals (Sweden)

    Hanzlik Robert P

    2009-06-01

    Full Text Available Abstract Background Protein covalent binding by reactive metabolites of drugs, chemicals and natural products can lead to acute cytotoxicity. Recent rapid progress in reactive metabolite target protein identification has shown that adduction is surprisingly selective and inspired the hope that analysis of target proteins might reveal protein factors that differentiate target- vs. non-target proteins and illuminate mechanisms connecting covalent binding to cytotoxicity. Results Sorting 171 known reactive metabolite target proteins revealed a number of GO categories and KEGG pathways to be significantly enriched in targets, but in most cases the classes were too large, and the "percent coverage" too small, to allow meaningful conclusions about mechanisms of toxicity. However, a similar analysis of the directlyinteracting partners of 28 common targets of multiple reactive metabolites revealed highly significant enrichments in terms likely to be highly relevant to cytotoxicity (e.g., MAP kinase pathways, apoptosis, response to unfolded protein. Machine learning was used to rank the contribution of 211 computed protein features to determining protein susceptibility to adduction. Protein lysine (but not cysteine content and protein instability index (i.e., rate of turnover in vivo were among the features most important to determining susceptibility. Conclusion As yet there is no good explanation for why some low-abundance proteins become heavily adducted while some abundant proteins become only lightly adducted in vivo. Analyzing the directly interacting partners of target proteins appears to yield greater insight into mechanisms of toxicity than analyzing target proteins per se. The insights provided can readily be formulated as hypotheses to test in future experimental studies.

  15. Prediction methodologies for target scene generation in the aerothermal targets analysis program (ATAP)

    Science.gov (United States)

    Hudson, Douglas J.; Torres, Manuel; Dougherty, Catherine; Rajendran, Natesan; Thompson, Rhoe A.

    2003-09-01

    The Air Force Research Laboratory (AFRL) Aerothermal Targets Analysis Program (ATAP) is a user-friendly, engineering-level computational tool that features integrated aerodynamics, six-degree-of-freedom (6-DoF) trajectory/motion, convective and radiative heat transfer, and thermal/material response to provide an optimal blend of accuracy and speed for design and analysis applications. ATAP is sponsored by the Kinetic Kill Vehicle Hardware-in-the-Loop Simulator (KHILS) facility at Eglin AFB, where it is used with the CHAMP (Composite Hardbody and Missile Plume) technique for rapid infrared (IR) signature and imagery predictions. ATAP capabilities include an integrated 1-D conduction model for up to 5 in-depth material layers (with options for gaps/voids with radiative heat transfer), fin modeling, several surface ablation modeling options, a materials library with over 250 materials, options for user-defined materials, selectable/definable atmosphere and earth models, multiple trajectory options, and an array of aerodynamic prediction methods. All major code modeling features have been validated with ground-test data from wind tunnels, shock tubes, and ballistics ranges, and flight-test data for both U.S. and foreign strategic and theater systems. Numerous applications include the design and analysis of interceptors, booster and shroud configurations, window environments, tactical missiles, and reentry vehicles.

  16. Positioning accuracy analysis of adjusting target mechanism of three-dimensional attitude

    International Nuclear Information System (INIS)

    Ma Li; Wang Kun; Sun Linzhi; Zhou Shasha

    2012-01-01

    A novel adjusting target mechanism of three-dimensional attitude is presented according to the characteristics of the target transport subsystem in inertial confinement fusion (ICF). The mechanism consists of a tangent mechanism adjusting rotation angle and a set of orthogonal tangent mechanism adjusting two-dimensional deflection angles. The structural parameters of the adjusting target mechanism are analyzed according to principle errors, structure errors and motion errors of following. The analysis results indicate that the system error of the adjusting target mechanism is influenced by the displacement of the linear actuators, the actuator ball radius, the working radius of the tangent mechanism, the angle error of the inclined installation hole, the centralization error of the actuators, the orthogonal error of the two tangent mechanism, and the angle errors of the inclined target rod inclined rotation shaft. The errors of the inclined target rod and inclined rotation shaft are the two greatest impact factors, the spherical contact error is the next. By means of precise assembly and control system compensation, the accuracy of the adjusting target mechanism can be less than 0.1 mrad. (authors)

  17. Stakeholder analysis and mapping as targeted communication strategy.

    Science.gov (United States)

    Shirey, Maria R

    2012-09-01

    This department highlights change management strategies that may be successful in strategically planning and executing organizational change initiatives. With the goal of presenting practical approaches helpful to nurse leaders advancing organizational change, content includes evidence-based projects, tools, and resources that mobilize and sustain organizational change initiatives. In this article, the author highlights the importance of stakeholder theory and discusses how to apply the theory to conduct a stakeholder analysis. This article also provides an explanation of how to use related stakeholder mapping techniques with targeted communication strategies.

  18. Ideal MHD stability analysis of KSTAR target AT mode

    International Nuclear Information System (INIS)

    Yi, S.M.; Kim, J.H.; You, K.I.; Kim, J.Y.

    2009-01-01

    Full text: A main research objective of KSTAR (Korea Superconducting Tokamak Advanced Research) device is to demonstrate the steady-state operation capability of high-performance AT (Advanced Tokamak) mode. To meet this goal, it is critical for KSTAR to have a good MHD stability boundary, particularly against the high-beta ideal instabilities such as the external kink and the ballooning modes. To support this MHD stability KSTAR has been designed to have a strong plasma shape and a close interval between plasma and passive- plate wall. During the conceptual design phase of KSTAR, a preliminary study was performed to estimate the high beta MHD stability limit of KSTAR target AT mode using PEST and VACUUM codes and it was shown that the target AT mode can be stable up to β N ∼ 5 with a well-defined plasma pressure and current profiles. Recently, a new calculation has been performed to estimate the ideal stability limit in various KSTAR operating conditions using DCON code, and it has been observed that there is some difference between the new and old calculation results, particularly in the dependence of the maximum β N value on the toroidal mode number. Here, we thus present a more detailed analysis of the ideal MHD stability limit of KSTAR target AT mode using various codes, which include GATO as well as PEST and DCON, in the comparison of calculation results among the three codes. (author)

  19. The likelihood of achieving quantified road safety targets: a binary logistic regression model for possible factors.

    Science.gov (United States)

    Sze, N N; Wong, S C; Lee, C Y

    2014-12-01

    In past several decades, many countries have set quantified road safety targets to motivate transport authorities to develop systematic road safety strategies and measures and facilitate the achievement of continuous road safety improvement. Studies have been conducted to evaluate the association between the setting of quantified road safety targets and road fatality reduction, in both the short and long run, by comparing road fatalities before and after the implementation of a quantified road safety target. However, not much work has been done to evaluate whether the quantified road safety targets are actually achieved. In this study, we used a binary logistic regression model to examine the factors - including vehicle ownership, fatality rate, and national income, in addition to level of ambition and duration of target - that contribute to a target's success. We analyzed 55 quantified road safety targets set by 29 countries from 1981 to 2009, and the results indicate that targets that are in progress and with lower level of ambitions had a higher likelihood of eventually being achieved. Moreover, possible interaction effects on the association between level of ambition and the likelihood of success are also revealed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Integrating human factors into process hazard analysis

    International Nuclear Information System (INIS)

    Kariuki, S.G.; Loewe, K.

    2007-01-01

    A comprehensive process hazard analysis (PHA) needs to address human factors. This paper describes an approach that systematically identifies human error in process design and the human factors that influence its production and propagation. It is deductive in nature and therefore considers human error as a top event. The combinations of different factors that may lead to this top event are analysed. It is qualitative in nature and is used in combination with other PHA methods. The method has an advantage because it does not look at the operator error as the sole contributor to the human failure within a system but a combination of all underlying factors

  1. Nutritional status in the era of target therapy: poor nutrition is a prognostic factor in non-small cell lung cancer with activating epidermal growth factor receptor mutations.

    Science.gov (United States)

    Park, Sehhoon; Park, Seongyeol; Lee, Se-Hoon; Suh, Beomseok; Keam, Bhumsuk; Kim, Tae Min; Kim, Dong-Wan; Kim, Young Whan; Heo, Dae Seog

    2016-11-01

    Pretreatment nutritional status is an important prognostic factor in patients treated with conventional cytotoxic chemotherapy. In the era of target therapies, its value is overlooked and has not been investigated. The aim of our study is to evaluate the value of nutritional status in targeted therapy. A total of 2012 patients with non-small cell lung cancer (NSCLC) were reviewed and 630 patients with activating epidermal growth factor receptor (EGFR) mutation treated with EGFR tyrosine kinase inhibitor (TKI) were enrolled for the final analysis. Anemia, body mass index (BMI), and prognostic nutritional index (PNI) were considered as nutritional factors. Hazard ratio (HR), progression-free survival (PFS) and overall survival (OS) for each group were calculated by Cox proportional analysis. In addition, scores were applied for each category and the sum of scores was used for survival analysis. In univariable analysis, anemia (HR, 1.29; p = 0.015), BMI lower than 18.5 (HR, 1.98; p = 0.002), and PNI lower than 45 (HR, 1.57; p nutritional status is a prognostic marker in NSCLC patients treated with EGFR TKI. Hence, baseline nutritional status should be more carefully evaluated and adequate nutrition should be supplied to these patients.

  2. Cohort Analysis of a 24-Week Randomized Controlled Trial to Assess the Efficacy of a Novel, Partial Meal Replacement Program Targeting Weight Loss and Risk Factor Reduction in Overweight/Obese Adults.

    Science.gov (United States)

    Brindal, Emily; Hendrie, Gilly A; Taylor, Pennie; Freyne, Jill; Noakes, Manny

    2016-05-04

    Our aim was to design and evaluate a weight-loss program, including a partial meal replacement program, point-of-care testing and face-to-face and smartphone app support, appropriate for delivery in a community pharmacy setting. Overweight or obese adults (n = 146, 71.2% female, 48.18 ± 11.75 years old) were recruited to participate in a 24-week weight loss study and randomised to two app conditions. The dietary intervention was consistent regardless of app. Twelve weeks of clinic appointments with a trained consultant were followed by only app support for an additional 12 weeks. By week 24, retention was 57.5%. There were no differences between app conditions. Based on a cohort analysis of the trial, the mean decrease in weight from baseline to week 24 was 6.43 ± 1.06 kg for males (p < 0.001) and 5.66 ± 0.70 kg for females (p < 0.001). Mixed models also revealed decreases for LDL Cholesterol (-0.13 ± 0.08 mmol/L, nonsignificant), triglycerides (-0.08 ± 0.05 mmol/L, nonsignificant) and an increase in HDL cholesterol (+0.08 ± 0.04 mmol/L, ns) were not significant by week 24. Blood glucose (-0.23 ± 0.08 mmol/L, p = 0.040) and blood pressure (Systolic blood pressure -5.77 ± 1.21 Hg/mm, p < 0.001) were significantly lower at week 24 compared to baseline. Weight loss self-efficacy increased and remained significantly higher than baseline at week 24 (16.85 ± 2.93, p < 0.001). Overall, the program supported participants and was successful in achieving significant weight loss and improvements in health outcomes over 24 weeks.

  3. Global analysis of small molecule binding to related protein targets.

    Directory of Open Access Journals (Sweden)

    Felix A Kruger

    2012-01-01

    Full Text Available We report on the integration of pharmacological data and homology information for a large scale analysis of small molecule binding to related targets. Differences in small molecule binding have been assessed for curated pairs of human to rat orthologs and also for recently diverged human paralogs. Our analysis shows that in general, small molecule binding is conserved for pairs of human to rat orthologs. Using statistical tests, we identified a small number of cases where small molecule binding is different between human and rat, some of which had previously been reported in the literature. Knowledge of species specific pharmacology can be advantageous for drug discovery, where rats are frequently used as a model system. For human paralogs, we demonstrate a global correlation between sequence identity and the binding of small molecules with equivalent affinity. Our findings provide an initial general model relating small molecule binding and sequence divergence, containing the foundations for a general model to anticipate and predict within-target-family selectivity.

  4. Tumor necrosis factor alpha converting enzyme: an encouraging target for various inflammatory disorders.

    Science.gov (United States)

    Bahia, Malkeet S; Silakari, Om

    2010-05-01

    Tumor necrosis factor alpha is one of the most common pro-inflammatory cytokines responsible for various inflammatory disorders. It plays an important role in the origin and progression of rheumatoid arthritis and also in other autoimmune disease conditions. Some anti-tumor necrosis factor alpha antibodies like Enbrel, Humira and Remicade have been successfully used in these disease conditions as antagonists of tumor necrosis factor alpha. Inhibition of generation of active form of tumor necrosis factor alpha is a promising therapy for various inflammatory disorders. Therefore, the inhibition of an enzyme (tumor necrosis factor alpha converting enzyme), which is responsible for processing inactive form of tumor necrosis factor alpha into its active soluble form, is an encouraging target. Many tumor necrosis factor alpha converting enzyme inhibitors have been the candidates of clinical trials but none of them have reached in to the market because of their broad spectrum inhibitory activity for other matrix metalloproteases. Selectivity of tumor necrosis factor alpha converting enzyme inhibition over matrix metalloproteases is of utmost importance. If selectivity is achieved successfully, side-effects can be over-ruled and this approach may become a novel therapy for treatment of rheumatoid arthritis and other inflammatory disorders. This cytokine not only plays a pivotal role in inflammatory conditions but also in some cancerous conditions. Thus, successful targeting of tumor necrosis factor alpha converting enzyme may result in multifunctional therapy.

  5. Protein targeting in the analysis of learning and memory: a potential alternative to gene targeting.

    Science.gov (United States)

    Gerlai, R; Williams, S P; Cairns, B; Van Bruggen, N; Moran, P; Shih, A; Caras, I; Sauer, H; Phillips, H S; Winslow, J W

    1998-11-01

    Gene targeting using homologous recombination in embryonic stem (ES) cells offers unprecedented precision with which one may manipulate single genes and investigate the in vivo effects of defined mutations in the mouse. Geneticists argue that this technique abrogates the lack of highly specific pharmacological tools in the study of brain function and behavior. However, by now it has become clear that gene targeting has some limitations too. One problem is spatial and temporal specificity of the generated mutation, which may appear in multiple brain regions or even in other organs and may also be present throughout development, giving rise to complex, secondary phenotypical alterations. This may be a disadvantage in the functional analysis of a number of genes associated with learning and memory processes. For example, several proteins, including neurotrophins--cell-adhesion molecules--and protein kinases, that play a significant developmental role have recently been suggested to be also involved in neural and behavioral plasticity. Knocking out genes of such proteins may lead to developmental alterations or even embryonic lethality in the mouse, making it difficult to study their function in neural plasticity, learning, and memory. Therefore, alternative strategies to gene targeting may be needed. Here, we suggest a potentially useful in vivo strategy based on systemic application of immunoadhesins, genetically engineered fusion proteins possessing the Fc portion of the human IgG molecule and, for example, a binding domain of a receptor of interest. These proteins are stable in vivo and exhibit high binding specificity and affinity for the endogenous ligand of the receptor, but lack the ability to signal. Thus, if delivered to the brain, immunoadhesins may specifically block signalling of the receptor of interest. Using osmotic minipumps, the protein can be infused in a localized region of the brain for a specified period of time (days or weeks). Thus, the location

  6. Targeting Host Factors to Treat West Nile and Dengue Viral Infections

    Directory of Open Access Journals (Sweden)

    Manoj N. Krishnan

    2014-02-01

    Full Text Available West Nile (WNV and Dengue (DENV viruses are major arboviral human pathogens belonging to the genus Flavivirus. At the current time, there are no approved prophylactics (e.g., vaccines or specific therapeutics available to prevent or treat human infections by these pathogens. Due to their minimal genome, these viruses require many host molecules for their replication and this offers a therapeutic avenue wherein host factors can be exploited as treatment targets. Since several host factors appear to be shared by many flaviviruses the strategy may result in pan-flaviviral inhibitors and may also attenuate the rapid emergence of drug resistant mutant viruses. The scope of this strategy is greatly enhanced by the recent en masse identification of host factors impacting on WNV and DENV infection. Excellent proof-of-principle experimental demonstrations for host-targeted control of infection and infection-induced pathogenesis have been reported for both WNV and DENV. These include exploiting not only those host factors supporting infection, but also targeting host processes contributing to pathogenesis and innate immune responses. While these early studies validated the host-targeting approach, extensive future investigations spanning a range of aspects are needed for a successful deployment in humans.

  7. Targeting host factors to treat West Nile and dengue viral infections.

    Science.gov (United States)

    Krishnan, Manoj N; Garcia-Blanco, Mariano A

    2014-02-10

    West Nile (WNV) and Dengue (DENV) viruses are major arboviral human pathogens belonging to the genus Flavivirus. At the current time, there are no approved prophylactics (e.g., vaccines) or specific therapeutics available to prevent or treat human infections by these pathogens. Due to their minimal genome, these viruses require many host molecules for their replication and this offers a therapeutic avenue wherein host factors can be exploited as treatment targets. Since several host factors appear to be shared by many flaviviruses the strategy may result in pan-flaviviral inhibitors and may also attenuate the rapid emergence of drug resistant mutant viruses. The scope of this strategy is greatly enhanced by the recent en masse identification of host factors impacting on WNV and DENV infection. Excellent proof-of-principle experimental demonstrations for host-targeted control of infection and infection-induced pathogenesis have been reported for both WNV and DENV. These include exploiting not only those host factors supporting infection, but also targeting host processes contributing to pathogenesis and innate immune responses. While these early studies validated the host-targeting approach, extensive future investigations spanning a range of aspects are needed for a successful deployment in humans.

  8. Impact of metabolic, hemodynamic and inflammatory factors on target organ damage in healthy subjects

    DEFF Research Database (Denmark)

    Blicher, M.; Kruger, R.; Olesen, Thomas Bastholm

    2015-01-01

    Objective: We wanted to test the impact of metabolic, hemodynamic and inflammatory factors on target organ damage (TOD) defined as cardiac hypertrophy, atherosclerosis, arterioclerosis and microvascular damage. Design and method: In a population based cohort study of 2115 healthy subjects (1049...... associated to hypertrophy, arteriosclerosis and microvascular damage in healthy subjects....

  9. Targeting Family Risk Factors in the Context of Treating Youth Depression: A Survey of Psychologists

    Science.gov (United States)

    Parra, Gilbert R.; Buckholdt, Kelly E.; Olsen, James P.; Jobe-Shields, Lisa; Davis, Genevieve L.; Gamble, Heather L.

    2011-01-01

    This study investigated the practices and perceptions of psychologists related to targeting family risk factors when treating youth depression. Participants were practicing psychologists recruited through the National Register of Health Service Providers in Psychology (N = 279). Psychologists completed a brief anonymous survey about addressing…

  10. Targeting School Factors that Contribute to Youth Alienation: Focused School Counseling Programs

    Science.gov (United States)

    Schulz, Lisa L.

    2011-01-01

    This article explores students at risk of academic non-completion. Schools and school counselors need to target the factors which put students at risk of academic non-completion to reduce the number of adolescents feeling a sense of alienation from school, from educators, and from learning. The construct of student alienation is examined based on…

  11. A single gene target of an ETS-family transcription factor determines neuronal CO2-chemosensitivity

    DEFF Research Database (Denmark)

    Brandt, Julia P; Aziz-Zaman, Sonya; Juozaityte, Vaida

    2012-01-01

    . We report here a mechanism that endows C. elegans neurons with the ability to detect CO(2). The ETS-5 transcription factor is necessary for the specification of CO(2)-sensing BAG neurons. Expression of a single ETS-5 target gene, gcy-9, which encodes a receptor-type guanylate cyclase, is sufficient...

  12. Identifying influential factors of business process performance using dependency analysis

    Science.gov (United States)

    Wetzstein, Branimir; Leitner, Philipp; Rosenberg, Florian; Dustdar, Schahram; Leymann, Frank

    2011-02-01

    We present a comprehensive framework for identifying influential factors of business process performance. In particular, our approach combines monitoring of process events and Quality of Service (QoS) measurements with dependency analysis to effectively identify influential factors. The framework uses data mining techniques to construct tree structures to represent dependencies of a key performance indicator (KPI) on process and QoS metrics. These dependency trees allow business analysts to determine how process KPIs depend on lower-level process metrics and QoS characteristics of the IT infrastructure. The structure of the dependencies enables a drill-down analysis of single factors of influence to gain a deeper knowledge why certain KPI targets are not met.

  13. Extending in silico mechanism-of-action analysis by annotating targets with pathways: application to cellular cytotoxicity readouts.

    Science.gov (United States)

    Liggi, Sonia; Drakakis, Georgios; Koutsoukas, Alexios; Cortes-Ciriano, Isidro; Martínez-Alonso, Patricia; Malliavin, Thérèse E; Velazquez-Campoy, Adrian; Brewerton, Suzanne C; Bodkin, Michael J; Evans, David A; Glen, Robert C; Carrodeguas, José Alberto; Bender, Andreas

    2014-01-01

    An in silico mechanism-of-action analysis protocol was developed, comprising molecule bioactivity profiling, annotation of predicted targets with pathways and calculation of enrichment factors to highlight targets and pathways more likely to be implicated in the studied phenotype. The method was applied to a cytotoxicity phenotypic endpoint, with enriched targets/pathways found to be statistically significant when compared with 100 random datasets. Application on a smaller apoptotic set (10 molecules) did not allowed to obtain statistically relevant results, suggesting that the protocol requires modification such as analysis of the most frequently predicted targets/annotated pathways. Pathway annotations improved the mechanism-of-action information gained by target prediction alone, allowing a better interpretation of the predictions and providing better mapping of targets onto pathways.

  14. Design and characteristics of cytotoxic fibroblast growth factor 1 conjugate for fibroblast growth factor receptor-targeted cancer therapy

    Directory of Open Access Journals (Sweden)

    Szlachcic A

    2016-08-01

    Full Text Available Anna Szlachcic, Malgorzata Zakrzewska, Michal Lobocki, Piotr Jakimowicz, Jacek Otlewski Department of Protein Engineering, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland Abstract: Fibroblast growth factor receptors (FGFRs are attractive candidate cancer therapy targets as they are overexpressed in multiple types of tumors, such as breast, prostate, bladder, and lung cancer. In this study, a natural ligand of FGFR, an engineered variant of fibroblast growth factor 1 (FGF1V, was conjugated to a potent cytotoxic drug, monomethyl auristatin E (MMAE, and used as a targeting agent for cancer cells overexpressing FGFRs, similar to antibodies in antibody–drug conjugates. The FGF1V–valine–citrulline–MMAE conjugate showed a favorable stability profile, bound FGFRs on the cell surface specifically, and efficiently released the drug (MMAE upon cleavage by the lysosomal protease cathepsin B. Importantly, the conjugate showed a prominent cytotoxic effect toward cell lines expressing FGFR. FGF1V–vcMMAE was highly cytotoxic at concentrations even an order of magnitude lower than those found for free MMAE. This effect was FGFR-specific as cells lacking FGFR did not show any increased mortality. Keywords: fibroblast growth factor 1, FGF receptor, targeted cancer therapy, cytotoxic conjugates, FGFR-dependent cancer, MMAE, auristatin

  15. Study on safety educations against individual causal factors of unsafe acts and specification of target trainees

    International Nuclear Information System (INIS)

    Hirose, Ayako; Takeda, Daisuke

    2016-01-01

    Many accidents and incidents are caused by unsafe acts. It is important to reduce these unsafe acts for preventing the accidents. The countermeasures for each causal factor behind unsafe acts are needed, however, comparing with improvement of facilities, workers-oriented measures such as safety educations are not sufficient. Then the purposes of this study are as follows: 1) to investigate the individual factors which have great impact of unsafe acts and the existing safety educations which aim to mitigate the impact of these factors, 2) to specify the target trainees to perform these safety educations. To identify common factors that affect unsafe act significantly, a web survey was conducted to 500 workers who have regularly carried out accident prediction training (i.e. Kiken-Yochi training). They were asked the situation which they were apt to act unsafely by free description. As the result, the following three main factors were extracted: impatience, overconfidence, and bothersome. Also, it was found that there were few existing safety educations which aim to mitigate the impact of these factors except for overconfidence. To specify the target trainees to perform safety educations which aim to mitigate the impact of these three factors, another web survey was conducted to 200 personnel in charge of safety at the workplace. They were asked the features of workers who tended to act unsafely by age group. The relationship between the factor that need to mitigate and the trainee who need to receive the education were clarified from the survey. (author)

  16. Analysis of Economic Factors Affecting Stock Market

    OpenAIRE

    Xie, Linyin

    2010-01-01

    This dissertation concentrates on analysis of economic factors affecting Chinese stock market through examining relationship between stock market index and economic factors. Six economic variables are examined: industrial production, money supply 1, money supply 2, exchange rate, long-term government bond yield and real estate total value. Stock market comprises fixed interest stocks and equities shares. In this dissertation, stock market is restricted to equity market. The stock price in thi...

  17. Challenges in thermal and hydraulic analysis of ADS target systems

    International Nuclear Information System (INIS)

    Groetzbach, G.; Batta, A.; Lefhalm, C.-H.; Otic, I.

    2004-01-01

    The liquid metal cooled spallation targets of Accelerator Driven nuclear reactor Systems obey high thermal loads; in addition some flow and cooling conditions are of a prototypical character; in contrast the operating conditions for the engaged materials are narrow; thus, the target development requires a very careful analysis by experimental and numerical means. Especially the cooling of the steel window, which is heated by the proton beam, needs special care. Some of the main goals of the experimental and numerical analyses of the thermal dynamics of those systems are discusses. The prediction of locally detached flows and of flows with larger recirculation areas suffers from insufficient turbulence modeling; this has to be compensated by using prototypical model experiments, e.g. with water, to select the adequate models and numerical schemes. The well known problems with the Reynolds analogy in predicting the heat transfer in liquid metals requires always prototypic liquid metal experiments to select and adapt the turbulent heat flux models. The uncertainties in liquid metal experiments cannot be neglected; so it is necessary to perform CFD calculations and experiments always hand in hand and to develop improve turbulent heat flux models. One contribution to an improved 3 or 4-equation model is deduced from recent Direct Numerical Simulation (DNS) data. (author)

  18. SeedVicious: Analysis of microRNA target and near-target sites.

    Science.gov (United States)

    Marco, Antonio

    2018-01-01

    Here I describe seedVicious, a versatile microRNA target site prediction software that can be easily fitted into annotation pipelines and run over custom datasets. SeedVicious finds microRNA canonical sites plus other, less efficient, target sites. Among other novel features, seedVicious can compute evolutionary gains/losses of target sites using maximum parsimony, and also detect near-target sites, which have one nucleotide different from a canonical site. Near-target sites are important to study population variation in microRNA regulation. Some analyses suggest that near-target sites may also be functional sites, although there is no conclusive evidence for that, and they may actually be target alleles segregating in a population. SeedVicious does not aim to outperform but to complement existing microRNA prediction tools. For instance, the precision of TargetScan is almost doubled (from 11% to ~20%) when we filter predictions by the distance between target sites using this program. Interestingly, two adjacent canonical target sites are more likely to be present in bona fide target transcripts than pairs of target sites at slightly longer distances. The software is written in Perl and runs on 64-bit Unix computers (Linux and MacOS X). Users with no computing experience can also run the program in a dedicated web-server by uploading custom data, or browse pre-computed predictions. SeedVicious and its associated web-server and database (SeedBank) are distributed under the GPL/GNU license.

  19. Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer

    Science.gov (United States)

    Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T.

    2018-01-01

    Introduction Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted. PMID:28271910

  20. Early clinical development of epidermal growth factor receptor targeted therapy in breast cancer.

    Science.gov (United States)

    Matsuda, Naoko; Lim, Bora; Wang, Xiaoping; Ueno, Naoto T

    2017-04-01

    Epidermal growth factor receptor (EGFR) targeted treatment has been evaluated but has not shown a clear clinical benefit for breast cancer. This review article aims to consider the knowledge of the biological background of EGFR pathways in dissecting clinical studies of EGFR targeted treatment in breast cancer. Areas covered: This review focuses on the role of the EGFR pathway and the investigational drugs that target EGFR for breast cancer. Expert opinion: Recent studies have indicated that EGFR targeted therapy for breast cancer has some promising effects for patients with triple-negative breast cancer, basal-like breast cancer, and inflammatory breast cancer. However, predictive and prognostic biomarkers for EGFR targeted therapy have not been identified. The overexpression or amplification of EGFR itself may not be the true factor of induction of the canonical pathway as an oncogenic driver of breast cancer. Instead, downstream, non-canonical pathways related to EGFR may contribute to some aspects of the biological behavior of breast cancer; therefore, the blockade of the receptor could result in sufficient suppression of downstream pathways to inhibit the aggressive behavior of breast cancer. Mechanistic studies to investigate the dynamic interaction between the EGFR pathway and non-canonical pathways are warranted.

  1. In-depth resistome analysis by targeted metagenomics.

    Science.gov (United States)

    Lanza, Val F; Baquero, Fernando; Martínez, José Luís; Ramos-Ruíz, Ricardo; González-Zorn, Bruno; Andremont, Antoine; Sánchez-Valenzuela, Antonio; Ehrlich, Stanislav Dusko; Kennedy, Sean; Ruppé, Etienne; van Schaik, Willem; Willems, Rob J; de la Cruz, Fernando; Coque, Teresa M

    2018-01-15

    Antimicrobial resistance is a major global health challenge. Metagenomics allows analyzing the presence and dynamics of "resistomes" (the ensemble of genes encoding antimicrobial resistance in a given microbiome) in disparate microbial ecosystems. However, the low sensitivity and specificity of available metagenomic methods preclude the detection of minority populations (often present below their detection threshold) and/or the identification of allelic variants that differ in the resulting phenotype. Here, we describe a novel strategy that combines targeted metagenomics using last generation in-solution capture platforms, with novel bioinformatics tools to establish a standardized framework that allows both quantitative and qualitative analyses of resistomes. We developed ResCap, a targeted sequence capture platform based on SeqCapEZ (NimbleGene) technology, which includes probes for 8667 canonical resistance genes (7963 antibiotic resistance genes and 704 genes conferring resistance to metals or biocides), and 2517 relaxase genes (plasmid markers) and 78,600 genes homologous to the previous identified targets (47,806 for antibiotics and 30,794 for biocides or metals). Its performance was compared with metagenomic shotgun sequencing (MSS) for 17 fecal samples (9 humans, 8 swine). ResCap significantly improves MSS to detect "gene abundance" (from 2.0 to 83.2%) and "gene diversity" (26 versus 14.9 genes unequivocally detected per sample per million of reads; the number of reads unequivocally mapped increasing up to 300-fold by using ResCap), which were calculated using novel bioinformatic tools. ResCap also facilitated the analysis of novel genes potentially involved in the resistance to antibiotics, metals, biocides, or any combination thereof. ResCap, the first targeted sequence capture, specifically developed to analyze resistomes, greatly enhances the sensitivity and specificity of available metagenomic methods and offers the possibility to analyze genes

  2. Histone Deacetylase Rpd3 Regulates Olfactory Projection Neuron Dendrite Targeting via the Transcription Factor Prospero

    Science.gov (United States)

    Tea, Joy S.; Chihara, Takahiro; Luo, Liqun

    2010-01-01

    Compared to the mechanisms of axon guidance, relatively little is known about the transcriptional control of dendrite guidance. The Drosophila olfactory system with its stereotyped organization provides an excellent model to study the transcriptional control of dendrite wiring specificity. Each projection neuron (PN) targets its dendrites to a specific glomerulus in the antennal lobe and its axon stereotypically to higher brain centers. Using a forward genetic screen, we identified a mutation in Rpd3 that disrupts PN targeting specificity. Rpd3 encodes a class I histone deacetylase (HDAC) homologous to mammalian HDAC1 and HDAC2. Rpd3−/− PN dendrites that normally target to a dorsolateral glomerulus mistarget to medial glomeruli in the antennal lobe, and axons exhibit a severe overbranching phenotype. These phenotypes can be rescued by postmitotic expression of Rpd3 but not HDAC3, the only other class I HDAC in Drosophila. Furthermore, disruption of the atypical homeodomain transcription factor Prospero (Pros) yields similar phenotypes, which can be rescued by Pros expression in postmitotic neurons. Strikingly, overexpression of Pros can suppress Rpd3−/− phenotypes. Our study suggests a specific function for the general chromatin remodeling factor Rpd3 in regulating dendrite targeting in neurons, largely through the postmitotic action of the Pros transcription factor. PMID:20660276

  3. Targeting Insulin-Like Growth Factor 1 Receptor Inhibits Pancreatic Cancer Growth and Metastasis

    Science.gov (United States)

    Subramani, Ramadevi; Lopez-Valdez, Rebecca; Arumugam, Arunkumar; Nandy, Sushmita; Boopalan, Thiyagarajan; Lakshmanaswamy, Rajkumar

    2014-01-01

    Pancreatic cancer is one of the most lethal cancers. Increasing incidence and mortality indicates that there is still much lacking in detection and management of the disease. This is partly due to a lack of specific symptoms during early stages of the disease. Several growth factor receptors have been associated with pancreatic cancer. Here, we have investigated if an RNA interference approach targeted to IGF-IR could be effective and efficient against pancreatic cancer growth and metastasis. For that, we evaluated the effects of IGF-1R inhibition using small interfering RNA (siRNAs) on tumor growth and metastasis in HPAC and PANC-1 pancreatic cancer cell lines. We found that silencing IGF-1R inhibits pancreatic cancer growth and metastasis by blocking key signaling pathways such AKT/PI3K, MAPK, JAK/STAT and EMT. Silencing IGF-1R resulted in an anti-proliferative effect in PANC-1 and HPAC pancreatic cancer cell lines. Matrigel invasion, transwell migration and wound healing assays also revealed a role for IGF-1R in metastatic properties of pancreatic cancer. These results were further confirmed using Western blotting analysis of key intermediates involved in proliferation, epithelial mesenchymal transition, migration, and invasion. In addition, soft agar assays showed that silencing IGF-1R also blocks the colony forming capabilities of pancreatic cancer cells in vitro. Western blots, as well as, flow cytometric analysis revealed the induction of apoptosis in IGF-1R silenced cells. Interestingly, silencing IGF-1R also suppressed the expression of insulin receptor β. All these effects together significantly control pancreatic cancer cell growth and metastasis. To conclude, our results demonstrate the significance of IGF-1R in pancreatic cancer. PMID:24809702

  4. National Climate Policies: Aiming at the Factor 4 Target by 2050?

    International Nuclear Information System (INIS)

    Godard, Olivier

    2016-01-01

    The paper considers how the governments of midsize developed countries could define national strategies to control greenhouse gas emissions, assuming that such strategies are the product of cognitive and ethical choices relating to global climate scenarios and the rule for allocating shares of expected global climate damage to individual States. After evaluating the carbon value linked to each cognitive-ethical configuration, I identify the configurations that justify the target of dividing national emissions by 4 between 1990 and 2050 - a goal known as 'Factor 4'. Lastly, I examine the resulting constraints on the shape of the control trajectory leading to that target

  5. Construction of a mouse model of factor VIII deficiency by gene targeting

    Energy Technology Data Exchange (ETDEWEB)

    Bi, L.; Lawler, A.; Gearhart, J. [Univ. of Pennsylvania School of Medicine, Philadelphia, PA (United States)] [and others

    1994-09-01

    To develop a small animal model of hemophilia A for gene therapy experiments, we set out to construct a mouse model for factor VIII deficiency by gene targeting. First, we screened a mouse liver cDNA library using a human FVIII cDNA probe. We cloned a 2.6 Kb partial mouse factor VIII cDNA which extends from 800 base pairs of the 3{prime} end of exon 14 to the 5{prime} end of exon 26. A mouse genomic library made from strain 129 was then screened to obtain genomic fragments covering the exons desired for homologous recombination. Two genomic clones were obtained, and one covering exon 15 through 22 was used for gene targeting. To make gene targeting constructs, a 5.8 Kb genomic DNA fragment covering exons 15 to 19 of the mouse FVIII gene was subcloned, and the neo expression cassette was inserted into exons 16 and 17 separately by different strategies. These two constructs were named MFVIIIC-16 and MFVIIIC-17. The constructs were linearized and transfected into strain 129 mouse ES cells by electroporation. Factor VIII gene-knockout ES cell lines were selected by G-418 and screened by genomic Southern blots. Eight exon 16 targeted cell lines and five exon 17 targeted cell lines were obtained. Three cell lines from each construct were injected into blastocysts and surgically transferred into foster mothers. Multiple chimeric mice with 70-90% hair color derived from the ES-cell genotype were seen with both constructs. Germ line transmission of the ES-cell genotype has been obtained for the MFVIIIC-16 construct, and multiple hemophilia A carrier females have been identified. Factor VIII-deficient males will be conceived soon.

  6. Factor Economic Analysis at Forestry Enterprises

    Directory of Open Access Journals (Sweden)

    M.Yu. Chik

    2018-03-01

    Full Text Available The article studies the importance of economic analysis according to the results of research of scientific works of domestic and foreign scientists. The calculation of the influence of factors on the change in the cost of harvesting timber products by cost items has been performed. The results of the calculation of the influence of factors on the change of costs on 1 UAH are determined using the full cost of sold products. The variable and fixed costs and their distribution are allocated that influences the calculation of the impact of factors on cost changes on 1 UAH of sold products. The paper singles out the general results of calculating the influence of factors on cost changes on 1 UAH of sold products. According to the results of the analysis, the list of reserves for reducing the cost of production at forest enterprises was proposed. The main sources of reserves for reducing the prime cost of forest products at forest enterprises are investigated based on the conducted factor analysis.

  7. Transcription profile of Escherichia coli: genomic SELEX search for regulatory targets of transcription factors.

    Science.gov (United States)

    Ishihama, Akira; Shimada, Tomohiro; Yamazaki, Yukiko

    2016-03-18

    Bacterial genomes are transcribed by DNA-dependent RNA polymerase (RNAP), which achieves gene selectivity through interaction with sigma factors that recognize promoters, and transcription factors (TFs) that control the activity and specificity of RNAP holoenzyme. To understand the molecular mechanisms of transcriptional regulation, the identification of regulatory targets is needed for all these factors. We then performed genomic SELEX screenings of targets under the control of each sigma factor and each TF. Here we describe the assembly of 156 SELEX patterns of a total of 116 TFs performed in the presence and absence of effector ligands. The results reveal several novel concepts: (i) each TF regulates more targets than hitherto recognized; (ii) each promoter is regulated by more TFs than hitherto recognized; and (iii) the binding sites of some TFs are located within operons and even inside open reading frames. The binding sites of a set of global regulators, including cAMP receptor protein, LeuO and Lrp, overlap with those of the silencer H-NS, suggesting that certain global regulators play an anti-silencing role. To facilitate sharing of these accumulated SELEX datasets with the research community, we compiled a database, 'Transcription Profile of Escherichia coli' (www.shigen.nig.ac.jp/ecoli/tec/). © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  8. An SPSSR -Menu for Ordinal Factor Analysis

    Directory of Open Access Journals (Sweden)

    Mario Basto

    2012-01-01

    Full Text Available Exploratory factor analysis is a widely used statistical technique in the social sciences. It attempts to identify underlying factors that explain the pattern of correlations within a set of observed variables. A statistical software package is needed to perform the calculations. However, there are some limitations with popular statistical software packages, like SPSS. The R programming language is a free software package for statistical and graphical computing. It offers many packages written by contributors from all over the world and programming resources that allow it to overcome the dialog limitations of SPSS. This paper offers an SPSS dialog written in theR programming language with the help of some packages, so that researchers with little or no knowledge in programming, or those who are accustomed to making their calculations based on statistical dialogs, have more options when applying factor analysis to their data and hence can adopt a better approach when dealing with ordinal, Likert-type data.

  9. Capital Cost Optimization for Prefabrication: A Factor Analysis Evaluation Model

    Directory of Open Access Journals (Sweden)

    Hong Xue

    2018-01-01

    Full Text Available High capital cost is a significant hindrance to the promotion of prefabrication. In order to optimize cost management and reduce capital cost, this study aims to explore the latent factors and factor analysis evaluation model. Semi-structured interviews were conducted to explore potential variables and then questionnaire survey was employed to collect professionals’ views on their effects. After data collection, exploratory factor analysis was adopted to explore the latent factors. Seven latent factors were identified, including “Management Index”, “Construction Dissipation Index”, “Productivity Index”, “Design Efficiency Index”, “Transport Dissipation Index”, “Material increment Index” and “Depreciation amortization Index”. With these latent factors, a factor analysis evaluation model (FAEM, divided into factor analysis model (FAM and comprehensive evaluation model (CEM, was established. The FAM was used to explore the effect of observed variables on the high capital cost of prefabrication, while the CEM was used to evaluate comprehensive cost management level on prefabrication projects. Case studies were conducted to verify the models. The results revealed that collaborative management had a positive effect on capital cost of prefabrication. Material increment costs and labor costs had significant impacts on production cost. This study demonstrated the potential of on-site management and standardization design to reduce capital cost. Hence, collaborative management is necessary for cost management of prefabrication. Innovation and detailed design were needed to improve cost performance. The new form of precast component factories can be explored to reduce transportation cost. Meanwhile, targeted strategies can be adopted for different prefabrication projects. The findings optimized the capital cost and improved the cost performance through providing an evaluation and optimization model, which helps managers to

  10. Growth factor receptors as molecular targets for cancer diagnosis and therapy

    International Nuclear Information System (INIS)

    Zalutsky, M. R.

    1997-01-01

    Growth factor receptors are of great interest as molecular targets for the diagnosis and treatment of cancer. Growth factor receptors are frequently over expressed on malignant cell populations since many cellular oncogenes encode either growth factors of their receptors. The wild-type epidermal growth factor receptor has a molecular weight of 170 kD and is over expressed on gliomas, bladder tumors, squamous cells carcinomas and breast carcinomas. Another growth factor oncogene, c-erb B-2, encodes a 185-kD glycoprotein found on the surface of gliomas, breast and ovarian cancers as well as other carcinomas of epithelial origin. In addition to causing over expression, oncogenic transformation also can result in genomic re-arrangements. An important example from the perspective of targeting is EGFRvIII, a deletion mutant which lacks amino acids 6-273 in the extracellular domain of the epiderma growth factor receptor. The EGFRvIII molecule (145 kD) may be of great value for targeting because it appears to be tumor-specific. Antibodies have been developed with specific reactivity with these growth factor receptors. Since these antibodies are internalized into the cell after receptor binding, it is necessary to use radiolabeling methods which residualize the radioactivity in the tumor cell after intracellular catabolism. To investigate this problem they have evaluated the effect of radioiodination method on the in vitro an in vivo properties of an anti-EGFRvIII antibody. Methods studied were Iodogen, tyramine-cellobiose, and N-succinimidyl 5-iodo-3-pyridine-carboxylate with the last offering optimal localization in a human xenograft model

  11. ANALYSIS OF THE FACTORS AFFECTING THE AVERAGE

    Directory of Open Access Journals (Sweden)

    Carmen BOGHEAN

    2013-12-01

    Full Text Available Productivity in agriculture most relevantly and concisely expresses the economic efficiency of using the factors of production. Labour productivity is affected by a considerable number of variables (including the relationship system and interdependence between factors, which differ in each economic sector and influence it, giving rise to a series of technical, economic and organizational idiosyncrasies. The purpose of this paper is to analyse the underlying factors of the average work productivity in agriculture, forestry and fishing. The analysis will take into account the data concerning the economically active population and the gross added value in agriculture, forestry and fishing in Romania during 2008-2011. The distribution of the average work productivity per factors affecting it is conducted by means of the u-substitution method.

  12. Structure-mechanism-based engineering of chemical regulators targeting distinct pathological factors in Alzheimer's disease.

    Science.gov (United States)

    Beck, Michael W; Derrick, Jeffrey S; Kerr, Richard A; Oh, Shin Bi; Cho, Woo Jong; Lee, Shin Jung C; Ji, Yonghwan; Han, Jiyeon; Tehrani, Zahra Aliakbar; Suh, Nayoung; Kim, Sujeong; Larsen, Scott D; Kim, Kwang S; Lee, Joo-Yong; Ruotolo, Brandon T; Lim, Mi Hee

    2016-10-13

    The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal-Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.

  13. An Adenovirus DNA Replication Factor, but Not Incoming Genome Complexes, Targets PML Nuclear Bodies.

    Science.gov (United States)

    Komatsu, Tetsuro; Nagata, Kyosuke; Wodrich, Harald

    2016-02-01

    Promyelocytic leukemia protein nuclear bodies (PML-NBs) are subnuclear domains implicated in cellular antiviral responses. Despite the antiviral activity, several nuclear replicating DNA viruses use the domains as deposition sites for the incoming viral genomes and/or as sites for viral DNA replication, suggesting that PML-NBs are functionally relevant during early viral infection to establish productive replication. Although PML-NBs and their components have also been implicated in the adenoviral life cycle, it remains unclear whether incoming adenoviral genome complexes target PML-NBs. Here we show using immunofluorescence and live-cell imaging analyses that incoming adenovirus genome complexes neither localize at nor recruit components of PML-NBs during early phases of infection. We further show that the viral DNA binding protein (DBP), an early expressed viral gene and essential DNA replication factor, independently targets PML-NBs. We show that DBP oligomerization is required to selectively recruit the PML-NB components Sp100 and USP7. Depletion experiments suggest that the absence of one PML-NB component might not affect the recruitment of other components toward DBP oligomers. Thus, our findings suggest a model in which an adenoviral DNA replication factor, but not incoming viral genome complexes, targets and modulates PML-NBs to support a conducive state for viral DNA replication and argue against a generalized concept that PML-NBs target incoming viral genomes. The immediate fate upon nuclear delivery of genomes of incoming DNA viruses is largely unclear. Early reports suggested that incoming genomes of herpesviruses are targeted and repressed by PML-NBs immediately upon nuclear import. Genome localization and/or viral DNA replication has also been observed at PML-NBs for other DNA viruses. Thus, it was suggested that PML-NBs may immediately sense and target nuclear viral genomes and hence serve as sites for deposition of incoming viral genomes and

  14. Nominal Performance Biosphere Dose Conversion Factor Analysis

    International Nuclear Information System (INIS)

    M. Wasiolek

    2004-01-01

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the Total System Performance Assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the groundwater exposure scenario, and the development of conversion factors for assessing compliance with the groundwater protection standard. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop biosphere BDCFs, which are input parameters for the TSPA-LA model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the ''Biosphere Model Report'' in Figure 1-1, contain detailed description of the model input parameters, their development, and the relationship between the parameters and specific features events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the groundwater exposure scenario. The objectives of this analysis are to develop BDCFs for the groundwater exposure scenario for the three climate states considered in the TSPA-LA as well as conversion factors for evaluating compliance with the groundwater protection standard. The BDCFs will be used in performance assessment for calculating all-pathway annual doses for a given concentration of radionuclides in groundwater. The conversion factors will be used for calculating gross alpha particle activity in groundwater and the annual dose

  15. Worry About Caregiving Performance: A Confirmatory Factor Analysis

    Directory of Open Access Journals (Sweden)

    Ruijie Li

    2018-03-01

    Full Text Available Recent studies on the Zarit Burden Interview (ZBI support the existence of a unique factor, worry about caregiving performance (WaP, beyond role and personal strain. Our current study aims to confirm the existence of WaP within the multidimensionality of ZBI and to determine if predictors of WaP differ from the role and personal strain. We performed confirmatory factor analysis (CFA on 466 caregiver-patient dyads to compare between one-factor (total score, two-factor (role/personal strain, three-factor (role/personal strain and WaP, and four-factor models (role strain split into two factors. We conducted linear regression analyses to explore the relationships between different ZBI factors with socio-demographic and disease characteristics, and investigated the stage-dependent differences between WaP with role and personal strain by dyadic relationship. The four-factor structure that incorporated WaP and split role strain into two factors yielded the best fit. Linear regression analyses reveal that different variables significantly predict WaP (adult child caregiver and Neuropsychiatric Inventory Questionnaire (NPI-Q severity from role/personal strain (adult child caregiver, instrumental activities of daily living, and NPI-Q distress. Unlike other factors, WaP was significantly endorsed in early cognitive impairment. Among spouses, WaP remained low across Clinical Dementia Rating (CDR stages until a sharp rise in CDR 3; adult child and sibling caregivers experience a gradual rise throughout the stages. Our results affirm the existence of WaP as a unique factor. Future research should explore the potential of WaP as a possible intervention target to improve self-efficacy in the milder stages of burden.

  16. Factor analysis for exercise stress radionuclide ventriculography

    International Nuclear Information System (INIS)

    Hirota, Kazuyoshi; Yasuda, Mitsutaka; Oku, Hisao; Ikuno, Yoshiyasu; Takeuchi, Kazuhide; Takeda, Tadanao; Ochi, Hironobu

    1987-01-01

    Using factor analysis, a new image processing in exercise stress radionuclide ventriculography, changes in factors associated with exercise were evaluated in 14 patients with angina pectoris or old myocardial infarction. The patients were imaged in the left anterior oblique projection, and three factor images were presented on a color coded scale. Abnormal factors (AF) were observed in 6 patients before exercise, 13 during exercise, and 4 after exercise. In 7 patients, the occurrence of AF was associated with exercise. Five of them became free from AF after exercise. Three patients showing AF before exercise had aggravation of AF during exercise. Overall, the occurrence or aggravation of AF was associated with exercise in ten (71 %) of the patients. The other three patients, however, had disappearance of AF during exercise. In the last patient, none of the AF was observed throughout the study. In view of a high incidence of AF associated with exercise, the factor analysis may have the potential in evaluating cardiac reverse from the viewpoint of left ventricular wall motion abnormality. (Namekawa, K.)

  17. Targeting Epidermal Growth Factor Receptor-Related Signaling Pathways in Pancreatic Cancer.

    Science.gov (United States)

    Philip, Philip A; Lutz, Manfred P

    2015-10-01

    Pancreatic cancer is aggressive, chemoresistant, and characterized by complex and poorly understood molecular biology. The epidermal growth factor receptor (EGFR) pathway is frequently activated in pancreatic cancer; therefore, it is a rational target for new treatments. However, the EGFR tyrosine kinase inhibitor erlotinib is currently the only targeted therapy to demonstrate a very modest survival benefit when added to gemcitabine in the treatment of patients with advanced pancreatic cancer. There is no molecular biomarker to predict the outcome of erlotinib treatment, although rash may be predictive of improved survival; EGFR expression does not predict the biologic activity of anti-EGFR drugs in pancreatic cancer, and no EGFR mutations are identified as enabling the selection of patients likely to benefit from treatment. Here, we review clinical studies of EGFR-targeted therapies in combination with conventional cytotoxic regimens or multitargeted strategies in advanced pancreatic cancer, as well as research directed at molecules downstream of EGFR as alternatives or adjuncts to receptor targeting. Limitations of preclinical models, patient selection, and trial design, as well as the complex mechanisms underlying resistance to EGFR-targeted agents, are discussed. Future clinical trials must incorporate translational research end points to aid patient selection and circumvent resistance to EGFR inhibitors.

  18. Common Virulence Factors and Tissue Targets of Entomopathogenic Bacteria for Biological Control of Lepidopteran Pests

    Directory of Open Access Journals (Sweden)

    Anaïs Castagnola

    2014-01-01

    Full Text Available This review focuses on common insecticidal virulence factors from entomopathogenic bacteria with special emphasis on two insect pathogenic bacteria Photorhabdus (Proteobacteria: Enterobacteriaceae and Bacillus (Firmicutes: Bacillaceae. Insect pathogenic bacteria of diverse taxonomic groups and phylogenetic origin have been shown to have striking similarities in the virulence factors they produce. It has been suggested that the detection of phage elements surrounding toxin genes, horizontal and lateral gene transfer events, and plasmid shuffling occurrences may be some of the reasons that virulence factor genes have so many analogs throughout the bacterial kingdom. Comparison of virulence factors of Photorhabdus, and Bacillus, two bacteria with dissimilar life styles opens the possibility of re-examining newly discovered toxins for novel tissue targets. For example, nematodes residing in the hemolymph may release bacteria with virulence factors targeting neurons or neuromuscular junctions. The first section of this review focuses on toxins and their context in agriculture. The second describes the mode of action of toxins from common entomopathogens and the third draws comparisons between Gram positive and Gram negative bacteria. The fourth section reviews the implications of the nervous system in biocontrol.

  19. Correction factor for hair analysis by PIXE

    International Nuclear Information System (INIS)

    Montenegro, E.C.; Baptista, G.B.; Castro Faria, L.V. de; Paschoa, A.S.

    1980-01-01

    The application of the Particle Induced X-ray Emission (PIXE) technique to analyse quantitatively the elemental composition of hair specimens brings about some difficulties in the interpretation of the data. The present paper proposes a correction factor to account for the effects of the energy loss of the incident particle with penetration depth, and X-ray self-absorption when a particular geometrical distribution of elements in hair is assumed for calculational purposes. The correction factor has been applied to the analysis of hair contents Zn, Cu and Ca as a function of the energy of the incident particle. (orig.)

  20. Boolean Factor Analysis by Attractor Neural Network

    Czech Academy of Sciences Publication Activity Database

    Frolov, A. A.; Húsek, Dušan; Muraviev, I. P.; Polyakov, P.Y.

    2007-01-01

    Roč. 18, č. 3 (2007), s. 698-707 ISSN 1045-9227 R&D Projects: GA AV ČR 1ET100300419; GA ČR GA201/05/0079 Institutional research plan: CEZ:AV0Z10300504 Keywords : recurrent neural network * Hopfield-like neural network * associative memory * unsupervised learning * neural network architecture * neural network application * statistics * Boolean factor analysis * dimensionality reduction * features clustering * concepts search * information retrieval Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.769, year: 2007

  1. Correction factor for hair analysis by PIXE

    International Nuclear Information System (INIS)

    Montenegro, E.C.; Baptista, G.B.; Castro Faria, L.V. de; Paschoa, A.S.

    1979-06-01

    The application of the Particle Induced X-ray Emission (PIXE) technique to analyse quantitatively the elemental composition of hair specimens brings about some difficulties in the interpretation of the data. The present paper proposes a correction factor to account for the effects of energy loss of the incident particle with penetration depth, and x-ray self-absorption when a particular geometrical distribution of elements in hair is assumed for calculational purposes. The correction factor has been applied to the analysis of hair contents Zn, Cu and Ca as a function of the energy of the incident particle.(Author) [pt

  2. Genome-Wide Identification of the Target Genes of AP2-O, a Plasmodium AP2-Family Transcription Factor.

    Directory of Open Access Journals (Sweden)

    Izumi Kaneko

    2015-05-01

    Full Text Available Stage-specific transcription is a fundamental biological process in the life cycle of the Plasmodium parasite. Proteins containing the AP2 DNA-binding domain are responsible for stage-specific transcriptional regulation and belong to the only known family of transcription factors in Plasmodium parasites. Comprehensive identification of their target genes will advance our understanding of the molecular basis of stage-specific transcriptional regulation and stage-specific parasite development. AP2-O is an AP2 family transcription factor that is expressed in the mosquito midgut-invading stage, called the ookinete, and is essential for normal morphogenesis of this stage. In this study, we identified the genome-wide target genes of AP2-O by chromatin immunoprecipitation-sequencing and elucidate how this AP2 family transcription factor contributes to the formation of this motile stage. The analysis revealed that AP2-O binds specifically to the upstream genomic regions of more than 500 genes, suggesting that approximately 10% of the parasite genome is directly regulated by AP2-O. These genes are involved in distinct biological processes such as morphogenesis, locomotion, midgut penetration, protection against mosquito immunity and preparation for subsequent oocyst development. This direct and global regulation by AP2-O provides a model for gene regulation in Plasmodium parasites and may explain how these parasites manage to control their complex life cycle using a small number of sequence-specific AP2 transcription factors.

  3. Nominal Performance Biosphere Dose Conversion Factor Analysis

    Energy Technology Data Exchange (ETDEWEB)

    M.A. Wasiolek

    2003-07-25

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the Total System Performance Assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the groundwater exposure scenario, and the development of conversion factors for assessing compliance with the groundwater protection standard. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop biosphere BDCFs, which are input parameters for the TSPA model. The ''Biosphere Model Report'' (BSC 2003 [DIRS 164186]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports (BSC 2003 [DIRS 160964]; BSC 2003 [DIRS 160965]; BSC 2003 [DIRS 160976]; BSC 2003 [DIRS 161239]; BSC 2003 [DIRS 161241]) contain detailed description of the model input parameters. This report describes biosphere model calculations and their output, the BDCFs, for the groundwater exposure scenario. The objectives of this analysis are to develop BDCFs and conversion factors for the TSPA. The BDCFs will be used in performance assessment for calculating annual doses for a given concentration of radionuclides in groundwater. The conversion factors will be used for calculating gross alpha particle activity in groundwater and the annual dose from beta- and photon-emitting radionuclides.

  4. Limonene inhibits streptococcal biofilm formation by targeting surface-associated virulence factors.

    Science.gov (United States)

    Subramenium, Ganapathy Ashwinkumar; Vijayakumar, Karuppiah; Pandian, Shunmugiah Karutha

    2015-08-01

    The present study explores the efficacy of limonene, a cyclic terpene found in the rind of citrus fruits, for antibiofilm potential against species of the genus Streptococcus, which have been deeply studied worldwide owing to their multiple pathogenic efficacy. Limonene showed a concentration-dependent reduction in the biofilm formation of Streptococcus pyogenes (SF370), with minimal biofilm inhibitory concentration (MBIC) of 400 μg ml - 1. Limonene was found to possess about 75-95 % antibiofilm activity against all the pathogens tested, viz. Streptococcus pyogenes (SF370 and 5 clinical isolates), Streptococcus mutans (UA159) and Streptococcus mitis (ATCC 6249) at 400 μg ml - 1 concentration. Microscopic analysis of biofilm architecture revealed a quantitative breach in biofilm formation. Results of a surface-coating assay suggested that the possible mode of action of limonene could be by inhibiting bacterial adhesion to surfaces, thereby preventing the biofilm formation cascade. Susceptibility of limonene-treated Streptococcus pyogenes to healthy human blood goes in unison with gene expression studies in which the mga gene was found to be downregulated. Anti-cariogenic efficacy of limonene against Streptococcus mutans was confirmed, with inhibition of acid production and downregulation of the vicR gene. Downregulation of the covR, mga and vicR genes, which play a critical role in regulating surface-associated proteins in Streptococcus pyogenes and Streptococcus mutans, respectively, is yet further evidence to show that limonene targets surface-associated proteins. The results of physiological assays and gene expression studies clearly show that the surface-associated antagonistic mechanism of limonene also reduces surface-mediated virulence factors.

  5. Nominal Performance Biosphere Dose Conversion Factor Analysis

    Energy Technology Data Exchange (ETDEWEB)

    M.A. Wasiolek

    2005-04-28

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the Total System Performance Assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the groundwater exposure scenario, and the development of conversion factors for assessing compliance with the groundwater protection standards. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop BDCFs, which are input parameters for the TSPA-LA model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the ''Biosphere Model Report'' in Figure 1-1, contain detailed description of the model input parameters, their development, and the relationship between the parameters and specific features events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the groundwater exposure scenario. This analysis receives direct input from the outputs of the ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) and the five analyses that develop parameter values for the biosphere model (BSC 2005 [DIRS 172827]; BSC 2004 [DIRS 169672]; BSC 2004 [DIRS 169673]; BSC 2004 [DIRS 169458]; BSC 2004 [DIRS 169459]). The results of this report are further analyzed in the ''Biosphere Dose Conversion Factor Importance and Sensitivity Analysis

  6. Nominal Performance Biosphere Dose Conversion Factor Analysis

    International Nuclear Information System (INIS)

    M.A. Wasiolek

    2005-01-01

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the Total System Performance Assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the groundwater exposure scenario, and the development of conversion factors for assessing compliance with the groundwater protection standards. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop BDCFs, which are input parameters for the TSPA-LA model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the ''Biosphere Model Report'' in Figure 1-1, contain detailed description of the model input parameters, their development, and the relationship between the parameters and specific features events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the groundwater exposure scenario. This analysis receives direct input from the outputs of the ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) and the five analyses that develop parameter values for the biosphere model (BSC 2005 [DIRS 172827]; BSC 2004 [DIRS 169672]; BSC 2004 [DIRS 169673]; BSC 2004 [DIRS 169458]; BSC 2004 [DIRS 169459]). The results of this report are further analyzed in the ''Biosphere Dose Conversion Factor Importance and Sensitivity Analysis'' (Figure 1-1). The objectives of this analysis are to develop BDCFs for the

  7. Qweak Data Analysis for Target Modeling Using Computational Fluid Dynamics

    Science.gov (United States)

    Moore, Michael; Covrig, Silviu

    2015-04-01

    The 2.5 kW liquid hydrogen (LH2) target used in the Qweak parity violation experiment is the highest power LH2 target in the world and the first to be designed with Computational Fluid Dynamics (CFD) at Jefferson Lab. The Qweak experiment determined the weak charge of the proton by measuring the parity-violating elastic scattering asymmetry of longitudinally polarized electrons from unpolarized liquid hydrogen at small momentum transfer (Q2 = 0 . 025 GeV2). This target met the design goals of bench-marked with the Qweak target data. This work is an essential ingredient in future designs of very high power low noise targets like MOLLER (5 kW, target noise asymmetry contribution < 25 ppm) and MESA (4.5 kW).

  8. Confirmatory factor analysis using Microsoft Excel.

    Science.gov (United States)

    Miles, Jeremy N V

    2005-11-01

    This article presents a method for using Microsoft (MS) Excel for confirmatory factor analysis (CFA). CFA is often seen as an impenetrable technique, and thus, when it is taught, there is frequently little explanation of the mechanisms or underlying calculations. The aim of this article is to demonstrate that this is not the case; it is relatively straightforward to produce a spreadsheet in MS Excel that can carry out simple CFA. It is possible, with few or no programming skills, to effectively program a CFA analysis and, thus, to gain insight into the workings of the procedure.

  9. A kernel version of spatial factor analysis

    DEFF Research Database (Denmark)

    Nielsen, Allan Aasbjerg

    2009-01-01

    . Schölkopf et al. introduce kernel PCA. Shawe-Taylor and Cristianini is an excellent reference for kernel methods in general. Bishop and Press et al. describe kernel methods among many other subjects. Nielsen and Canty use kernel PCA to detect change in univariate airborne digital camera images. The kernel...... version of PCA handles nonlinearities by implicitly transforming data into high (even infinite) dimensional feature space via the kernel function and then performing a linear analysis in that space. In this paper we shall apply kernel versions of PCA, maximum autocorrelation factor (MAF) analysis...

  10. Radiological error: analysis, standard setting, targeted instruction and teamworking

    International Nuclear Information System (INIS)

    FitzGerald, Richard

    2005-01-01

    Diagnostic radiology does not have objective benchmarks for acceptable levels of missed diagnoses [1]. Until now, data collection of radiological discrepancies has been very time consuming. The culture within the specialty did not encourage it. However, public concern about patient safety is increasing. There have been recent innovations in compiling radiological interpretive discrepancy rates which may facilitate radiological standard setting. However standard setting alone will not optimise radiologists' performance or patient safety. We must use these new techniques in radiological discrepancy detection to stimulate greater knowledge sharing, targeted instruction and teamworking among radiologists. Not all radiological discrepancies are errors. Radiological discrepancy programmes must not be abused as an instrument for discrediting individual radiologists. Discrepancy rates must not be distorted as a weapon in turf battles. Radiological errors may be due to many causes and are often multifactorial. A systems approach to radiological error is required. Meaningful analysis of radiological discrepancies and errors is challenging. Valid standard setting will take time. Meanwhile, we need to develop top-up training, mentoring and rehabilitation programmes. (orig.)

  11. MicroRNA-125b Affects Vascular Smooth Muscle Cell Function by Targeting Serum Response Factor

    Directory of Open Access Journals (Sweden)

    Zhibo Chen

    2018-04-01

    Full Text Available Background/Aims: Increasing evidence links microRNAs to the pathogenesis of peripheral vascular disease. We recently found microRNA-125b (miR-125b to be one of the most significantly down‑regulated microRNAs in human arteries with arteriosclerosis obliterans (ASO of the lower extremities. However, its function in the process of ASO remains unclear. This study aimed to investigate the expression, regulatory mechanisms, and functions of miR-125b in the process of ASO. Methods: Using the tissue explants adherent method, vascular smooth muscle cells (VSMCs were prepared for this study. A rat carotid artery balloon injury model was constructed to simulate the development of vascular neointima, and a lentiviral transduction system was used to overexpress serum response factor (SRF or miR-125b. Quantitative real‑time PCR (qRT‑PCR was used to detect the expression levels of miR‑125b and SRF mRNA. Western blotting was performed to determine the expression levels of SRF and Ki67. In situ hybridization analysis was used to analyze the location and expression levels of miR-125b. CCK-8 and EdU assays were used to assess cell proliferation, and transwell and wound closure assays were performed to measure cell migration. Flow cytometry was used to evaluate cell apoptosis, and a dual-luciferase reporter assay was conducted to examine the effects of miR‑125b on SRF. Immunohistochemistry and immunofluorescence analyses were performed to analyze the location and expression levels of SRF and Ki67. Results: miR-125b expression was decreased in ASO arteries and platelet-derived growth factor (PDGF-BB-stimulated VSMCs. miR-125b suppressed VSMC proliferation and migration but promoted VSMC apoptosis. SRF was determined to be a direct target of miR-125b. Exogenous miR-125b expression modulated SRF expression and inhibited vascular neointimal formation in balloon-injured rat carotid arteries. Conclusions: These findings demonstrate a specific role of the mi

  12. DISRUPTIVE EVENT BIOSPHERE DOSE CONVERSION FACTOR ANALYSIS

    International Nuclear Information System (INIS)

    M.A. Wasiolek

    2005-01-01

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the total system performance assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the volcanic ash exposure scenario, and the development of dose factors for calculating inhalation dose during volcanic eruption. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop biosphere BDCFs, which are input parameters for the TSPA model. The Biosphere Model Report (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the Biosphere Model Report in Figure 1-1, contain detailed descriptions of the model input parameters, their development and the relationship between the parameters and specific features, events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the volcanic ash exposure scenario. This analysis receives direct input from the outputs of the ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) and from the five analyses that develop parameter values for the biosphere model (BSC 2005 [DIRS 172827]; BSC 2004 [DIRS 169672]; BSC 2004 [DIRS 169673]; BSC 2004 [DIRS 169458]; and BSC 2004 [DIRS 169459]). The results of this report are further analyzed in the ''Biosphere Dose Conversion Factor Importance and Sensitivity Analysis'' (Figure 1-1). The objective of this analysis was to develop the BDCFs for the volcanic

  13. Next-to leading order analysis of target mass corrections to structure functions and asymmetries

    International Nuclear Information System (INIS)

    Brady, L.T.; Accardi, A.; Hobbs, T.J.; Melnitchouk, W.

    2011-01-01

    We perform a comprehensive analysis of target mass corrections (TMCs) to spin-averaged structure functions and asymmetries at next-to-leading order. Several different prescriptions for TMCs are considered, including the operator product expansion, and various approximations to it, collinear factorization, and xi-scaling. We assess the impact of each of these on a number of observables, such as the neutron to proton F 2 structure function ratio, and parity-violating electron scattering asymmetries for protons and deuterons which are sensitive to gamma-Z interference effects. The corrections from higher order radiative and nuclear effects on the parity-violating deuteron asymmetry are also quantified.

  14. A Beginner’s Guide to Factor Analysis: Focusing on Exploratory Factor Analysis

    Directory of Open Access Journals (Sweden)

    An Gie Yong

    2013-10-01

    Full Text Available The following paper discusses exploratory factor analysis and gives an overview of the statistical technique and how it is used in various research designs and applications. A basic outline of how the technique works and its criteria, including its main assumptions are discussed as well as when it should be used. Mathematical theories are explored to enlighten students on how exploratory factor analysis works, an example of how to run an exploratory factor analysis on SPSS is given, and finally a section on how to write up the results is provided. This will allow readers to develop a better understanding of when to employ factor analysis and how to interpret the tables and graphs in the output.

  15. CRISPRTarget: bioinformatic prediction and analysis of crRNA targets

    NARCIS (Netherlands)

    Biswas, A.; Gagnon, J.N.; Brouns, S.J.J.; Fineran, P.C.; Brown, C.M.

    2013-01-01

    The bacterial and archaeal CRISPR/Cas adaptive immune system targets specific protospacer nucleotide sequences in invading organisms. This requires base pairing between processed CRISPR RNA and the target protospacer. For type I and II CRISPR/Cas systems, protospacer adjacent motifs (PAM) are

  16. Nominal Performance Biosphere Dose Conversion Factor Analysis

    Energy Technology Data Exchange (ETDEWEB)

    M. Wasiolek

    2004-09-08

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the Total System Performance Assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the groundwater exposure scenario, and the development of conversion factors for assessing compliance with the groundwater protection standard. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop biosphere BDCFs, which are input parameters for the TSPA-LA model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the ''Biosphere Model Report'' in Figure 1-1, contain detailed description of the model input parameters, their development, and the relationship between the parameters and specific features events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the groundwater exposure scenario. The objectives of this analysis are to develop BDCFs for the groundwater exposure scenario for the three climate states considered in the TSPA-LA as well as conversion factors for evaluating compliance with the groundwater protection standard. The BDCFs will be used in performance assessment for calculating all-pathway annual doses for a given concentration of radionuclides in groundwater. The conversion factors will be used for calculating gross alpha particle

  17. Determining the Number of Factors in P-Technique Factor Analysis

    Science.gov (United States)

    Lo, Lawrence L.; Molenaar, Peter C. M.; Rovine, Michael

    2017-01-01

    Determining the number of factors is a critical first step in exploratory factor analysis. Although various criteria and methods for determining the number of factors have been evaluated in the usual between-subjects R-technique factor analysis, there is still question of how these methods perform in within-subjects P-technique factor analysis. A…

  18. Disruptive Event Biosphere Dose Conversion Factor Analysis

    Energy Technology Data Exchange (ETDEWEB)

    M. A. Wasiolek

    2003-07-21

    This analysis report, ''Disruptive Event Biosphere Dose Conversion Factor Analysis'', is one of the technical reports containing documentation of the ERMYN (Environmental Radiation Model for Yucca Mountain Nevada) biosphere model for the geologic repository at Yucca Mountain, its input parameters, and the application of the model to perform the dose assessment for the repository. The biosphere model is one of a series of process models supporting the Total System Performance Assessment (TSPA) for the Yucca Mountain repository. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of the two reports that develop biosphere dose conversion factors (BDCFs), which are input parameters for the TSPA model. The ''Biosphere Model Report'' (BSC 2003 [DIRS 164186]) describes in detail the conceptual model as well as the mathematical model and lists its input parameters. Model input parameters are developed and described in detail in five analysis report (BSC 2003 [DIRS 160964], BSC 2003 [DIRS 160965], BSC 2003 [DIRS 160976], BSC 2003 [DIRS 161239], and BSC 2003 [DIRS 161241]). The objective of this analysis was to develop the BDCFs for the volcanic ash exposure scenario and the dose factors (DFs) for calculating inhalation doses during volcanic eruption (eruption phase of the volcanic event). The volcanic ash exposure scenario is hereafter referred to as the volcanic ash scenario. For the volcanic ash scenario, the mode of radionuclide release into the biosphere is a volcanic eruption through the repository with the resulting entrainment of contaminated waste in the tephra and the subsequent atmospheric transport and dispersion of contaminated material in

  19. Disruptive Event Biosphere Dose Conversion Factor Analysis

    International Nuclear Information System (INIS)

    M. A. Wasiolek

    2003-01-01

    This analysis report, ''Disruptive Event Biosphere Dose Conversion Factor Analysis'', is one of the technical reports containing documentation of the ERMYN (Environmental Radiation Model for Yucca Mountain Nevada) biosphere model for the geologic repository at Yucca Mountain, its input parameters, and the application of the model to perform the dose assessment for the repository. The biosphere model is one of a series of process models supporting the Total System Performance Assessment (TSPA) for the Yucca Mountain repository. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of the two reports that develop biosphere dose conversion factors (BDCFs), which are input parameters for the TSPA model. The ''Biosphere Model Report'' (BSC 2003 [DIRS 164186]) describes in detail the conceptual model as well as the mathematical model and lists its input parameters. Model input parameters are developed and described in detail in five analysis report (BSC 2003 [DIRS 160964], BSC 2003 [DIRS 160965], BSC 2003 [DIRS 160976], BSC 2003 [DIRS 161239], and BSC 2003 [DIRS 161241]). The objective of this analysis was to develop the BDCFs for the volcanic ash exposure scenario and the dose factors (DFs) for calculating inhalation doses during volcanic eruption (eruption phase of the volcanic event). The volcanic ash exposure scenario is hereafter referred to as the volcanic ash scenario. For the volcanic ash scenario, the mode of radionuclide release into the biosphere is a volcanic eruption through the repository with the resulting entrainment of contaminated waste in the tephra and the subsequent atmospheric transport and dispersion of contaminated material in the biosphere. The biosphere process

  20. Exploratory Bi-Factor Analysis: The Oblique Case

    Science.gov (United States)

    Jennrich, Robert I.; Bentler, Peter M.

    2012-01-01

    Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger and Swineford ("Psychometrika" 47:41-54, 1937). The bi-factor model has a general factor, a number of group factors, and an explicit bi-factor structure. Jennrich and Bentler ("Psychometrika" 76:537-549, 2011) introduced an exploratory form of bi-factor…

  1. Exploratory factor analysis in Rehabilitation Psychology: a content analysis.

    Science.gov (United States)

    Roberson, Richard B; Elliott, Timothy R; Chang, Jessica E; Hill, Jessica N

    2014-11-01

    Our objective was to examine the use and quality of exploratory factor analysis (EFA) in articles published in Rehabilitation Psychology. Trained raters examined 66 separate exploratory factor analyses in 47 articles published between 1999 and April 2014. The raters recorded the aim of the EFAs, the distributional statistics, sample size, factor retention method(s), extraction and rotation method(s), and whether the pattern coefficients, structure coefficients, and the matrix of association were reported. The primary use of the EFAs was scale development, but the most widely used extraction and rotation method was principle component analysis, with varimax rotation. When determining how many factors to retain, multiple methods (e.g., scree plot, parallel analysis) were used most often. Many articles did not report enough information to allow for the duplication of their results. EFA relies on authors' choices (e.g., factor retention rules extraction, rotation methods), and few articles adhered to all of the best practices. The current findings are compared to other empirical investigations into the use of EFA in published research. Recommendations for improving EFA reporting practices in rehabilitation psychology research are provided.

  2. Exploratory Bi-factor Analysis: The Oblique Case

    OpenAIRE

    Jennrich, Robert L.; Bentler, Peter M.

    2011-01-01

    Bi-factor analysis is a form of confirmatory factor analysis originally introduced by Holzinger and Swineford (1937). The bi-factor model has a general factor, a number of group factors, and an explicit bi-factor structure. Jennrich and Bentler (2011) introduced an exploratory form of bi-factor analysis that does not require one to provide an explicit bi-factor structure a priori. They use exploratory factor analysis and a bi-factor rotation criterion designed to produce a rotated loading mat...

  3. Trial Characteristics as Contextual Factors when Evaluating Targeted Therapies in Patients with Psoriatic Disease

    DEFF Research Database (Denmark)

    Ballegaard, Christine; Jørgensen, Tanja S; Skougaard, Marie

    2018-01-01

    (PsA) and psoriasis (8 biologics and apremilast). The effect of targeted therapies was analyzed in the two psoriatic conditions combined by using drug retention as common outcome, and separately by using ACR20 for PsA and PASI75 for psoriasis. We explored potential effect modification of trial...... characteristics in stratified and meta-regression analyses. Odds ratios (OR) were calculated and compared among the trial eligibility criteria via the Ratio of Odds Ratios (ROR). RESULTS: Forty-eight PsA and psoriasis trials (51 comparisons, 17,737 patients) were eligible. Overall retention was OR 2.16 (1.70 to 2.......75) with higher odds for PsA trials compared with psoriasis trials (ROR = 2.55 [1.64 to 3.97]). The eligibility criteria "targeted therapy history", "minimum required disease duration", "required negative rheumatoid factor", and "required CASPAR criteria" were of importance for achieving ACR20 in PsA...

  4. miR-27 regulates mitochondrial networks by directly targeting the mitochondrial fission factor.

    Science.gov (United States)

    Tak, Hyosun; Kim, Jihye; Jayabalan, Aravinth Kumar; Lee, Heejin; Kang, Hoin; Cho, Dong-Hyung; Ohn, Takbum; Nam, Suk Woo; Kim, Wook; Lee, Eun Kyung

    2014-11-28

    Mitochondrial morphology is dynamically regulated by forming small, fragmented units or interconnected networks, and this is a pivotal process that is used to maintain mitochondrial homeostasis. Although dysregulation of mitochondrial dynamics is related to the pathogenesis of several human diseases, its molecular mechanism is not fully elucidated. In this study, we demonstrate the potential role of miR-27 in the regulation of mitochondrial dynamics. Mitochondrial fission factor (MFF) mRNA is a direct target of miR-27, whose ectopic expression decreases MFF expression through binding to its 3'-untranslated region. Expression of miR-27 results in the elongation of mitochondria as well as an increased mitochondrial membrane potential and mitochondrial ATP level. Our results suggest that miR-27 is a novel regulator affecting morphological mitochondrial changes by targeting MFF.

  5. Covalent Targeting of Fibroblast Growth Factor Receptor Inhibits Metastatic Breast Cancer.

    Science.gov (United States)

    Brown, Wells S; Tan, Li; Smith, Andrew; Gray, Nathanael S; Wendt, Michael K

    2016-09-01

    Therapeutic targeting of late-stage breast cancer is limited by an inadequate understanding of how tumor cell signaling evolves during metastatic progression and by the currently available small molecule inhibitors capable of targeting these processes. Herein, we demonstrate that both β3 integrin and fibroblast growth factor receptor-1 (FGFR1) are part of an epithelial-mesenchymal transition (EMT) program that is required to facilitate metastatic outgrowth in response to fibroblast growth factor-2 (FGF2). Mechanistically, β3 integrin physically disrupts an interaction between FGFR1 and E-cadherin, leading to a dramatic redistribution of FGFR1 subcellular localization, enhanced FGF2 signaling and increased three-dimensional (3D) outgrowth of metastatic breast cancer cells. This ability of β3 integrin to drive FGFR signaling requires the enzymatic activity of focal adhesion kinase (FAK). Consistent with these mechanistic data, we demonstrate that FGFR, β3 integrin, and FAK constitute a molecular signature capable of predicting decreased survival of patients with the basal-like subtype of breast cancer. Importantly, covalent targeting of a conserved cysteine in the P-loop of FGFR1-4 with our newly developed small molecule, FIIN-4, more effectively blocks 3D metastatic outgrowth as compared with currently available FGFR inhibitors. In vivo application of FIIN-4 potently inhibited the growth of metastatic, patient-derived breast cancer xenografts and murine-derived metastases growing within the pulmonary microenvironment. Overall, the current studies demonstrate that FGFR1 works in concert with other EMT effector molecules to drive aberrant downstream signaling, and that these events can be effectively targeted using our novel therapeutics for the treatment of the most aggressive forms of breast cancer. Mol Cancer Ther; 15(9); 2096-106. ©2016 AACR. ©2016 American Association for Cancer Research.

  6. Targeting gender: A content analysis of alcohol advertising in magazines.

    Science.gov (United States)

    Jung, A-Reum; Hovland, Roxanne

    2016-01-01

    Creating target specific advertising is fundamental to maximizing advertising effectiveness. When crafting an advertisement, message and creative strategies are considered important because they affect target audiences' attitudes toward advertised products. This study endeavored to find advertising strategies that are likely to have special appeal for men or women by examining alcohol advertising in magazines. The results show that the substance of the messages is the same for men and women, but they only differ in terms of presentation. However, regardless of gender group, the most commonly used strategies in alcohol advertising are appeals to the target audience's emotions.

  7. Risk factors that affect reproductive target achievement in fertile dairy cows.

    Science.gov (United States)

    Aungier, S P M; Roche, J F; Diskin, M G; Crowe, M A

    2014-01-01

    The aims of the present study were to investigate (1) the risk factors that influence the achievement of reproductive targets postpartum (pp) and (2) the key factors that influence pregnancy rate following first artificial insemination (AI) in dairy cows. Ninety-eight Holstein-Friesian pp cows were blood sampled from wk 1 to 4 pp for hematology and biochemistry. Reproductive tract health was assessed weekly by ultrasonography and vaginal mucus scoring. Body condition score (BCS), lameness score, and milk yield were assessed every 2 wk. Milk samples for progesterone assay were collected twice weekly and on d 4, 5, and 7 after AI. Risk factors associated with achieving reproductive targets depended on (1) increased metabolic activity of the liver (increased glutamate dehydrogenase at calving and increased γ-glutamyl transpeptidase in wk 4), (2) a competent immune system (increased neutrophils in wk 1; decreased α1-acid glycoprotein in wk 1, 2, and 3), (3) an endocrine system that was capable of responding by producing sufficient triiodothyronine in wk 2 and increased insulin-like growth factor I in wk 3 and 4, (4) a lower negative energy balance status (decreased nonesterified fatty acid concentration in wk 1; decreased β-hydroxybutyrate concentration in wk 2; BCS loss between calving and d 28 pp mucus discharge at first ovulation and at d 45 pp; resumed ovarian cyclicity by the end of the voluntary waiting period (≥ d 35 pp)], and (6) adequate diet (to ensure increased glutathione peroxidase in wk 2 and 3 and increased magnesium in wk 4). Risk factors that increased the odds of a successful first AI were previous ovulation(s) (odds ratio=3.17 per ovulation), BCS >2.5 at AI (odds ratio=3.01), and clear vaginal mucus (score=0) compared with purulent mucus (score >0) 4 d after first AI (odds ratio=2.99). In conclusion, this study identified key risk factors in the early pp period that give a higher probability of cows achieving their reproductive targets and of

  8. Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines

    International Nuclear Information System (INIS)

    Xu, Ling; Hausmann, Martin; Dietmaier, Wolfgang; Kellermeier, Silvia; Pesch, Theresa; Stieber-Gunckel, Manuela; Lippert, Elisabeth; Klebl, Frank; Rogler, Gerhard

    2010-01-01

    Cholangiocarcinoma (CC) is a malignant neoplasm of the bile ducts or the gallbladder. Targeting of growth factor receptors showed therapeutic potential in palliative settings for many solid tumors. The aim of this study was to determine the expression of seven growth factor receptors in CC cell lines and to assess the effect of blocking the EGFR receptor in vitro. Expression of EGFR (epithelial growth factor receptor), HGFR (hepatocyte growth factor receptor) IGF1R (insulin-like growth factor 1 receptor), IGF2R (insulin-like growth factor 2 receptor) and VEGFR1-3 (vascular endothelial growth factor receptor 1-3) were examined in four human CC cell lines (EGI-1, HuH28, OZ and TFK-1). The effect of the anti-EGFR-antibody cetuximab on cell growth and apoptosis was studied and cell lines were examined for KRAS mutations. EGFR, HGFR and IGFR1 were present in all four cell lines tested. IGFR2 expression was confirmed in EGI-1 and TFK-1. No growth-inhibitory effect was found in EGI-1 cells after incubation with cetuximab. Cetuximab dose-dependently inhibited growth in TFK-1. Increased apoptosis was only seen in TFK-1 cells at the highest cetuximab dose tested (1 mg/ml), with no dose-response-relationship at lower concentrations. In EGI-1 a heterozygous KRAS mutation was found in codon 12 (c.35G>A; p.G12D). HuH28, OZ and TFK-1 lacked KRAS mutation. CC cell lines express a pattern of different growth receptors in vitro. Growth factor inhibitor treatment could be affected from the KRAS genotype in CC. The expression of EGFR itself does not allow prognoses on growth inhibition by cetuximab

  9. Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines

    Directory of Open Access Journals (Sweden)

    Kellermeier Silvia

    2010-06-01

    Full Text Available Abstract Background Cholangiocarcinoma (CC is a malignant neoplasm of the bile ducts or the gallbladder. Targeting of growth factor receptors showed therapeutic potential in palliative settings for many solid tumors. The aim of this study was to determine the expression of seven growth factor receptors in CC cell lines and to assess the effect of blocking the EGFR receptor in vitro. Methods Expression of EGFR (epithelial growth factor receptor, HGFR (hepatocyte growth factor receptor IGF1R (insulin-like growth factor 1 receptor, IGF2R (insulin-like growth factor 2 receptor and VEGFR1-3 (vascular endothelial growth factor receptor 1-3 were examined in four human CC cell lines (EGI-1, HuH28, OZ and TFK-1. The effect of the anti-EGFR-antibody cetuximab on cell growth and apoptosis was studied and cell lines were examined for KRAS mutations. Results EGFR, HGFR and IGFR1 were present in all four cell lines tested. IGFR2 expression was confirmed in EGI-1 and TFK-1. No growth-inhibitory effect was found in EGI-1 cells after incubation with cetuximab. Cetuximab dose-dependently inhibited growth in TFK-1. Increased apoptosis was only seen in TFK-1 cells at the highest cetuximab dose tested (1 mg/ml, with no dose-response-relationship at lower concentrations. In EGI-1 a heterozygous KRAS mutation was found in codon 12 (c.35G>A; p.G12D. HuH28, OZ and TFK-1 lacked KRAS mutation. Conclusion CC cell lines express a pattern of different growth receptors in vitro. Growth factor inhibitor treatment could be affected from the KRAS genotype in CC. The expression of EGFR itself does not allow prognoses on growth inhibition by cetuximab.

  10. Synthesis of tumor necrosis factor α for use as a mirror-image phage display target.

    Science.gov (United States)

    Petersen, Mark E; Jacobsen, Michael T; Kay, Michael S

    2016-06-21

    Tumor Necrosis Factor alpha (TNFα) is an inflammatory cytokine that plays a central role in the pathogenesis of chronic inflammatory disease. Here we describe the chemical synthesis of l-TNFα along with the mirror-image d-protein for use as a phage display target. The synthetic strategy utilized native chemical ligation and desulfurization to unite three peptide segments, followed by oxidative folding to assemble the 52 kDa homotrimeric protein. This synthesis represents the foundational step for discovering an inhibitory d-peptide with the potential to improve current anti-TNFα therapeutic strategies.

  11. The Terahertz Scattering Analysis of Rough Metallic and Dielectric Targets

    Directory of Open Access Journals (Sweden)

    Mou Yuan

    2018-02-01

    Full Text Available The terahertz scattering characteristics of metallic and dielectric rough targets is important for the investigation of the terahertz radar targets properties. According to the stationary phase theory and scalar approximation, if the radius of curvature at any point of the surface is much larger than the incident wavelength, and the wavelength is also much longer than the surface height function and Root-Mean-Square (RMS surface slope, the coherent and incoherent scattering Radar Cross Section (RCS of rough metallic and dielectric targets can be obtained. Based on the stationary phase approximation, the coherent RCS of rough conductors, smooth dielectric targets and rough dielectric targets can be easily deputed. The scattering characteristics of electrically large smooth Al and painted spheres are investigated in this paper, and the calculated RCS are verified by Mie scattering theory, the error is less than 0.1 dBm2. Based on lambert theory, it is demonstrated that the incoherent RCS is analyzed with better precision if the rough surfaces are divided into much more facets. In this paper, the coherent and incoherent scattering of rough Al and painted spheres are numerically observed, and the effects of surface roughness and materials are analyzed. The conclusions provide theoretical foundation for the terahertz scattering characteristics of electrically large rough targets.

  12. Disruptive Event Biosphere Dose Conversion Factor Analysis

    Energy Technology Data Exchange (ETDEWEB)

    M. Wasiolek

    2004-09-08

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the total system performance assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the volcanic ash exposure scenario, and the development of dose factors for calculating inhalation dose during volcanic eruption. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop biosphere BDCFs, which are input parameters for the TSPA model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the Biosphere Model Report in Figure 1-1, contain detailed descriptions of the model input parameters, their development and the relationship between the parameters and specific features, events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the volcanic ash exposure scenario. This analysis receives direct input from the outputs of the ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) and from the five analyses that develop parameter values for the biosphere model (BSC 2004 [DIRS 169671]; BSC 2004 [DIRS 169672]; BSC 2004 [DIRS 169673]; BSC 2004 [DIRS 169458]; and BSC 2004 [DIRS 169459]). The results of this report are further analyzed in the ''Biosphere Dose Conversion Factor Importance and Sensitivity Analysis''. The objective of this

  13. Scalable group level probabilistic sparse factor analysis

    DEFF Research Database (Denmark)

    Hinrich, Jesper Løve; Nielsen, Søren Føns Vind; Riis, Nicolai Andre Brogaard

    2017-01-01

    Many data-driven approaches exist to extract neural representations of functional magnetic resonance imaging (fMRI) data, but most of them lack a proper probabilistic formulation. We propose a scalable group level probabilistic sparse factor analysis (psFA) allowing spatially sparse maps, component...... pruning using automatic relevance determination (ARD) and subject specific heteroscedastic spatial noise modeling. For task-based and resting state fMRI, we show that the sparsity constraint gives rise to components similar to those obtained by group independent component analysis. The noise modeling...... shows that noise is reduced in areas typically associated with activation by the experimental design. The psFA model identifies sparse components and the probabilistic setting provides a natural way to handle parameter uncertainties. The variational Bayesian framework easily extends to more complex...

  14. Disruptive Event Biosphere Dose Conversion Factor Analysis

    International Nuclear Information System (INIS)

    M. Wasiolek

    2004-01-01

    This analysis report is one of the technical reports containing documentation of the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), a biosphere model supporting the total system performance assessment (TSPA) for the license application (LA) for the Yucca Mountain repository. This analysis report describes the development of biosphere dose conversion factors (BDCFs) for the volcanic ash exposure scenario, and the development of dose factors for calculating inhalation dose during volcanic eruption. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and provides an understanding of how this analysis report contributes to biosphere modeling. This report is one of two reports that develop biosphere BDCFs, which are input parameters for the TSPA model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the ERMYN conceptual model and mathematical model. The input parameter reports, shown to the right of the Biosphere Model Report in Figure 1-1, contain detailed descriptions of the model input parameters, their development and the relationship between the parameters and specific features, events and processes (FEPs). This report describes biosphere model calculations and their output, the BDCFs, for the volcanic ash exposure scenario. This analysis receives direct input from the outputs of the ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) and from the five analyses that develop parameter values for the biosphere model (BSC 2004 [DIRS 169671]; BSC 2004 [DIRS 169672]; BSC 2004 [DIRS 169673]; BSC 2004 [DIRS 169458]; and BSC 2004 [DIRS 169459]). The results of this report are further analyzed in the ''Biosphere Dose Conversion Factor Importance and Sensitivity Analysis''. The objective of this analysis was to develop the BDCFs for the volcanic ash

  15. Kernel parameter dependence in spatial factor analysis

    DEFF Research Database (Denmark)

    Nielsen, Allan Aasbjerg

    2010-01-01

    kernel PCA. Shawe-Taylor and Cristianini [4] is an excellent reference for kernel methods in general. Bishop [5] and Press et al. [6] describe kernel methods among many other subjects. The kernel version of PCA handles nonlinearities by implicitly transforming data into high (even infinite) dimensional...... feature space via the kernel function and then performing a linear analysis in that space. In this paper we shall apply a kernel version of maximum autocorrelation factor (MAF) [7, 8] analysis to irregularly sampled stream sediment geochemistry data from South Greenland and illustrate the dependence...... of the kernel width. The 2,097 samples each covering on average 5 km2 are analyzed chemically for the content of 41 elements....

  16. CD4+ T cells targeting dominant and cryptic epitopes from Bacillus anthracis Lethal Factor

    Directory of Open Access Journals (Sweden)

    Stephanie eAscough

    2016-01-01

    Full Text Available Anthrax is an endemic infection in many countries, particularly in the developing world. The causative agent, Bacillus anthracis, mediates disease through the secretion of binary exotoxins. Until recently, research into adaptive immunity targeting this bacterial pathogen has largely focused on the humoral response to these toxins. There is, however, growing recognition that cellular immune responses involving IFNγ producing CD4+ T cells also contribute significantly to a protective memory response. An established concept in adaptive immunity to infection is that during infection of host cells, new microbial epitopes may be revealed, leading to immune recognition of so called ‘cryptic’ or ‘subdominant’ epitopes. We analysed the response to both cryptic and immunodominant T cell epitopes derived from the toxin component lethal factor and presented by a range of HLA-DR alleles. Using IFNγ-ELISPOT assays we characterised epitopes that elicited a response following immunisation with synthetic peptide and the whole protein and tested their capacities to bind purified HLA-DR molecules in vitro. We found that DR1 transgenics demonstrated T cell responses to a greater number of domain III cryptic epitopes than other HLA-DR transgenics, and that this pattern was repeated with the immunodominant epitopes, a greater proportion of these epitopes induced a T cell response when presented within the context of the whole protein. Immunodominant epitopes LF457-476 and LF467-487 were found to induce a T cell response to the peptide, as well as to the whole native LF protein in DR1 and DR15, but not in DR4 trangenics. The analysis of Domain I revealed the presence of several unique cryptic epitopes all of which showed a strong to moderate relative binding affinity to HLA-DR4 molecules. However, none of the cryptic epitopes from either domain III or I displayed notably high binding affinities across all HLA-DR alleles assayed. These responses were

  17. Management of severe asthma: targeting the airways, comorbidities and risk factors.

    Science.gov (United States)

    Gibson, Peter G; McDonald, Vanessa M

    2017-06-01

    Severe asthma is a complex heterogeneous disease that is refractory to standard treatment and is complicated by multiple comorbidities and risk factors. In mild to moderate asthma, the burden of disease can be minimised by inhaled corticosteroids, bronchodilators and self-management education. In severe asthma, however, management is more complex. When patients with asthma continue to experience symptoms and exacerbations despite optimal management, severe refractory asthma (SRA) should be suspected and confirmed, and other aetiologies ruled out. Once a diagnosis of SRA is established, patients should undergo a systematic and multidimensional assessment to identify inflammatory endotypes, risk factors and comorbidities, with targeted and individualised management initiated. We describe a practical approach to assessment and management of patients with SRA. © 2017 Royal Australasian College of Physicians.

  18. Transcription Factor STAT3 as a Novel Molecular Target for Cancer Prevention

    International Nuclear Information System (INIS)

    Xiong, Ailian; Yang, Zhengduo; Shen, Yicheng; Zhou, Jia; Shen, Qiang

    2014-01-01

    Signal Transducers and Activators of Transcription (STATs) are a family of transcription factors that regulate cell proliferation, differentiation, apoptosis, immune and inflammatory responses, and angiogenesis. Cumulative evidence has established that STAT3 has a critical role in the development of multiple cancer types. Because it is constitutively activated during disease progression and metastasis in a variety of cancers, STAT3 has promise as a drug target for cancer therapeutics. Recently, STAT3 was found to have an important role in maintaining cancer stem cells in vitro and in mouse tumor models, suggesting STAT3 is integrally involved in tumor initiation, progression and maintenance. STAT3 has been traditionally considered as nontargetable or undruggable, and the lag in developing effective STAT3 inhibitors contributes to the current lack of FDA-approved STAT3 inhibitors. Recent advances in cancer biology and drug discovery efforts have shed light on targeting STAT3 globally and/or specifically for cancer therapy. In this review, we summarize current literature and discuss the potential importance of STAT3 as a novel target for cancer prevention and of STAT3 inhibitors as effective chemopreventive agents

  19. Epidermal growth factor (EGF) as a potential targeting agent for delivery of boron to malignant gliomas

    International Nuclear Information System (INIS)

    Capala, J.; Barth, R.F.; Adams, D.M.; Bailey, M.Q.; Soloway, A.H.; Carlsson, J.

    1994-01-01

    The majority of high grade gliomas express an amplified epidermal growth factor receptor (EGFR) gene, and this often is associated with an increase in cell surface receptor expression. The rapid internalization and degradation of EGF-EGFR complexes, as well as their high affinity make EGF a potential targeting agent for delivery of 10 B to tumor cells with an amplified number of EGFR. Human glioma cells can expresses as many as 10 5 -10 6 EGF receptors per cell, and if these could be saturated with boronated EGF, then > 10 8 boron atoms would be delivered per cell. Since EGF has a comparatively low molecular weight (∼ 6 kD), this has allowed us to construct relatively small bioconjugates containing ∼ 900 boron atoms per EGF molecule 3 , which also had high affinity for EGFR on tumor cells. In the present study, the feasibility of using EGF receptors as a potential target for therapy of gliomas was investigated by in vivo scintigraphic studies using 131 I- or 99m T c -labeled EGF in a rat brain tumor model. Our results indicate that intratumorally delivered boron- EGF conjugates might be useful for targeting EGFR on glioma cells if the boron containing moiety of the conjugates persisted intracellularly. Further studies are required, however, to determine if this approach can be used for BNCT of the rat glioma

  20. MiR-32 promotes gastric carcinoma tumorigenesis by targeting Kruppel-like factor 4

    Energy Technology Data Exchange (ETDEWEB)

    Yan, Chao [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Yu, Jianchun, E-mail: yu_jchpumch@163.com [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China); Liu, Yuqin [Cell Culture Center, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005 (China); Kang, Weiming; Ma, Zhiqiang; Zhou, Li [Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730 (China)

    2015-11-27

    Gastric cancer (GC) is a prevalent malignant cancer worldwide and is highly lethal because of its fast growth. Currently, the clinical therapy options for GC remain limited. MiR-32 has been reported as an oncogenic microRNA in many cancers, but its role in GC is unclear. Here, we found that miR-32 was overexpressed in GC tissues compared with adjacent normal tissue, and miR-32 was higher in GC patients' plasma compared with healthy individuals. Furthermore, we have identified miR-32 to be oncogenic, by promoting gastric cell proliferation, migration and invasion. We also identified Kruppel-like factor 4 (KLF4) as a direct target of miR-32. Knockdown of KLF4 promoted proliferation, migration and invasion of GC cells. We conclude that miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4, suggesting that the miR-32-KLF4 pathway may be useful in clinical diagnosis and therapeutics. - Highlights: • miR-32 was overexpression in GC tissues than adjacent normal tissue. • miR-32 was higher in GC patients' plasma compared with healthy people. • miR-32 promotes GC cell proliferation, migration and invasion by targeting KLF4.

  1. Hypoxia-Inducible Factors: Mediators of Cancer Progression; Prognostic and Therapeutic Targets in Soft Tissue Sarcomas

    International Nuclear Information System (INIS)

    Sadri, Navid; Zhang, Paul J.

    2013-01-01

    Soft-tissue sarcomas remain aggressive tumors that result in death in greater than a third of patients due to either loco-regional recurrence or distant metastasis. Surgical resection remains the main choice of treatment for soft tissue sarcomas with pre- and/or post-operational radiation and neoadjuvant chemotherapy employed in more advanced stage disease. However, in recent decades, there has been little progress in the average five-year survival for the majority of patients with high-grade soft tissue sarcomas, highlighting the need for improved targeted therapeutic agents. Clinical and preclinical studies demonstrate that tumor hypoxia and up-regulation of hypoxia-inducible factors (HIFs) is associated with decreased survival, increased metastasis, and resistance to therapy in soft tissue sarcomas. HIF-mediated gene expression regulates many critical aspects of tumor biology, including cell survival, metabolic programming, angiogenesis, metastasis, and therapy resistance. In this review, we discuss HIFs and HIF-mediated genes as potential prognostic markers and therapeutic targets in sarcomas. Many pharmacological agents targeting hypoxia-related pathways are in development that may hold therapeutic potential for treating both primary and metastatic sarcomas that demonstrate increased HIF expression

  2. Connective tissue growth factor as a novel therapeutic target in high grade serous ovarian cancer.

    Science.gov (United States)

    Moran-Jones, Kim; Gloss, Brian S; Murali, Rajmohan; Chang, David K; Colvin, Emily K; Jones, Marc D; Yuen, Samuel; Howell, Viive M; Brown, Laura M; Wong, Carol W; Spong, Suzanne M; Scarlett, Christopher J; Hacker, Neville F; Ghosh, Sue; Mok, Samuel C; Birrer, Michael J; Samimi, Goli

    2015-12-29

    Ovarian cancer is the most common cause of death among women with gynecologic cancer. We examined molecular profiles of fibroblasts from normal ovary and high-grade serous ovarian tumors to identify novel therapeutic targets involved in tumor progression. We identified 2,300 genes that are significantly differentially expressed in tumor-associated fibroblasts. Fibroblast expression of one of these genes, connective tissue growth factor (CTGF), was confirmed by immunohistochemistry. CTGF protein expression in ovarian tumor fibroblasts significantly correlated with gene expression levels. CTGF is a secreted component of the tumor microenvironment and is being pursued as a therapeutic target in pancreatic cancer. We examined its effect in in vitro and ex vivo ovarian cancer models, and examined associations between CTGF expression and clinico-pathologic characteristics in patients. CTGF promotes migration and peritoneal adhesion of ovarian cancer cells. These effects are abrogated by FG-3019, a human monoclonal antibody against CTGF, currently under clinical investigation as a therapeutic agent. Immunohistochemical analyses of high-grade serous ovarian tumors reveal that the highest level of tumor stromal CTGF expression was correlated with the poorest prognosis. Our findings identify CTGF as a promoter of peritoneal adhesion, likely to mediate metastasis, and a potential therapeutic target in high-grade serous ovarian cancer. These results warrant further studies into the therapeutic efficacy of FG-3019 in high-grade serous ovarian cancer.

  3. Identification of direct regulatory targets of the transcription factor Sox10 based on function and conservation

    Directory of Open Access Journals (Sweden)

    Lee Sanghyuk

    2008-09-01

    Full Text Available Abstract Background Sox10, a member of the Sry-related HMG-Box gene family, is a critical transcription factor for several important cell lineages, most notably the neural crest stem cells and the derivative peripheral glial cells and melanocytes. Thus far, only a handful of direct target genes are known for this transcription factor limiting our understanding of the biological network it governs. Results We describe identification of multiple direct regulatory target genes of Sox10 through a procedure based on function and conservation. By combining RNA interference technique and DNA microarray technology, we have identified a set of genes that show significant down-regulation upon introduction of Sox10 specific siRNA into Schwannoma cells. Subsequent comparative genomics analyses led to potential binding sites for Sox10 protein conserved across several mammalian species within the genomic region proximal to these genes. Multiple sites belonging to 4 different genes (proteolipid protein, Sox10, extracellular superoxide dismutase, and pleiotrophin were shown to directly interact with Sox10 by chromatin immunoprecipitation assay. We further confirmed the direct regulation through the identified cis-element for one of the genes, extracellular superoxide dismutase, using electrophoretic mobility shift assay and reporter assay. Conclusion In sum, the process of combining differential expression profiling and comparative genomics successfully led to further defining the role of Sox10, a critical transcription factor for the development of peripheral glia. Our strategy utilizing relatively accessible techniques and tools should be applicable to studying the function of other transcription factors.

  4. Potential downstream target genes of aberrant ETS transcription factors are differentially affected in Ewing's sarcoma and prostate carcinoma.

    Directory of Open Access Journals (Sweden)

    Maria J Camões

    Full Text Available FLI1 and ERG, the major ETS transcription factors involved in rearrangements in the Ewing's sarcoma family of tumors (ESFT and in prostate carcinomas (PCa, respectively, belong to the same subfamily, having 98% sequence identity in the DNA binding domain. We therefore decided to investigate whether the aberrant transcription factors in both malignancies have some common downstream targets. We crossed a publicly available list of all putative EWSR1-FLI1 target genes in ESFT with our microarray expression data on 24 PCa and 6 non-malignant prostate tissues (NPT and choose four genes among the top-most differentially expressed between PCa with (PCa ERG+ and without (PCa ETS- ETS fusion genes (HIST1H4L, KCNN2, ECRG4 and LDOC1, as well as four well-validated direct targets of the EWSR1-FLI1 chimeric protein in ESFT (NR0B1, CAV1, IGFBP3 and TGFBR2. Using quantitative expression analysis in 16 ESFT and seven alveolar rhabdomyosarcomas (ARMS, we were able to validate the four genes previously described as direct targets of the EWSR1-FLI1 oncoprotein, showing overexpression of CAV1 and NR0B1 and underexpression of IGFBP3 and TGFBR2 in ESFT as compared to ARMS. Although none of these four genes showed significant expression differences between PCa ERG+ and PCa ETS-, CAV1, IGFBP3 and TGFBR2 were less expressed in PCa in an independent series of 56 PCa and 15 NPT, as also observed for ECRG4 and LDOC1, suggesting a role in prostate carcinogenesis in general. On the other hand, we demonstrate for the first time that both HIST1H4L and KCNN2 are significantly overexpressed in PCa ERG+ and that ERG binds to the promoter of these genes. Conversely, KCNN2 was found underexpressed in ESFT relative to ARMS, suggesting that the EWSR1-ETS oncoprotein may have the opposite effect of ERG rearrangements in PCa. We conclude that aberrant ETS transcription factors modulate target genes differently in ESFT and PCa.

  5. Development of epidermal growth factor receptor targeted therapy in pancreatic cancer.

    Science.gov (United States)

    Qing, Liu; Qing, Wang

    2018-02-01

    The epidermal growth factor receptor (EGFR) family are a series of important cancer therapeutic targets involved in cancer biology. These genes play an important role in tumor biological characteristics including angiogenesis, cell survival, invasion and glucose metabolism. In recent years, progresses have been achieved upon the cellular and molecular biological characteristics of EGFR and its role in cancer development based on the study of tumor specimens and experimental animal model. EGFR(HER1/ErbB) is overexpressed in over sixty percent of triple-negative breast cancers and occurs in pancreatic, bladder, lung and head-and-neck cancers. Up to now, EGFR inhibitors have been applied in various of cancer, such as lung, breast, bladder and head and neck cancers etc., in which the combination of EGFR inhibitors plus chemotherapeutic agents is now seen as the standard of care for advanced/metastatic pancreatic cancer. For these reasons, EGFR inhibitors and their therapeutic effect for pancreatic cancer is becoming the focus in Laboratory and clinical research. In this paper, research progress of the development of epidermal growth factor receptor targeted therapy in pancreatic cancer is introduced.

  6. Modifying chemotherapy response by targeted inhibition of eukaryotic initiation factor 4A

    International Nuclear Information System (INIS)

    Cencic, R; Robert, F; Galicia-Vázquez, G; Malina, A; Ravindar, K; Somaiah, R; Pierre, P; Tanaka, J; Deslongchamps, P; Pelletier, J

    2013-01-01

    Translation is regulated predominantly at the initiation phase by several signal transduction pathways that are often usurped in human cancers, including the PI3K/Akt/mTOR axis. mTOR exerts unique administration over translation by regulating assembly of eukaryotic initiation factor (eIF) 4F, a heterotrimeric complex responsible for recruiting 40S ribosomes (and associated factors) to mRNA 5′ cap structures. Hence, there is much interest in targeted therapies that block eIF4F activity to assess the consequences on tumor cell growth and chemotherapy response. We report here that hippuristanol (Hipp), a translation initiation inhibitor that selectively inhibits the eIF4F RNA helicase subunit, eIF4A, resensitizes Eμ-Myc lymphomas to DNA damaging agents, including those that overexpress eIF4E—a modifier of rapamycin responsiveness. As Mcl-1 levels are significantly affected by Hipp, combining its use with the Bcl-2 family inhibitor, ABT-737, leads to a potent synergistic response in triggering cell death in mouse and human lymphoma and leukemia cells. Suppression of eIF4AI using RNA interference also synergized with ABT-737 in murine lymphomas, highlighting eIF4AI as a therapeutic target for modulating tumor cell response to chemotherapy

  7. Parental Factors Associated with Child Post-traumatic Stress Following Injury: A Consideration of Intervention Targets

    Directory of Open Access Journals (Sweden)

    Anna E. Wise

    2017-08-01

    Full Text Available Post-traumatic stress disorder (PTSD symptoms are relatively common following pediatric traumatic injury and are related to poor long-term child outcomes. However, due to concerns regarding the efficacy of early child preventive interventions, and difficulty intervening with injured and medicated children soon after the event, it is not feasible to provide early psychological interventions to children exposed to traumatic injury. Parental PTSD symptoms and reactions to the child’s traumatic injury impact child outcomes and provide potential targets for early intervention to reduce child symptom development without involving the child. The authors conducted a review of the literature using Psycinfo and Pubmed research databases (publication years = 1990–2017 and identified 65 published studies relevant to the topic of the review. The present review considers parent factors [parenting styles, parental post-traumatic pathology (PTS, adaptive and maladaptive coping strategies, and communication regarding the traumatic injury] and their impact on child PTS. We focus specifically on factors amenable to intervention. We further review moderators of these relationships (e.g., child age and gender, parent gender and conclude that it is unlikely that a one-size-fits-all approach to treatment will be successful. Rather, it is necessary to consider the age and gender of parent child dyads in designing and providing targeted interventions to families following the traumatic injury of a child.

  8. Verification of maximum radial power peaking factor due to insertion of FPM-LEU target in the core of RSG-GAS reactor

    Energy Technology Data Exchange (ETDEWEB)

    Setyawan, Daddy, E-mail: d.setyawan@bapeten.go.id [Center for Assessment of Regulatory System and Technology for Nuclear Installations and Materials, Indonesian Nuclear Energy Regulatory Agency (BAPETEN), Jl. Gajah Mada No. 8 Jakarta 10120 (Indonesia); Rohman, Budi [Licensing Directorate for Nuclear Installations and Materials, Indonesian Nuclear Energy Regulatory Agency (BAPETEN), Jl. Gajah Mada No. 8 Jakarta 10120 (Indonesia)

    2014-09-30

    Verification of Maximum Radial Power Peaking Factor due to insertion of FPM-LEU target in the core of RSG-GAS Reactor. Radial Power Peaking Factor in RSG-GAS Reactor is a very important parameter for the safety of RSG-GAS reactor during operation. Data of radial power peaking factor due to the insertion of Fission Product Molybdenum with Low Enriched Uranium (FPM-LEU) was reported by PRSG to BAPETEN through the Safety Analysis Report RSG-GAS for FPM-LEU target irradiation. In order to support the evaluation of the Safety Analysis Report incorporated in the submission, the assessment unit of BAPETEN is carrying out independent assessment in order to verify safety related parameters in the SAR including neutronic aspect. The work includes verification to the maximum radial power peaking factor change due to the insertion of FPM-LEU target in RSG-GAS Reactor by computational method using MCNP5and ORIGEN2. From the results of calculations, the new maximum value of the radial power peaking factor due to the insertion of FPM-LEU target is 1.27. The results of calculations in this study showed a smaller value than 1.4 the limit allowed in the SAR.

  9. Pharmacological targeting of the transcription factor SOX18 delays breast cancer in mice

    Science.gov (United States)

    Overman, Jeroen; Fontaine, Frank; Moustaqil, Mehdi; Mittal, Deepak; Sierecki, Emma; Sacilotto, Natalia; Zuegg, Johannes; Robertson, Avril AB; Holmes, Kelly; Salim, Angela A; Mamidyala, Sreeman; Butler, Mark S; Robinson, Ashley S; Lesieur, Emmanuelle; Johnston, Wayne; Alexandrov, Kirill; Black, Brian L; Hogan, Benjamin M; De Val, Sarah; Capon, Robert J; Carroll, Jason S; Bailey, Timothy L; Koopman, Peter; Jauch, Ralf; Smyth, Mark J; Cooper, Matthew A; Gambin, Yann; Francois, Mathias

    2017-01-01

    Pharmacological targeting of transcription factors holds great promise for the development of new therapeutics, but strategies based on blockade of DNA binding, nuclear shuttling, or individual protein partner recruitment have yielded limited success to date. Transcription factors typically engage in complex interaction networks, likely masking the effects of specifically inhibiting single protein-protein interactions. Here, we used a combination of genomic, proteomic and biophysical methods to discover a suite of protein-protein interactions involving the SOX18 transcription factor, a known regulator of vascular development and disease. We describe a small-molecule that is able to disrupt a discrete subset of SOX18-dependent interactions. This compound selectively suppressed SOX18 transcriptional outputs in vitro and interfered with vascular development in zebrafish larvae. In a mouse pre-clinical model of breast cancer, treatment with this inhibitor significantly improved survival by reducing tumour vascular density and metastatic spread. Our studies validate an interactome-based molecular strategy to interfere with transcription factor activity, for the development of novel disease therapeutics. DOI: http://dx.doi.org/10.7554/eLife.21221.001 PMID:28137359

  10. Mipu1, a novel direct target gene, is involved in hypoxia inducible factor 1-mediated cytoprotection.

    Directory of Open Access Journals (Sweden)

    Kangkai Wang

    Full Text Available Mipu1 (myocardial ischemic preconditioning up-regulated protein 1, recently identified in our lab, is a novel zinc-finger transcription factor which is up-regulated during ischemic preconditioning. However, it is not clear what transcription factor contributes to its inducible expression. In the present study, we reported that HIF-1 regulates the inducible expression of Mipu1 which is involved in the cytoprotection of HIF-1α against oxidative stress by inhibiting Bax expression. Our results showed that the inducible expression of Mipu1 was associated with the expression and activation of transcription factor HIF-1 as indicated by cobalt chloride (CoCl2 treatment, HIF-1α overexpression and knockdown assays. EMSA and luciferase reporter gene assays showed that HIF-1α bound to the hypoxia response element (HRE within Mipu1 promoter region and promoted its transcription. Moreover, our results revealed that Mipu1 inhibited the expression of Bax, an important pro-apoptosis protein associated with the intrinsic pathway of apoptosis, elevating the cytoprotection of HIF-1 against hydrogen peroxide (H2O2-mediated injury in H9C2 cells. Our findings implied that Bax may be a potential target gene of transcription factor Mipu1, and provided a novel insight for understanding the cytoprotection of HIF-1 and new clues for further elucidating the mechanisms by which Mipu1 protects cell against pathological stress.

  11. Complexity of CNC transcription factors as revealed by gene targeting of the Nrf3 locus.

    Science.gov (United States)

    Derjuga, Anna; Gourley, Tania S; Holm, Teresa M; Heng, Henry H Q; Shivdasani, Ramesh A; Ahmed, Rafi; Andrews, Nancy C; Blank, Volker

    2004-04-01

    Cap'n'collar (CNC) family basic leucine zipper transcription factors play crucial roles in the regulation of mammalian gene expression and development. To determine the in vivo function of the CNC protein Nrf3 (NF-E2-related factor 3), we generated mice deficient in this transcription factor. We performed targeted disruption of two Nrf3 exons coding for CNC homology, basic DNA-binding, and leucine zipper dimerization domains. Nrf3 null mice developed normally and revealed no obvious phenotypic differences compared to wild-type animals. Nrf3(-/-) mice were fertile, and gross anatomy as well as behavior appeared normal. The mice showed normal age progression and did not show any apparent additional phenotype during their life span. We observed no differences in various blood parameters and chemistry values. We infected wild-type and Nrf3(-/-) mice with acute lymphocytic choriomeningitis virus and found no differences in these animals with respect to their number of virus-specific CD8 and CD4 T cells as well as their B-lymphocyte response. To determine whether the mild phenotype of Nrf3 null animals is due to functional redundancy, we generated mice deficient in multiple CNC factors. Contrary to our expectations, an absence of Nrf3 does not seem to cause additional lethality in compound Nrf3(-/-)/Nrf2(-/-) and Nrf3(-/-)/p45(-/-) mice. We hypothesize that the role of Nrf3 in vivo may become apparent only after appropriate challenge to the mice.

  12. Expression of hypoxia-inducible factor 1 alpha and its downstream targets in fibroepithelial tumors of the breast

    NARCIS (Netherlands)

    Kuijper, Arno; Groep, P. van der; Wall, E. van der; Diest, P.J. van

    2005-01-01

    INTRODUCTION Hypoxia-inducible factor 1 (HIF-1) alpha and its downstream targets carbonic anhydrase IX (CAIX) and vascular endothelial growth factor (VEGF) are key factors in the survival of proliferating tumor cells in a hypoxic microenvironment. We studied the expression and prognostic relevance

  13. Network motif-based identification of transcription factor-target gene relationships by integrating multi-source biological data

    Directory of Open Access Journals (Sweden)

    de los Reyes Benildo G

    2008-04-01

    Full Text Available Abstract Background Integrating data from multiple global assays and curated databases is essential to understand the spatio-temporal interactions within cells. Different experiments measure cellular processes at various widths and depths, while databases contain biological information based on established facts or published data. Integrating these complementary datasets helps infer a mutually consistent transcriptional regulatory network (TRN with strong similarity to the structure of the underlying genetic regulatory modules. Decomposing the TRN into a small set of recurring regulatory patterns, called network motifs (NM, facilitates the inference. Identifying NMs defined by specific transcription factors (TF establishes the framework structure of a TRN and allows the inference of TF-target gene relationship. This paper introduces a computational framework for utilizing data from multiple sources to infer TF-target gene relationships on the basis of NMs. The data include time course gene expression profiles, genome-wide location analysis data, binding sequence data, and gene ontology (GO information. Results The proposed computational framework was tested using gene expression data associated with cell cycle progression in yeast. Among 800 cell cycle related genes, 85 were identified as candidate TFs and classified into four previously defined NMs. The NMs for a subset of TFs are obtained from literature. Support vector machine (SVM classifiers were used to estimate NMs for the remaining TFs. The potential downstream target genes for the TFs were clustered into 34 biologically significant groups. The relationships between TFs and potential target gene clusters were examined by training recurrent neural networks whose topologies mimic the NMs to which the TFs are classified. The identified relationships between TFs and gene clusters were evaluated using the following biological validation and statistical analyses: (1 Gene set enrichment

  14. Inflation targeting and inflation performance : a comparative analysis

    NARCIS (Netherlands)

    Samarina, Anna; De Haan, Jakob; Terpstra, M.

    2014-01-01

    This article examines how the impact of inflation targeting on inflation performance depends on the choice of country samples, adoption dates, time periods and methodological approaches. We apply two different estimation methods - difference-in-differences and propensity score matching - for our

  15. Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis

    Directory of Open Access Journals (Sweden)

    Huthmacher Carola

    2010-08-01

    Full Text Available Abstract Background Despite enormous efforts to combat malaria the disease still afflicts up to half a billion people each year of which more than one million die. Currently no approved vaccine is available and resistances to antimalarials are widely spread. Hence, new antimalarial drugs are urgently needed. Results Here, we present a computational analysis of the metabolism of Plasmodium falciparum, the deadliest malaria pathogen. We assembled a compartmentalized metabolic model and predicted life cycle stage specific metabolism with the help of a flux balance approach that integrates gene expression data. Predicted metabolite exchanges between parasite and host were found to be in good accordance with experimental findings when the parasite's metabolic network was embedded into that of its host (erythrocyte. Knock-out simulations identified 307 indispensable metabolic reactions within the parasite. 35 out of 57 experimentally demonstrated essential enzymes were recovered and another 16 enzymes, if additionally the assumption was made that nutrient uptake from the host cell is limited and all reactions catalyzed by the inhibited enzyme are blocked. This predicted set of putative drug targets, shown to be enriched with true targets by a factor of at least 2.75, was further analyzed with respect to homology to human enzymes, functional similarity to therapeutic targets in other organisms and their predicted potency for prophylaxis and disease treatment. Conclusions The results suggest that the set of essential enzymes predicted by our flux balance approach represents a promising starting point for further drug development.

  16. Thermal shock analysis of liquid-mercury spallation target

    CERN Document Server

    Ishikura, S; Futakawa, M; Hino, R; Date, H

    2002-01-01

    The developments of the neutron scattering facilities are carried out under the high-intensity proton accelerator project promoted by JAERI and KEK. To estimate the structural integrity of the heavy liquid-metal (Hg) target used as a spallation neutron source in a MW-class neutron scattering facility, dynamic stress behavior due to the incident of a 1 MW-pulsed proton beam was analyzed by using FEM code. Two-type target containers with semi-cylindrical type and flat-plate type window were used as models for analyses. As a result, it is confirmed that the stress (pressure wave) generated by dynamic thermal shock becomes the largest at the center of window, and the flat-plate type window is more advantageous from the structural viewpoint than the semi-cylindrical type window. It has been understood that the stress generated in the window by the pressure wave can be treated as the secondary stress. (author)

  17. Transcription Factors Expressed in Lateral Organ Boundaries: Identification of Downstream Targets

    Energy Technology Data Exchange (ETDEWEB)

    Springer, Patricia S

    2010-07-12

    The processes of lateral organ initiation and patterning are central to the generation of mature plant form. Characterization of the molecular mechanisms underlying these processes is essential to our understanding of plant development. Communication between the shoot apical meristem and initiating organ primordia is important both for functioning of the meristem and for proper organ patterning, and very little is known about this process. In particular, the boundary between meristem and leaf is emerging as a critical region that is important for SAM maintenance and regulation of organogenesis. The goal of this project was to characterize three boundary-expressed genes that encode predicted transcription factors. Specifically, we have studied LATERAL ORGAN BOUNDARIES (LOB), LATERAL ORGAN FUSION1 (LOF1), and LATERAL ORGAN FUSION2 (LOF2). LOB encodes the founding member of the LOB-DOMAIN (LBD) plant-specific DNA binding transcription factor family and LOF1 and LOF2 encode paralogous MYB-domain transcription factors. We characterized the genetic relationship between these three genes and other boundary and meristem genes. We also used an ectopic inducible expression system to identify direct targets of LOB.

  18. B-cell activating factor in the pathophysiology of multiple myeloma: a target for therapy?

    International Nuclear Information System (INIS)

    Hengeveld, P J; Kersten, M J

    2015-01-01

    Multiple myeloma (MM) is a currently incurable malignancy of plasma cells. Malignant myeloma cells (MMCs) are heavily dependent upon the bone marrow (BM) microenvironment for their survival. One component of this tumor microenvironment, B-Cell Activating Factor (BAFF), has been implicated as a key player in this interaction. This review discusses the role of BAFF in the pathophysiology of MM, and the potential of BAFF-inhibitory therapy for the treatment of MM. Multiple studies have shown that BAFF functions as a survival factor for MMCs. Furthermore, MMCs express several BAFF-binding receptors. Of these, only Transmembrane Activator and CAML Interactor (TACI) correlates with the MMC's capability to ligate BAFF. Additionally, the level of expression of TACI correlates with the level of the MMC's BM dependency. Ligation of BAFF receptors on MMCs causes activation of the Nuclear Factor of κ-B (NF-κB) pathway, a crucial pathway for the pathogenesis of many B-cell malignancies. Serum BAFF levels are significantly elevated in MM patients when compared to healthy controls, and correlate inversely with overall survival. BAFF signaling is thus an interesting target for the treatment of MM. Several BAFF-inhibitory drugs are currently under evaluation for the treatment of MM. These include BAFF-monoclonal antibodies (tabalumab) and antibody-drug conjugates (GSK2857916)

  19. Analysis of an XADS Target with the System Code TRACE

    International Nuclear Information System (INIS)

    Jaeger, Wadim; Sanchez Espinoza, Victor H.; Feng, Bo

    2008-01-01

    Accelerator-driven systems (ADS) present an option to reduce the radioactive waste of the nuclear industry. The experimental Accelerator-Driven System (XADS) has been designed to investigate the feasibility of using ADS on an industrial scale to burn minor actinides. The target section lies in the middle of the subcritical core and is bombarded by a proton beam to produce spallation neutrons. The thermal energy produced from this reaction requires a heat removal system for the target section. The target is cooled by liquid lead-bismuth-eutectics (LBE) in the primary system which in turn transfers the heat via a heat exchanger (HX) to the secondary coolant, Diphyl THT (DTHT), a synthetic diathermic fluid. Since this design is still in development, a detailed investigation of the system is necessary to evaluate the behavior during normal and transient operations. Due to the lack of experimental facilities and data for ADS, the analyses are mostly done using thermal hydraulic codes. In addition to evaluating the thermal hydraulics of the XADS, this paper also benchmarks a new code developed by the NRC, TRACE, against other established codes. The events used in this study are beam power switch-on/off transients and a loss of heat sink accident. The obtained results from TRACE were in good agreement with the results of various other codes. (authors)

  20. Analysis of Mo99 production irradiating 20% U targets

    International Nuclear Information System (INIS)

    Calabrese, C. Ruben; Grant, Carlos R.; Marajofsky, Andres; Parkansky, David G.

    1999-01-01

    At present time, the National Atomic Energy Commission is producing about 800 Ci of Mo99 per week irradiating 90% enriched uranium-aluminum alloy plate targets in the RA-3 reactor, a 5 MW. Mtr type one. In order to change to 20% enriched uranium, and to increase the production to about 3000 Ci per week some configurations were studied with rod and plate geometry with uranium (20% enriched) -aluminum targets. The first case was the irradiation of a plate target element in the normal reactor configuration. Results showed a good efficiency, but both reactivity value and power density were too high. An element with rods was also analyzed, but results showed a poor efficiency, too much aluminum involved in the process, although a low reactivity and an acceptable rod power density. Finally, a solution consisting of plate elements with a Zircaloy cladding was adopted, which has shown not only a good efficiency, but it is also acceptable from the viewpoint of safety, heat transference criteria and feasibility

  1. Elongation factor 1 alpha1 and genes associated with Usher syndromes are downstream targets of GBX2.

    Directory of Open Access Journals (Sweden)

    David A Roeseler

    Full Text Available Gbx2 encodes a DNA-binding transcription factor that plays pivotal roles during embryogenesis. Gain-and loss-of-function studies in several vertebrate species have demonstrated a requirement for Gbx2 in development of the anterior hindbrain, spinal cord, inner ear, heart, and neural crest cells. However, the target genes through which GBX2 exerts its effects remain obscure. Using chromatin immunoprecipitation coupled with direct sequencing (ChIP-Seq analysis in a human prostate cancer cell line, we identified cis-regulatory elements bound by GBX2 to provide insight into its direct downstream targets. The analysis revealed more than 286 highly significant candidate target genes, falling into various functional groups, of which 51% are expressed in the nervous system. Several of the top candidate genes include EEF1A1, ROBO1, PLXNA4, SLIT3, NRP1, and NOTCH2, as well as genes associated with the Usher syndrome, PCDH15 and USH2A, and are plausible candidates contributing to the developmental defects in Gbx2(-/- mice. We show through gel shift analyses that sequences within the promoter or introns of EEF1A1, ROBO1, PCDH15, USH2A and NOTCH2, are directly bound by GBX2. Consistent with these in vitro results, analyses of Gbx2(-/- embryos indicate that Gbx2 function is required for migration of Robo1-expressing neural crest cells out of the hindbrain. Furthermore, we show that GBX2 activates transcriptional activity through the promoter of EEF1A1, suggesting that GBX2 could also regulate gene expression indirectly via EEF1A. Taken together, our studies show that GBX2 plays a dynamic role in development and diseases.

  2. Comprehensive reanalysis of transcription factor knockout expression data in Saccharomyces cerevisiae reveals many new targets.

    Science.gov (United States)

    Reimand, Jüri; Vaquerizas, Juan M; Todd, Annabel E; Vilo, Jaak; Luscombe, Nicholas M

    2010-08-01

    Transcription factor (TF) perturbation experiments give valuable insights into gene regulation. Genome-scale evidence from microarray measurements may be used to identify regulatory interactions between TFs and targets. Recently, Hu and colleagues published a comprehensive study covering 269 TF knockout mutants for the yeast Saccharomyces cerevisiae. However, the information that can be extracted from this valuable dataset is limited by the method employed to process the microarray data. Here, we present a reanalysis of the original data using improved statistical techniques freely available from the BioConductor project. We identify over 100,000 differentially expressed genes-nine times the total reported by Hu et al. We validate the biological significance of these genes by assessing their functions, the occurrence of upstream TF-binding sites, and the prevalence of protein-protein interactions. The reanalysed dataset outperforms the original across all measures, indicating that we have uncovered a vastly expanded list of relevant targets. In summary, this work presents a high-quality reanalysis that maximizes the information contained in the Hu et al. compendium. The dataset is available from ArrayExpress (accession: E-MTAB-109) and it will be invaluable to any scientist interested in the yeast transcriptional regulatory system.

  3. A Plant Immune Receptor Detects Pathogen Effectors that Target WRKY Transcription Factors.

    Science.gov (United States)

    Sarris, Panagiotis F; Duxbury, Zane; Huh, Sung Un; Ma, Yan; Segonzac, Cécile; Sklenar, Jan; Derbyshire, Paul; Cevik, Volkan; Rallapalli, Ghanasyam; Saucet, Simon B; Wirthmueller, Lennart; Menke, Frank L H; Sohn, Kee Hoon; Jones, Jonathan D G

    2015-05-21

    Defense against pathogens in multicellular eukaryotes depends on intracellular immune receptors, yet surveillance by these receptors is poorly understood. Several plant nucleotide-binding, leucine-rich repeat (NB-LRR) immune receptors carry fusions with other protein domains. The Arabidopsis RRS1-R NB-LRR protein carries a C-terminal WRKY DNA binding domain and forms a receptor complex with RPS4, another NB-LRR protein. This complex detects the bacterial effectors AvrRps4 or PopP2 and then activates defense. Both bacterial proteins interact with the RRS1 WRKY domain, and PopP2 acetylates lysines to block DNA binding. PopP2 and AvrRps4 interact with other WRKY domain-containing proteins, suggesting these effectors interfere with WRKY transcription factor-dependent defense, and RPS4/RRS1 has integrated a "decoy" domain that enables detection of effectors that target WRKY proteins. We propose that NB-LRR receptor pairs, one member of which carries an additional protein domain, enable perception of pathogen effectors whose function is to target that domain. Copyright © 2015 Elsevier Inc. All rights reserved.

  4. Molecular Imaging of Hepatocellular Carcinoma Xenografts with Epidermal Growth Factor Receptor Targeted Affibody Probes

    Directory of Open Access Journals (Sweden)

    Ping Zhao

    2013-01-01

    Full Text Available Hepatocellular carcinoma (HCC is a highly aggressive and lethal cancer. It is typically asymptomatic at the early stage, with only 10%–20% of HCC patients being diagnosed early enough for appropriate surgical treatment. The delayed diagnosis of HCC is associated with limited treatment options and much lower survival rates. Therefore, the early and accurate detection of HCC is crucial to improve its currently dismal prognosis. The epidermal growth factor receptor (EGFR has been reported to be involved in HCC tumorigenesis and to represent an attractive target for HCC imaging and therapy. In this study, an affibody molecule, Ac-Cys-ZEGFR:1907, targeting the extracellular domain of EGFR, was used for the first time to assess its potential to detect HCC xenografts. By evaluating radio- or fluorescent-labeled Ac-Cys-ZEGFR:1907 as a probe for positron emission tomography (PET or optical imaging of HCC, subcutaneous EGFR-positive HCC xenografts were found to be successfully imaged by the PET probe. Thus, affibody-based PET imaging of EGFR provides a promising approach for detecting HCC in vivo.

  5. An Interbacterial NAD(P)+ Glycohydrolase Toxin Requires Elongation Factor Tu for Delivery to Target Cells

    Energy Technology Data Exchange (ETDEWEB)

    Whitney, John C.; Quentin, Dennis; Sawai, Shin; LeRoux, Michele; Harding, Brittany N.; Ledvina, Hannah E.; Tran, Bao Q.; Robinson, Howard; Goo, Young Ah; Goodlett, David R.; Raunser, Stefan; Mougous, Joseph D.

    2015-10-08

    Type VI secretion (T6S) influences the composition of microbial communities by catalyzing the delivery of toxins between adjacent bacterial cells. Here, we demonstrate that a T6S integral membrane toxin from Pseudomonas aeruginosa, Tse6, acts on target cells by degrading the universally essential dinucleotides NAD+ and NADP+. Structural analyses of Tse6 show that it resembles mono-ADP-ribosyltransferase proteins, such as diphtheria toxin, with the exception of a unique loop that both excludes proteinaceous ADP-ribose acceptors and contributes to hydrolysis. We find that entry of Tse6 into target cells requires its binding to an essential housekeeping protein, translation elongation factor Tu (EF-Tu). These proteins participate in a larger assembly that additionally directs toxin export and provides chaperone activity. Visualization of this complex by electron microscopy defines the architecture of a toxin-loaded T6S apparatus and provides mechanistic insight into intercellular membrane protein delivery between bacteria.

  6. Hypoxia-Inducible Factor-1 as a Therapeutic Target in Endometrial Cancer Management

    Directory of Open Access Journals (Sweden)

    Laura M. S. Seeber

    2010-01-01

    Full Text Available In the Western world, endometrial cancer (EC is the most common malignant tumor of the female genital tract. Solid tumors like EC outgrow their vasculature resulting in hypoxia. Tumor hypoxia is important because it renders an aggressive phenotype and leads to radio- and chemo-therapy resistance. Hypoxia-inducible factor-1 (HIF-1 plays an essential role in the adaptive cellular response to hypoxia and is associated with poor clinical outcome in EC. Therefore, HIF-1 could be an attractive therapeutic target. Selective HIF-1 inhibitors have not been identified. A number of nonselective inhibitors which target signaling pathways upstream or downstream HIF-1 are known to decrease HIF-1 protein levels. In clinical trials for the treatment of advanced and/or recurrent EC are the topoisomerase I inhibitor Topotecan, mTOR-inhibitor Rapamycin, and angiogenesis inhibitor Bevacizumab. Preliminary data shows encouraging results for these agents. Further work is needed to identify selective HIF-1 inhibitors and to translate these into clinical trials.

  7. Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

    Directory of Open Access Journals (Sweden)

    David Olmos

    2011-01-01

    Full Text Available Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response.

  8. Targeting the Insulin-Like Growth Factor 1 Receptor in Ewing's Sarcoma: Reality and Expectations

    Science.gov (United States)

    Olmos, David; Martins, Ana Sofia; Jones, Robin L.; Alam, Salma; Scurr, Michelle; Judson, Ian R.

    2011-01-01

    Ewing's sarcoma family of tumours comprises a group of very aggressive diseases that are potentially curable with multimodality treatment. Despite the undoubted success of current treatment, approximately 30% of patients will relapse and ultimately die of disease. The insulin-like growth factor 1 receptor (IGF-1R) has been implicated in the genesis, growth, proliferation, and the development of metastatic disease in Ewing's sarcoma. In addition, IGF1-R has been validated, both in vitro and in vivo, as a potential therapeutic target in Ewing's sarcoma. Phase I studies of IGF-1R monoclonal antibodies reported several radiological and clinical responses in Ewing's sarcoma patients, and initial reports of several Phase II studies suggest that about a fourth of the patients would benefit from IGF-1R monoclonal antibodies as single therapy, with approximately 10% of patients achieving objective responses. Furthermore, these therapies are well tolerated, and thus far severe toxicity has been rare. Other studies assessing IGF-1R monoclonal antibodies in combination with traditional cytotoxics or other targeted therapies are expected. Despite, the initial promising results, not all patients benefit from IGF-1R inhibition, and consequently, there is an urgent need for the identification of predictive markers of response. PMID:21647361

  9. The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

    Science.gov (United States)

    Garcia-Huerta, Paula; Troncoso-Escudero, Paulina; Jerez, Carolina; Hetz, Claudio; Vidal, Rene L

    2016-10-15

    One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Targeting Insulin and Insulin-Like Growth Factor Pathways in Epithelial Ovarian Cancer

    Directory of Open Access Journals (Sweden)

    Marie-Claude Beauchamp

    2010-01-01

    Full Text Available Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment.

  11. Factors affecting physical therapists' job satisfaction: questionnaire survey targeting first-year physical therapists.

    Science.gov (United States)

    Kota, Munetsugu; Kudo, Hiroyuki; Okita, Kazuhiko

    2018-04-01

    [Purpose] The survey aimed to clarify the factors that affect physiotherapists' job satisfaction. [Subjects and Methods] To examine factors affecting physical therapists' job satisfaction using a cross-sectional study with a questionnaire survey. Subjects were 193 first-year physical therapists who participated in a newcomer orientation at Hiroshima Prefectural Physical Therapy Association. The questionnaire comprised items concerning physical therapists' satisfaction with their work, motives for becoming physical therapists, education in school, internships, the workplace, and comfort in the workplace. [Results] Subjects were divided into two groups according to their satisfaction with their occupation. The "high satisfaction" group included 157 subjects, and the group "low satisfaction" group included 36 subjects. Using logistic regression analysis, items concerning comfort in the workplace, motives for becoming physical therapists, and learning in school were analysed. [Conclusion] Factors affecting physical therapists' job satisfaction were primarily influenced by previous experience and working conditions.

  12. CD47 is an adverse prognostic factor and a therapeutic target in gastric cancer

    International Nuclear Information System (INIS)

    Yoshida, Kazumichi; Tsujimoto, Hironori; Matsumura, Kouji; Kinoshita, Manabu; Takahata, Risa; Matsumoto, Yusuke; Hiraki, Shuichi; Ono, Satoshi; Seki, Shuhji; Yamamoto, Junji; Hase, Kazuo

    2015-01-01

    CD47 is an antiphagocytic molecule that acts via ligation to signal regulatory protein alpha on phagocytes; its enhanced expression and therapeutic targeting have recently been reported for several malignancies. However, CD47 expression in gastric cancer is not well documented. Immunohistochemical expression of CD47 in surgical specimens was investigated. Expression of CD47 and CD44, a known gastric cancer stem cell marker, were investigated in gastric cancer cell lines by flow cytometry. MKN45 and MKN74 gastric cancer cells were sorted by fluorescence-activated cell sorting according to CD44 and CD47 expression levels, and their in vitro proliferation, spheroid-forming capacity, and in vivo tumorigenicity were studied. In vitro phagocytosis of cancer cells by human macrophages in the presence of a CD47 blocking monoclonal antibody (B6H12) and the survival of immunodeficient mice intraperitoneally engrafted with MKN45 cells and B6H12 were compared to experiments using control antibodies. Immunohistochemistry of the clinical specimens indicated that CD47 was positive in 57 out of 115 cases, and its positivity was an independent adverse prognostic factor. Approximately 90% of the MKN45 and MKN74 cells expressed CD47 and CD44. CD47 hi gastric cancer cells showed significantly higher proliferation and spheroid colony formation than CD47 lo , and CD44 hi CD47 hi cells showed the highest proliferation in vitro and tumorigenicity in vivo. B6H12 significantly enhanced in vitro phagocytosis of cancer cells by human macrophages and prolonged the survival of intraperitoneal cancer dissemination in mice compared to control antibodies. In conclusion, CD47 is an adverse prognostic factor and promising therapeutic target in gastric cancer

  13. Recombinant epidermal growth factor-like domain-1 from coagulation factor VII functionalized iron oxide nanoparticles for targeted glioma magnetic resonance imaging.

    Science.gov (United States)

    Liu, Heng; Chen, Xiao; Xue, Wei; Chu, Chengchao; Liu, Yu; Tong, Haipeng; Du, Xuesong; Xie, Tian; Liu, Gang; Zhang, Weiguo

    The highly infiltrative and invasive nature of glioma cells often leads to blurred tumor margins, resulting in incomplete tumor resection and tumor recurrence. Accurate detection and precise delineation of glioma help in preoperative delineation, surgical planning and survival prediction. In this study, recombinant epidermal growth factor-like domain-1, derived from human coagulation factor VII, was conjugated to iron oxide nanoparticles (IONPs) for targeted glioma magnetic resonance (MR) imaging. The synthesized EGF1-EGFP-IONPs exhibited excellent targeting ability toward tissue factor (TF)-positive U87MG cells and human umbilical vein endothelial cells in vitro, and demonstrated persistent and efficient MR contrast enhancement up to 12 h for preclinical glioma models with high targeting specificity in vivo. They hold great potential for clinical translation and developing targeted theranostics against brain glioma.

  14. Daboxin P, a Major Phospholipase A2 Enzyme from the Indian Daboia russelii russelii Venom Targets Factor X and Factor Xa for Its Anticoagulant Activity.

    Directory of Open Access Journals (Sweden)

    Maitreyee Sharma

    Full Text Available In the present study a major protein has been purified from the venom of Indian Daboia russelii russelii using gel filtration, ion exchange and Rp-HPLC techniques. The purified protein, named daboxin P accounts for ~24% of the total protein of the crude venom and has a molecular mass of 13.597 kDa. It exhibits strong anticoagulant and phospholipase A2 activity but is devoid of any cytotoxic effect on the tested normal or cancerous cell lines. Its primary structure was deduced by N-terminal sequencing and chemical cleavage using Edman degradation and tandem mass spectrometry. It is composed of 121 amino acids with 14 cysteine residues and catalytically active His48 -Asp49 pair. The secondary structure of daboxin P constitutes 42.73% of α-helix and 12.36% of β-sheet. It is found to be stable at acidic (pH 3.0 and neutral pH (pH 7.0 and has a Tm value of 71.59 ± 0.46°C. Daboxin P exhibits anticoagulant effect under in-vitro and in-vivo conditions. It does not inhibit the catalytic activity of the serine proteases but inhibits the activation of factor X to factor Xa by the tenase complexes both in the presence and absence of phospholipids. It also inhibits the tenase complexes when active site residue (His48 was alkylated suggesting its non-enzymatic mode of anticoagulant activity. Moreover, it also inhibits prothrombinase complex when pre-incubated with factor Xa prior to factor Va addition. Fluorescence emission spectroscopy and affinity chromatography suggest the probable interaction of daboxin P with factor X and factor Xa. Molecular docking analysis reveals the interaction of the Ca+2 binding loop; helix C; anticoagulant region and C-terminal region of daboxin P with the heavy chain of factor Xa. This is the first report of a phospholipase A2 enzyme from Indian viper venom which targets both factor X and factor Xa for its anticoagulant activity.

  15. Time Series Factor Analysis with an Application to Measuring Money

    NARCIS (Netherlands)

    Gilbert, Paul D.; Meijer, Erik

    2005-01-01

    Time series factor analysis (TSFA) and its associated statistical theory is developed. Unlike dynamic factor analysis (DFA), TSFA obviates the need for explicitly modeling the process dynamics of the underlying phenomena. It also differs from standard factor analysis (FA) in important respects: the

  16. Evaluating Transcription Factor Activity Changes by Scoring Unexplained Target Genes in Expression Data.

    Directory of Open Access Journals (Sweden)

    Evi Berchtold

    Full Text Available Several methods predict activity changes of transcription factors (TFs from a given regulatory network and measured expression data. But available gene regulatory networks are incomplete and contain many condition-dependent regulations that are not relevant for the specific expression measurement. It is not known which combination of active TFs is needed to cause a change in the expression of a target gene. A method to systematically evaluate the inferred activity changes is missing. We present such an evaluation strategy that indicates for how many target genes the observed expression changes can be explained by a given set of active TFs. To overcome the problem that the exact combination of active TFs needed to activate a gene is typically not known, we assume a gene to be explained if there exists any combination for which the predicted active TFs can possibly explain the observed change of the gene. We introduce the i-score (inconsistency score, which quantifies how many genes could not be explained by the set of activity changes of TFs. We observe that, even for these minimal requirements, published methods yield many unexplained target genes, i.e. large i-scores. This holds for all methods and all expression datasets we evaluated. We provide new optimization methods to calculate the best possible (minimal i-score given the network and measured expression data. The evaluation of this optimized i-score on a large data compendium yields many unexplained target genes for almost every case. This indicates that currently available regulatory networks are still far from being complete. Both the presented Act-SAT and Act-A* methods produce optimal sets of TF activity changes, which can be used to investigate the difficult interplay of expression and network data. A web server and a command line tool to calculate our i-score and to find the active TFs associated with the minimal i-score is available from https://services.bio.ifi.lmu.de/i-score.

  17. Proteomics analysis of antimalarial targets of Garcinia mangostana Linn.

    Institute of Scientific and Technical Information of China (English)

    Wanna; Chaijaroenkul; Artitiya; Thiengsusuk; Kanchana; Rungsihirunrat; Stephen; Andrew; Ward; Kesara; Na-Bangchang

    2014-01-01

    Objective:To investigate possible protein targets for antimalarial activity of Garcina mangostana Linn.(G.mangostana)(pericarp)in 3D7 Plasmodium falciparum clone using 2-dimensional electrophoresis and liquid chromatography mass-spectrometry(LC/MS/MS).Methods:3D7 Plasmodium falciparum was exposed to the crude ethanolic extract of G.mangostana Linn.(pericarp)at the concentrations of 12μg/mL(1C50level:concentration that inhibits parasite growth by 50%)and 30μg/mL(1C90level:concentration that inhibits parasite growth by 90%)for 12 h.Parasite proteins were separated by 2-dimensional electrophoresis and identified by LC/MS/MS.Results:At the IC50concentration,about 82%of the expressed parasite proteins were matched with the control(non-exposed),while at the IC90concentration,only 15%matched proteins were found.The selected protein spots from parasite exposed to the plant extract at the concentration of 12μg/mL were identified as eneymes that play role in glycolysis pathway,i.e.,phosphoglyeerate mutase putative,L-lactate dehydrogenase/glyceraldehyde-3-phosphate dehydrogenase,and fruetose-bisphosphate aldolase/phosphoglyeerate kinase.The proteosome was found in parasite exposed to 30μg/mL of the extract.Conclusions:Results suggest that proteins involved in the glycolysis pathway may be the targets for antimalarial activity of G.mangostana Linn.(pericarp).

  18. miR-370 suppresses HBV gene expression and replication by targeting nuclear factor IA.

    Science.gov (United States)

    Fan, Hongxia; Lv, Ping; Lv, Jing; Zhao, Xiaopei; Liu, Min; Zhang, Guangling; Tang, Hua

    2017-05-01

    Hepatitis B virus (HBV) infection is a major health problem worldwide. The roles of microRNAs in the regulation of HBV expression are being increasingly recognized. In this study, we found that overexpression of miR-370 suppressed HBV gene expression and replication in Huh7 cells, whereas antisense knockdown of endogenous miR-370 enhanced HBV gene expression and replication in Huh7 cells and HepG2.2.15 cells. Further, we identified the transcription factor nuclear factor IA (NFIA) as a new host target of miR-370. Overexpression and knockdown studies showed that NFIA stimulated HBV gene expression and replication. Importantly, overexpression of NFIA counteracted the effect of miR-370 on HBV gene expression and replication. Further mechanistic studies showed that miR-370 suppressed HBV replication and gene expression by repressing HBV Enhancer I activity, and one of the NFIA binding site in the Enhancer I element was responsible for the repressive effect of miR-370 on HBV Enhancer I activity. Altogether, our results demonstrated that miR-370 suppressed HBV gene expression and replication through repressing NFIA expression, which stimulates HBV replication via direct regulation on HBV Enhancer I activities. Our findings may provide a new antiviral strategy for HBV infection. J. Med. Virol. 89:834-844, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  19. Thermal analysis of titanium drive-in target for D-D neutron generation.

    Science.gov (United States)

    Jung, N S; Kim, I J; Kim, S J; Choi, H D

    2010-01-01

    Thermal analysis was performed for a titanium drive-in target of a D-D neutron generator. Computational fluid dynamics code CFX-5 was used in this study. To define the heat flux term for the thermal analysis, beam current profile was measured. Temperature of the target was calculated at some of the operating conditions. The cooling performance of the target was evaluated by means of the comparison of the calculated maximum target temperature and the critical temperature of titanium. Copyright 2009 Elsevier Ltd. All rights reserved.

  20. The efficacy of targeted interventions for modifiable psychosocial risk factors of persistent nonspecific low back pain e A systematic review

    DEFF Research Database (Denmark)

    Kent, Peter; Kjær, Per

    2012-01-01

    Background: There is considerable interest in whether best practice management of nonspecific low back pain (NSLBP) should include the targeting of treatment to subgroups of people with identifiable clinical characteristics. However, there are no published systematic reviews of the efficacy...... were randomised controlled trials of targeted psychosocial interventions that used trial designs capable of providing robust information on the efficacy of targeted treatment (treatment effect modification) for the outcomes of pain, activity limitation and psychosocial factors (fear avoidance...... limitation at 12 months, when targeted to people with higher movement-related pain. Few studies have investigated targeted psychosocial interventions in NSLBP, using trial designs suitable for measuring treatment effect modification, and they do not provide consistent evidence supporting such targeting...

  1. An integrative genomic and transcriptomic analysis reveals potential targets associated with cell proliferation in uterine leiomyomas.

    Directory of Open Access Journals (Sweden)

    Priscila Daniele Ramos Cirilo

    Full Text Available Uterine Leiomyomas (ULs are the most common benign tumours affecting women of reproductive age. ULs represent a major problem in public health, as they are the main indication for hysterectomy. Approximately 40-50% of ULs have non-random cytogenetic abnormalities, and half of ULs may have copy number alterations (CNAs. Gene expression microarrays studies have demonstrated that cell proliferation genes act in response to growth factors and steroids. However, only a few genes mapping to CNAs regions were found to be associated with ULs.We applied an integrative analysis using genomic and transcriptomic data to identify the pathways and molecular markers associated with ULs. Fifty-one fresh frozen specimens were evaluated by array CGH (JISTIC and gene expression microarrays (SAM. The CONEXIC algorithm was applied to integrate the data.The integrated analysis identified the top 30 significant genes (P<0.01, which comprised genes associated with cancer, whereas the protein-protein interaction analysis indicated a strong association between FANCA and BRCA1. Functional in silico analysis revealed target molecules for drugs involved in cell proliferation, including FGFR1 and IGFBP5. Transcriptional and protein analyses showed that FGFR1 (P = 0.006 and P<0.01, respectively and IGFBP5 (P = 0.0002 and P = 0.006, respectively were up-regulated in the tumours when compared with the adjacent normal myometrium.The integrative genomic and transcriptomic approach indicated that FGFR1 and IGFBP5 amplification, as well as the consequent up-regulation of the protein products, plays an important role in the aetiology of ULs and thus provides data for potential drug therapies development to target genes associated with cellular proliferation in ULs.

  2. MOOC Success Factors: Proposal of an Analysis Framework

    Directory of Open Access Journals (Sweden)

    Margarida M. Marques

    2017-10-01

    Full Text Available Aim/Purpose: From an idea of lifelong-learning-for-all to a phenomenon affecting higher education, Massive Open Online Courses (MOOCs can be the next step to a truly universal education. Indeed, MOOC enrolment rates can be astoundingly high; still, their completion rates are frequently disappointingly low. Nevertheless, as courses, the participants’ enrolment and learning within the MOOCs must be considered when assessing their success. In this paper, the authors’ aim is to reflect on what makes a MOOC successful to propose an analysis framework of MOOC success factors. Background: A literature review was conducted to identify reported MOOC success factors and to propose an analysis framework. Methodology: This literature-based framework was tested against data of a specific MOOC and refined, within a qualitative interpretivist methodology. The data were collected from the ‘As alterações climáticas nos média escolares - Clima@EduMedia’ course, which was developed by the project Clima@EduMedia and was submitted to content analysis. This MOOC aimed to support science and school media teachers in the use of media to teach climate change Contribution: By proposing a MOOC success factors framework the authors are attempting to contribute to fill in a literature gap regarding what concerns criteria to consider a specific MOOC successful. Findings: This work major finding is a literature-based and empirically-refined MOOC success factors analysis framework. Recommendations for Practitioners: The proposed framework is also a set of best practices relevant to MOOC developers, particularly when targeting teachers as potential participants. Recommendation for Researchers: This work’s relevance is also based on its contribution to increasing empirical research on MOOCs. Impact on Society: By providing a proposal of a framework on factors to make a MOOC successful, the authors hope to contribute to the quality of MOOCs. Future Research: Future

  3. Housing price forecastability: A factor analysis

    DEFF Research Database (Denmark)

    Bork, Lasse; Møller, Stig Vinther

    of the model stays high at longer horizons. The estimated factors are strongly statistically signi…cant according to a bootstrap resampling method which takes into account that the factors are estimated regressors. The simple three-factor model also contains substantial out-of-sample predictive power...

  4. Erikson Psychosocial Stage Inventory: A Factor Analysis

    Science.gov (United States)

    Gray, Mary McPhail; And Others

    1986-01-01

    The 72-item Erikson Psychosocial Stage Inventory (EPSI) was factor analyzed for a group of 534 university freshmen and sophomore students. Seven factors emerged, which were labeled Initiative, Industry, Identity, Friendship, Dating, Goal Clarity, and Self-Confidence. Item's representing Erikson's factors, Trust and Autonomy, were dispersed across…

  5. An Analysis of Determinants of Under-5 Mortality across Countries: Defining Priorities to Achieve Targets in Sustainable Developmental Goals.

    Science.gov (United States)

    Acheampong, Michael; Ejiofor, Chukwudi; Salinas-Miranda, Abraham

    2017-06-01

    Objectives The end of the era of millennium development goals (MDGs) ushered in the sustainable development goals (SDGs) with a new target for the reduction of under-five mortality rates (U5MR). Although U5MR decreased globally, the reduction was insufficient to meet MDGs targets because significant socioeconomic inequities remain unaddressed across and within countries. Thus, further progress in achieving the new SDGs target will be hindered if there is no adequate prioritization of important socioeconomic, healthcare, and environmental factors. The objective of this study was to assess factors that account most for the differences in U5MR between countries around the globe. Methods We conducted an ordinary least squares (OLS) regression-based prioritization analysis of socioeconomic, healthcare, and environmental variables from 109 countries to understand which factors explain the differences in U5MR best. Results All indicators examined individually affected differences in U5MR between countries. However, the results of multivariate OLS regression showed that the most important factors that accounted for the differences were, in order: fertility rate, total health expenditure per capita, access to improved water and sanitation, and female employment rate. Conclusions To achieve the new global target for U5MR, policymakers must focus on certain priority areas, such as interventions that address access to affordable maternal healthcare services, educational programs for mothers, especially those who are adolescents, and safe drinking water and sanitation.

  6. Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes

    International Nuclear Information System (INIS)

    Chantarawong, Wipa; Takeda, Kazuhisa; Sangartit, Weerapon; Yoshizawa, Miki; Pradermwong, Kantimanee; Shibahara, Shigeki

    2014-01-01

    Highlights: • In human melanocytes, cadmium decreases the expression of MITF-M and tyrosinase and their mRNAs. • In human melanoma cells, cadmium decreases the expression of MITF-M protein and tyrosinase mRNA. • Expression of MITF-H is less sensitive to cadmium toxicity in melanocyte-linage cells. • Cadmium does not decrease the expression of MITF-H in retinal pigment epithelial cells. • MITF-M is the molecular target of cadmium toxicity in melanocytes. - Abstract: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure

  7. Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes

    Energy Technology Data Exchange (ETDEWEB)

    Chantarawong, Wipa [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan); Inter Departmental Multidisciplinary Graduate Program in Bioscience, Faculty of Science, Kasetsart University, Bangkok (Thailand); Takeda, Kazuhisa; Sangartit, Weerapon; Yoshizawa, Miki [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan); Pradermwong, Kantimanee [Department of Zoology, Faculty of Science, Kasetsart University, Bangkok (Thailand); Shibahara, Shigeki, E-mail: shibahar@med.tohoku.ac.jp [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan)

    2014-11-28

    Highlights: • In human melanocytes, cadmium decreases the expression of MITF-M and tyrosinase and their mRNAs. • In human melanoma cells, cadmium decreases the expression of MITF-M protein and tyrosinase mRNA. • Expression of MITF-H is less sensitive to cadmium toxicity in melanocyte-linage cells. • Cadmium does not decrease the expression of MITF-H in retinal pigment epithelial cells. • MITF-M is the molecular target of cadmium toxicity in melanocytes. - Abstract: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.

  8. MicroRNA-214 suppresses gluconeogenesis by targeting activating transcriptional factor 4.

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-03-27

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

  9. MicroRNA-214 Suppresses Gluconeogenesis by Targeting Activating Transcriptional Factor 4*

    Science.gov (United States)

    Li, Kai; Zhang, Jin; Yu, Junjie; Liu, Bin; Guo, Yajie; Deng, Jiali; Chen, Shanghai; Wang, Chunxia; Guo, Feifan

    2015-01-01

    Although the gluconeogenesis pathway is already a target for the treatment of type 2 diabetes, the potential role of microRNAs (miRNAs) in gluconeogenesis remains unclear. Here, we investigated the physiological functions of miR-214 in gluconeogenesis. The expression of miR-214 was suppressed by glucagon via protein kinase A signaling in primary hepatocytes, and miR-214 was down-regulated in the livers of fasted, high fat diet-induced diabetic and leptin receptor-mutated (db/db) mice. The overexpression of miR-214 in primary hepatocytes suppressed glucose production, and silencing miR-214 reversed this effect. Gluconeogenesis was suppressed in the livers of mice injected with an adenovirus expressing miR-214 (Ad-miR-214). Additionally, Ad-miR-214 alleviated high fat diet-induced elevation of gluconeogenesis and hyperglycemia. Furthermore, we found that activating transcription factor 4 (ATF4), a reported target of miR-214, can reverse the suppressive effect of miR-214 on gluconeogenesis in primary hepatocytes, and this suppressive effect was blocked in liver-specific ATF4 knock-out mice. ATF4 regulated gluconeogenesis via affecting forkhead box protein O1 (FOXO1) transcriptional activity. Finally, liver-specific miR-214 transgenic mice exhibited suppressed gluconeogenesis and reduced expression of ATF4, phosphoenolpyruvate carboxykinase, and glucose-6-phosphatase in liver. Taken together, our results suggest that the miR-214-ATF4 axis is a novel pathway for the regulation of hepatic gluconeogenesis. PMID:25657009

  10. The epidermal growth factor receptor as a target for gastrointestinal cancer therapy.

    Science.gov (United States)

    Tedesco, Karen L; Lockhart, A Craig; Berlin, Jordan D

    2004-10-01

    The epidermal growth factor receptor (EGFR) is a member of the family of transmembrane protein kinase receptors known as the erbB or HER receptor family. When activated, EGFR phosphorylates and activates other intracellular proteins that affect cell signaling pathways, cellular proliferation, control of apoptosis and angiogenesis. EGFR signaling is best thought of as a network of activating and inactivating proteins with EGFR as the entry point into the network. EGFR overexpression occurs in most GI malignancies and while data are not entirely consistent, EGFR overexpression often confers a poor prognosis in those GI malignancies that have been studied. It often correlates with poorly differentiated histology, more advanced stage and other known poor prognostic markers. The EGFR is a tempting target because of its presence and overexpression on so many tumor types. However, downstream of the EGFR are several proteins that may be activated without EGFR thus allowing blockade to be overcome. Therefore, while blocking the activity of the EGFR protein appears to be a promising anticancer strategy, a simplistic strategy of blocking only EGFR is likely to only impact a minority of patients. It is time for the laboratory and clinical researchers to work closely together to develop this treatment strategy, moving back and forth from clinical to laboratory to best understand how to block this network effectively enough to produce a broader antitumor effect. While multiple methods of targeting the EGFR pathway are under development, including the inhibition of downstream proteins, only two modalities have entered clinical trials in GI malignancies: small molecule inhibitors of the intracellular kinase domain of EGFR and antibodies designed to block the extracellular ligand-binding domain of EGFR. EGFR inhibitors are still experimental in every GI malignancy with the notable exception of cetuximab that is approved for second or third-line therapy of metastatic colorectal

  11. In Vivo Chromatin Targets of the Transcription Factor Yin Yang 2 in Trophoblast Stem Cells

    Science.gov (United States)

    Pérez-Palacios, Raquel; Macías-Redondo, Sofía; Climent, María; Contreras-Moreira, Bruno; Muniesa, Pedro; Schoorlemmer, Jon

    2016-01-01

    Background Yin Yang 2 (YY2) is a zinc finger protein closely related to the well-characterized Yin Yang 1 (YY1). YY1 is a DNA-binding transcription factor, with defined functions in multiple developmental processes, such as implantation, cell differentiation, X inactivation, imprinting and organogenesis. Yy2 has been treated as a largely immaterial duplication of Yy1, as they share high homology in the Zinc Finger-region and similar if not identical in vitro binding sites. In contrast to these similarities, gene expression alterations in HeLa cells with attenuated levels of either Yy1 or Yy2 were to some extent gene-specific. Moreover, the chromatin binding sites for YY2, except for its association with transposable retroviral elements (RE) and Endogenous Retroviral Elements (ERVs), remain to be identified. As a first step towards defining potential Yy2 functions matching or complementary to Yy1, we considered in vivo DNA binding sites of YY2 in trophoblast stem (TS) cells. Results We report the presence of YY2 protein in mouse-derived embryonic stem (ES) and TS cell lines. Following up on our previous report on ERV binding by YY2 in TS cells, we investigated the tissue-specificity of REX1 and YY2 binding and confirm binding to RE/ERV targets in both ES cells and TS cells. Because of the higher levels of expression, we chose TS cells to understand the role of Yy2 in gene and chromatin regulation. We used in vivo YY2 association as a measure to identify potential target genes. Sequencing of chromatin obtained in chromatin-immunoprecipitation (ChIP) assays carried out with αYY2 serum allowed us to identify a limited number of chromatin targets for YY2. Some putative binding sites were validated in regular ChIP assays and gene expression of genes nearby was altered in the absence of Yy2. Conclusions YY2 binding to ERVs is not confined to TS cells. In vivo binding sites share the presence of a consensus binding motif. Selected sites were uniquely bound by YY2 as

  12. Bioinformatic analysis to discover putative drug targets against ...

    African Journals Online (AJOL)

    /

    2012-01-26

    Jan 26, 2012 ... JVIRTUAL GEL. GELBANK was available from the NCBI FTP server. This website incorporates only completed genomes and information pertinent to 2-DE. Link is available at www.gelbank.anl.gov. JVirGel is a software for the simulation and analysis of proteomics data (http://www.jvirgel.de/). The Java TM.

  13. Residual Tumor After Neoadjuvant Chemoradiation Outside the Radiation Therapy Target Volume: A New Prognostic Factor for Survival in Esophageal Cancer

    International Nuclear Information System (INIS)

    Muijs, Christina; Smit, Justin; Karrenbeld, Arend; Beukema, Jannet; Mul, Veronique; Dam, Go van; Hospers, Geke; Kluin, Phillip; Langendijk, Johannes; Plukker, John

    2014-01-01

    Purpose/Objective(s): The aim of this study was to analyze the accuracy of gross tumor volume (GTV) delineation and clinical target volume (CTV) margins for neoadjuvant chemoradiation therapy (neo-CRT) in esophageal carcinoma at pathologic examination and to determine the impact on survival. Methods and Materials: The study population consisted of 63 esophageal cancer patients treated with neo-CRT. GTV and CTV borders were demarcated in situ during surgery on the esophagus, using anatomical reference points to provide accurate information regarding tumor location at pathologic evaluation. To identify prognostic factors for disease-free survival (DFS) and overall survival (OS), a Cox regression analysis was performed. Results: After resection, macroscopic residual tumor was found outside the GTV in 7 patients (11%). Microscopic residual tumor was located outside the CTV in 9 patients (14%). The median follow-up was 15.6 months. With multivariate analysis, only microscopic tumor outside the CTV (hazard ratio [HR], 4.96; 95% confidence interval [CI], 1.03-15.36), and perineural growth (HR, 5.77; 95% CI, 1.27-26.13) were identified as independent prognostic factors for OS. The 1-year OS was 20% for patients with tumor outside the CTV and 86% for those without (P<.01). For DFS, microscopic tumor outside the CTV (HR, 5.92; 95% CI, 1.89-18.54) and ypN+ (HR, 3.36; 95% CI, 1.33-8.48) were identified as independent adverse prognostic factors. The 1-year DFS was 23% versus 77% for patients with or without tumor outside the CTV (P<.01). Conclusions: Microscopic tumor outside the CTV is associated with markedly worse OS after neo-CRT. This may either stress the importance of accurate tumor delineation or reflect aggressive tumor behavior requiring new adjuvant treatment modalities

  14. MicroRNA-195 induced apoptosis in hypoxic chondrocytes by targeting hypoxia-inducible factor 1 alpha.

    Science.gov (United States)

    Bai, R; Zhao, A-Q; Zhao, Z-Q; Liu, W-L; Jian, D-M

    2015-02-01

    The chondrocytes, the resident cells of cartilage, are maintained and take effects in the whole life upon chronic hypoxic exposure, which hypoxia-inducible factor 1 alpha (HIF-1α) play pivotal roles in response to. Dysregulation of some microRNA (miRNAs) have also been identified to be involved in hypoxia-related physiologic and pathophysiologic responses in some tissues or cell lines. However, the mechanism of miRNAs reponse to hypoxia remain largely unknown in chondrocytes, including the microRNA-195 (miR-195). AIM To investigate the effects of microRNAs (miRNAs) and hypoxia-inducible factor 1 alpha (HIF-1α) on chondrocytes in physiologic environment. We compared the expression of miR-195 and HIF-1α mRNA on hypoxia with that on normoxia in ATDC 5 cells by qRT-PCR. Further experiments was performed to confirmed the relationships of miR-195 and HIF-1α by bioinformatics analysis and dual reporter gene assay. we also assessed the effect of miR-195 on apoptosis in hypoxic ATDC 5 cells by transfect with miR-195 mimics. It was found the downregulated miR-195 and upregulated HIF-1α were present in hypoxic ATDC 5 cells. miR-195 negatively regulated HIF-1α by targeting its 3'-untranslated region. Moreover, the founding indicated miR-195 greatly increased apoptosis and downregulated HIF-1α mRNA occurred simultaneously in hypoxic chondrocytes. We concluded that miR-195 induced apoptosis in hypoxic chondrocytes by directly targeting HIF-1α.

  15. Targeting factor VIII expression to platelets for hemophilia A gene therapy does not induce an apparent thrombotic risk in mice.

    Science.gov (United States)

    Baumgartner, C K; Mattson, J G; Weiler, H; Shi, Q; Montgomery, R R

    2017-01-01

    Essentials Platelet-Factor (F) VIII gene therapy is a promising treatment in hemophilia A. This study aims to evaluate if platelet-FVIII expression would increase the risk for thrombosis. Targeting FVIII expression to platelets does not induce or elevate thrombosis risk. Platelets expressing FVIII are neither hyper-activated nor hyper-responsive. Background Targeting factor (F) VIII expression to platelets is a promising gene therapy approach for hemophilia A, and is successful even in the presence of inhibitors. It is well known that platelets play important roles not only in hemostasis, but also in thrombosis and inflammation. Objective To evaluate whether platelet-FVIII expression might increase thrombotic risk and thereby compromise the safety of this approach. Methods In this study, platelet-FVIII-expressing transgenic mice were examined either in steady-state conditions or under prothrombotic conditions induced by inflammation or the FV Leiden mutation. Native whole blood thrombin generation assay, rotational thromboelastometry analysis and ferric chloride-induced vessel injury were used to evaluate the hemostatic properties. Various parameters associated with thrombosis risk, including D-dimer, thrombin-antithrombin complexes, fibrinogen, tissue fibrin deposition, platelet activation status and activatability, and platelet-leukocyte aggregates, were assessed. Results We generated a new line of transgenic mice that expressed 30-fold higher levels of platelet-expressed FVIII than are therapeutically required to restore hemostasis in hemophilic mice. Under both steady-state conditions and prothrombotic conditions induced by lipopolysaccharide-mediated inflammation or the FV Leiden mutation, supratherapeutic levels of platelet-expressed FVIII did not appear to be thrombogenic. Furthermore, FVIII-expressing platelets were neither hyperactivated nor hyperactivatable upon agonist activation. Conclusion We conclude that, in mice, more than 30-fold higher levels of

  16. Activating transcription factor 3 is a target molecule linking hepatic steatosis to impaired glucose homeostasis.

    Science.gov (United States)

    Kim, Ji Yeon; Park, Keon Jae; Hwang, Joo-Yeon; Kim, Gyu Hee; Lee, DaeYeon; Lee, Yoo Jeong; Song, Eun Hyun; Yoo, Min-Gyu; Kim, Bong-Jo; Suh, Young Ho; Roh, Gu Seob; Gao, Bin; Kim, Won; Kim, Won-Ho

    2017-08-01

    Non-alcoholic fatty liver disease (NAFLD) contributes to impaired glucose tolerance, leading to type 2 diabetes (T2D); however, the precise mechanisms and target molecules that are involved remain unclear. Activating transcription factor 3 (ATF3) is associated with β-cell dysfunction that is induced by severe stress signals in T2D. We aimed to explore the exact functional role of ATF3 as a mechanistic link between hepatic steatosis and T2D development. Zucker diabetic fatty (ZDF) rats were utilized for animal experiments. An in vivo-jetPEI siRNA delivery system against ATF3 was used for loss-of-function experiments. We analyzed the baseline cross-sectional data derived from the biopsy-proven NAFLD registry (n=322). Human sera and liver tissues were obtained from 43 patients with biopsy-proven NAFLD and from seven healthy participants. ATF3 was highly expressed in the livers of ZDF rats and in human participants with NAFLD and/or T2D. Insulin resistance and hepatic steatosis were associated with increased ATF3 expression and decreased fatty acid oxidation via mitochondrial dysfunction and were attenuated by in vivo ATF3 silencing. Knockdown of ATF3 also ameliorated glucose intolerance, impaired insulin action, and inflammatory responses in ZDF rats. In patients with NAFLD and/or T2D, a significant positive correlation was observed between hepatic ATF3 expression and surrogate markers of T2D, mitochondrial dysfunction, and macrophage infiltration. Increased hepatic ATF3 expression is closely associated with hepatic steatosis and incident T2D; therefore, ATF3 may serve as a potential therapeutic target for NAFLD and hepatic steatosis-induced T2D. Hepatic activating transcription factor 3 (ATF3) may play an important role in oxidative stress-mediated hepatic steatosis and the development of type 2 diabetes (T2D) in a Zucker diabetic fatty (ZDF) rat model and in human patients with non-alcoholic fatty liver disease (NAFLD). Therefore, ATF3 may be a useful biomarker for

  17. Nominal Performance Biosphere Dose Conversion Factor Analysis

    International Nuclear Information System (INIS)

    Wasiolek, M.

    2000-01-01

    The purpose of this report was to document the process leading to development of the Biosphere Dose Conversion Factors (BDCFs) for the postclosure nominal performance of the potential repository at Yucca Mountain. BDCF calculations concerned twenty-four radionuclides. This selection included sixteen radionuclides that may be significant nominal performance dose contributors during the compliance period of up to 10,000 years, five additional radionuclides of importance for up to 1 million years postclosure, and three relatively short-lived radionuclides important for the human intrusion scenario. Consideration of radionuclide buildup in soil caused by previous irrigation with contaminated groundwater was taken into account in the BDCF development. The effect of climate evolution, from the current arid conditions to a wetter and cooler climate, on the BDCF values was evaluated. The analysis included consideration of different exposure pathway's contribution to the BDCFs. Calculations of nominal performance BDCFs used the GENII-S computer code in a series of probabilistic realizations to propagate the uncertainties of input parameters into the output. BDCFs for the nominal performance, when combined with the concentrations of radionuclides in groundwater allow calculation of potential radiation doses to the receptor of interest. Calculated estimates of radionuclide concentration in groundwater result from the saturated zone modeling. The integration of the biosphere modeling results (BDCFs) with the outcomes of the other component models is accomplished in the Total System Performance Assessment (TSPA) to calculate doses to the receptor of interest from radionuclides postulated to be released to the environment from the potential repository at Yucca Mountain

  18. Disruptive Event Biosphere Doser Conversion Factor Analysis

    Energy Technology Data Exchange (ETDEWEB)

    M. Wasiolek

    2000-12-28

    The purpose of this report was to document the process leading to, and the results of, development of radionuclide-, exposure scenario-, and ash thickness-specific Biosphere Dose Conversion Factors (BDCFs) for the postulated postclosure extrusive igneous event (volcanic eruption) at Yucca Mountain. BDCF calculations were done for seventeen radionuclides. The selection of radionuclides included those that may be significant dose contributors during the compliance period of up to 10,000 years, as well as radionuclides of importance for up to 1 million years postclosure. The approach documented in this report takes into account human exposure during three different phases at the time of, and after, volcanic eruption. Calculations of disruptive event BDCFs used the GENII-S computer code in a series of probabilistic realizations to propagate the uncertainties of input parameters into the output. The pathway analysis included consideration of different exposure pathway's contribution to the BDCFs. BDCFs for volcanic eruption, when combined with the concentration of radioactivity deposited by eruption on the soil surface, allow calculation of potential radiation doses to the receptor of interest. Calculation of radioactivity deposition is outside the scope of this report and so is the transport of contaminated ash from the volcano to the location of the receptor. The integration of the biosphere modeling results (BDCFs) with the outcomes of the other component models is accomplished in the Total System Performance Assessment (TSPA), in which doses are calculated to the receptor of interest from radionuclides postulated to be released to the environment from the potential repository at Yucca Mountain.

  19. Evaluation in medical education: A topical review of target parameters, data collection tools and confounding factors

    Science.gov (United States)

    Schiekirka, Sarah; Feufel, Markus A.; Herrmann-Lingen, Christoph; Raupach, Tobias

    2015-01-01

    Background and objective: Evaluation is an integral part of education in German medical schools. According to the quality standards set by the German Society for Evaluation, evaluation tools must provide an accurate and fair appraisal of teaching quality. Thus, data collection tools must be highly reliable and valid. This review summarises the current literature on evaluation of medical education with regard to the possible dimensions of teaching quality, the psychometric properties of survey instruments and potential confounding factors. Methods: We searched Pubmed, PsycINFO and PSYNDEX for literature on evaluation in medical education and included studies published up until June 30, 2011 as well as articles identified in the “grey literature”. Results are presented as a narrative review. Results: We identified four dimensions of teaching quality: structure, process, teacher characteristics, and outcome. Student ratings are predominantly used to address the first three dimensions, and a number of reliable tools are available for this purpose. However, potential confounders of student ratings pose a threat to the validity of these instruments. Outcome is usually operationalised in terms of student performance on examinations, but methodological problems may limit the usability of these data for evaluation purposes. In addition, not all examinations at German medical schools meet current quality standards. Conclusion: The choice of tools for evaluating medical education should be guided by the dimension that is targeted by the evaluation. Likewise, evaluation results can only be interpreted within the context of the construct addressed by the data collection tool that was used as well as its specific confounding factors. PMID:26421003

  20. Functional analysis of jasmonate-responsive transcription factors in Arabidopsis thaliana

    NARCIS (Netherlands)

    Zarei, Adel

    2007-01-01

    The aim of the studies described in this thesis was the functional analysis of JA-responsive transcription factors in Arabidopsis with an emphasis on the interaction with the promoters of their target genes. In short, the following new results were obtained. The promoter of the PDF1.2 gene contains

  1. Identification of the Drosophila Mes4 gene as a novel target of the transcription factor DREF

    Energy Technology Data Exchange (ETDEWEB)

    Suyari, Osamu; Ida, Hiroyuki [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Yoshioka, Yasuhide; Kato, Yasuko; Hashimoto, Reina [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Venture Laboratory, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Yamaguchi, Masamitsu, E-mail: myamaguc@kit.ac.jp [Department of Applied Biology, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Sakyo-ku, Kyoto 606-8585 (Japan)

    2009-05-01

    The Mes4 gene has been identified as one of the maternal Dorsal target genes in Drosophila. In the present study, we found a DNA replication-related element (DRE, 5'-TATCGATA) in the Mes4 promoter recognized by the DRE-binding factor (DREF). Luciferase transient expression assays in S2 cells using Mes4 promoter-luciferase fusion plasmids revealed that the DRE sequence is essential for Mes4 promoter activity. Requirement of DRE for Mes4 promoter activity was further confirmed by anti-{beta}-galactosidase antibody-staining of various tissues from transgenic flies carrying Mes4 promoter-lacZ fusion genes. Furthermore, wild type Mes4 promoter activity was decreased by 40% in DREF-depleted S2 cells. These results indicate that DREF positively regulates Mes4 gene expression. Band mobility shift analyses using Kc cell nuclear extracts further indicated that the DRE sequence in the Mes4 promoter is especially important for binding to DREF. Moreover, specific binding of DREF to the involved genomic region could be demonstrated by chromatin immunoprecipitation assays using anti-DREF antibodies. These results, taken together, indicate that the DRE/DREF system activates transcription of the Mes4 gene. In addition, knockdown of the Mes4 gene in wing imaginal discs using the GAL4-UAS system caused an atrophied wing phenotype, suggesting that Mes4 is required for wing morphogenesis.

  2. Effects of a Workplace Intervention Targeting Psychosocial Risk Factors on Safety and Health Outcomes

    Directory of Open Access Journals (Sweden)

    Leslie B. Hammer

    2015-01-01

    Full Text Available The goal of this study was to test the effectiveness of a workplace intervention targeting work-life stress and safety-related psychosocial risk factors on health and safety outcomes. Data were collected over time using a randomized control trial design with 264 construction workers employed in an urban municipal department. The intervention involved family- and safety-supportive supervisor behavior training (computer-based, followed by two weeks of behavior tracking and a four-hour, facilitated team effectiveness session including supervisors and employees. A significant positive intervention effect was found for an objective measure of blood pressure at the 12-month follow-up. However, no significant intervention results were found for self-reported general health, safety participation, or safety compliance. These findings suggest that an intervention focused on supervisor support training and a team effectiveness process for planning and problem solving should be further refined and utilized in order to improve employee health with additional research on the beneficial effects on worker safety.

  3. Identification of the Drosophila Mes4 gene as a novel target of the transcription factor DREF

    International Nuclear Information System (INIS)

    Suyari, Osamu; Ida, Hiroyuki; Yoshioka, Yasuhide; Kato, Yasuko; Hashimoto, Reina; Yamaguchi, Masamitsu

    2009-01-01

    The Mes4 gene has been identified as one of the maternal Dorsal target genes in Drosophila. In the present study, we found a DNA replication-related element (DRE, 5'-TATCGATA) in the Mes4 promoter recognized by the DRE-binding factor (DREF). Luciferase transient expression assays in S2 cells using Mes4 promoter-luciferase fusion plasmids revealed that the DRE sequence is essential for Mes4 promoter activity. Requirement of DRE for Mes4 promoter activity was further confirmed by anti-β-galactosidase antibody-staining of various tissues from transgenic flies carrying Mes4 promoter-lacZ fusion genes. Furthermore, wild type Mes4 promoter activity was decreased by 40% in DREF-depleted S2 cells. These results indicate that DREF positively regulates Mes4 gene expression. Band mobility shift analyses using Kc cell nuclear extracts further indicated that the DRE sequence in the Mes4 promoter is especially important for binding to DREF. Moreover, specific binding of DREF to the involved genomic region could be demonstrated by chromatin immunoprecipitation assays using anti-DREF antibodies. These results, taken together, indicate that the DRE/DREF system activates transcription of the Mes4 gene. In addition, knockdown of the Mes4 gene in wing imaginal discs using the GAL4-UAS system caused an atrophied wing phenotype, suggesting that Mes4 is required for wing morphogenesis.

  4. Circumvention of nuclear factor kappaB-induced chemoresistance by cytoplasmic-targeted anthracyclines.

    Science.gov (United States)

    Bilyeu, Jennifer D; Panta, Ganesh R; Cavin, Lakita G; Barrett, Christina M; Turner, Eddie J; Sweatman, Trevor W; Israel, Mervyn; Lothstein, Leonard; Arsura, Marcello

    2004-04-01

    Nuclear factor kappaB (NF-kappaB) has been implicated in inducible chemoresistance against anthracyclines. In an effort to improve the cytotoxicity of anthracyclines while reducing their cardiotoxic effects, we have developed a novel class of extranuclear-localizing 14-O-acylanthracyclines that bind to the phorbol ester/diacylglycerol-binding C1b domain of conventional and novel protein kinase C (PKC) isoforms, thereby promoting an apoptotic response. Because PKCs have been shown to be involved in NF-kappaB activation, in this report, we determined the mechanism of NF-kappaB activation by N-benzyladriamycin-14-valerate (AD 198) and N-benzyladriamycin-14-pivalate (AD 445), two novel 14-O-acylanthracylines. We show that the induction of NF-kappaB activity in response to drug treatment relies on the activation of PKC-delta and NF-kappaB-activating kinase (NAK), independent of ataxia telengectasia mutated and p53 activities. In turn, NAK activates the IKK complex through phosphorylation of the IKK-2 subunit. We find that neither NF-kappaB activation nor ectopic expression of Bcl-X(L) confers protection from AD 198-induced cell killing. Overall, our data indicate that activation of novel PKC isoforms by cytoplasmic-targeted 14-O-acylanthracyclines promotes an apoptotic response independent of DNA damage, which is unimpeded by inducible activation of NF-kappaB.

  5. Cell physiology regulation by hypoxia inducible factor-1: Targeting oxygen-related nanomachineries of hypoxic cells.

    Science.gov (United States)

    Eskandani, Morteza; Vandghanooni, Somayeh; Barar, Jaleh; Nazemiyeh, Hossein; Omidi, Yadollah

    2017-06-01

    Any dysfunctionality in maintaining the oxygen homeostasis by mammalian cells may elicit hypoxia/anoxia, which results in inescapable oxidative stress and possible subsequent detrimental impacts on certain cells/tissues with high demands to oxygen molecules. The ischemic damage in turn can trigger initiation of a number of diseases including organs ischemia, metabolic disorders, inflammatory diseases, different types of malignancies, and alteration in wound healing process. Thus, full comprehension of molecular mechanism(s) and cellular physiology of the oxygen homeostasis is the cornerstone of the mammalian cells metabolism, energetic pathways and health and disease conditions. An imbalance in oxygen content within the cellular microenvironment activates a cascade of molecular events that are often compensated, otherwise pathologic condition occurs through a complexed network of biomolecules. Hypoxia inducible factor-1 (HIF-1) plays a key transcriptional role in the adaptation of cell physiology in relation with the oxygen content within a cell. In this current study, we provide a comprehensive review on the molecular mechanisms of oxygen sensing and homeostasis and the impacts of HIF-1 in hypoxic/anoxic conditions. Moreover, different molecular and biochemical responses of the cells to the surrounding environment are discussed in details. Finally, modern technological approaches for targeting the hypoxia related proteins are articulated. Copyright © 2017. Published by Elsevier B.V.

  6. Radiolabeled Probes Targeting Hypoxia-Inducible Factor-1-Active Tumor Microenvironments

    Directory of Open Access Journals (Sweden)

    Masashi Ueda

    2014-01-01

    Full Text Available Because tumor cells grow rapidly and randomly, hypoxic regions arise from the lack of oxygen supply in solid tumors. Hypoxic regions in tumors are known to be resistant to chemotherapy and radiotherapy. Hypoxia-inducible factor-1 (HIF-1 expressed in hypoxic regions regulates the expression of genes related to tumor growth, angiogenesis, metastasis, and therapy resistance. Thus, imaging of HIF-1-active regions in tumors is of great interest. HIF-1 activity is regulated by the expression and degradation of its α subunit (HIF-1α, which is degraded in the proteasome under normoxic conditions, but escapes degradation under hypoxic conditions, allowing it to activate transcription of HIF-1-target genes. Therefore, to image HIF-1-active regions, HIF-1-dependent reporter systems and injectable probes that are degraded in a manner similar to HIF-1α have been recently developed and used in preclinical studies. However, no probe currently used in clinical practice directly assesses HIF-1 activity. Whether the accumulation of 18F-FDG or 18F-FMISO can be utilized as an index of HIF-1 activity has been investigated in clinical studies. In this review, the current status of HIF-1 imaging in preclinical and clinical studies is discussed.

  7. Diacetoxyscirpenol as a new anticancer agent to target hypoxia-inducible factor 1

    Science.gov (United States)

    Choi, Yong-Joon; Shin, Hyun-Woo; Chun, Yang-Sook; Leutou, Alain Simplice; Son, Byeng Wha; Park, Jong-Wan

    2016-01-01

    Hypoxia activates hypoxia-inducible factor 1, which promotes the progression of malignancy by stimulating angiogenesis and by augmenting the ability of tumors to survive. Thus, HIF-1 is one of the most compelling targets for treating cancers. The aim of this study was to find a small molecule that inhibits HIF-1 under hypoxia in cancer cells. 7,280 compounds in a chemical library were tested in a cancer cell line expressing luciferase HIF-dependently. Through three rounds of screening, we finally picked up a compound that originates from a marine bacterium parasitizing red alga. The antibiotic potently inhibited HIF-1 expression and its transcriptional activity in cancer cells exposed to hypoxia. Through two-step fractionation, diacetoxyscirpenol was purified and identified as a HIF-inhibiting ingredient. Mechanistically, diacetoxyscirpenol inhibits the synthesis of HIF-1α protein and also interferes with the dimerization of HIF-1α and ARNT. It attenuates HIF-mediated gene expression in cancer cells exposed to hypoxia, and by doing so reduces tumorigenic and angiogenic potentials of cancer cells. More importantly, diacetoxyscirpenol retarded tumor growth in mice, and reduced HIF-1α expression and vascular formation in the tumors. Overall, diacetoxyscirpenol is considered a potential drug deregulating the HIF-1 signaling pathway, and it could be beneficially employed for treating malignant tumors with hypoxic microenvironment. PMID:27613833

  8. Targeting of liposomes to cells bearing nerve growth factor receptors mediated by biotinylated NGF

    International Nuclear Information System (INIS)

    Rosenberg, M.B.

    1986-01-01

    Previous studies of liposome targeting have concentrated on immunological systems, the use of ligand-receptor interactions has received little attention. The protein hormone beta-nerve growth factor (NGF) was modified by biotinylation via carboxyl group substitution (C-bio-NGF) under reaction conditions that yielded an average of 3 biotin additions per NGF subunit. NGF was also biotinylated through amino group substitution to produce derivatives with ratios of 1, 2 and 4 biotin moieties per NGF subunit (N-bio-NGF). These derivatives were compared with native NGF for their ability to compete with 125 I-NGF for binding to NGF receptors on rat pheochromocytoma (PC 12) cells at 4 0 C. C-bio-NGF was as effective as native NGF in binding to NGF receptors, while N-bio-NGF containing 1 biotin per NGF subunit was only 28% as active in binding as native NGF. C-bio-NGF, but not N-bio-NGF, mediated the specific binding of 125 I-streptavidin to PC12 cells. Biocytin-NGF, a derivative of C-bio-NGF with an extended spacer chain, was also synthesized and retained full biological and receptor binding activities. C-bio-NGF and biocytin-NGF were as effective as native NGF in a bioassay involving induction of neurite outgrowth from PC12 cells

  9. Orexin–Corticotropin-Releasing Factor Receptor Heteromers in the Ventral Tegmental Area as Targets for Cocaine

    Science.gov (United States)

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A.; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I.

    2015-01-01

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R–OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R–OX1R heteromer. Cocaine binding to the σ1R–CRF1R–OX1R complex promotes a long-term disruption of the orexin-A–CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. PMID:25926444

  10. Orexin-corticotropin-releasing factor receptor heteromers in the ventral tegmental area as targets for cocaine.

    Science.gov (United States)

    Navarro, Gemma; Quiroz, César; Moreno-Delgado, David; Sierakowiak, Adam; McDowell, Kimberly; Moreno, Estefanía; Rea, William; Cai, Ning-Sheng; Aguinaga, David; Howell, Lesley A; Hausch, Felix; Cortés, Antonio; Mallol, Josefa; Casadó, Vicent; Lluís, Carme; Canela, Enric I; Ferré, Sergi; McCormick, Peter J

    2015-04-29

    Release of the neuropeptides corticotropin-releasing factor (CRF) and orexin-A in the ventral tegmental area (VTA) play an important role in stress-induced cocaine-seeking behavior. We provide evidence for pharmacologically significant interactions between CRF and orexin-A that depend on oligomerization of CRF1 receptor (CRF1R) and orexin OX1 receptors (OX1R). CRF1R-OX1R heteromers are the conduits of a negative crosstalk between orexin-A and CRF as demonstrated in transfected cells and rat VTA, in which they significantly modulate dendritic dopamine release. The cocaine target σ1 receptor (σ1R) also associates with the CRF1R-OX1R heteromer. Cocaine binding to the σ1R-CRF1R-OX1R complex promotes a long-term disruption of the orexin-A-CRF negative crosstalk. Through this mechanism, cocaine sensitizes VTA cells to the excitatory effects of both CRF and orexin-A, thus providing a mechanism by which stress induces cocaine seeking. Copyright © 2015 the authors 0270-6474/15/356639-15$15.00/0.

  11. Effects of a Workplace Intervention Targeting Psychosocial Risk Factors on Safety and Health Outcomes

    Science.gov (United States)

    Hammer, Leslie B.; Truxillo, Donald M.; Bodner, Todd; Rineer, Jennifer; Pytlovany, Amy C.; Richman, Amy

    2015-01-01

    The goal of this study was to test the effectiveness of a workplace intervention targeting work-life stress and safety-related psychosocial risk factors on health and safety outcomes. Data were collected over time using a randomized control trial design with 264 construction workers employed in an urban municipal department. The intervention involved family- and safety-supportive supervisor behavior training (computer-based), followed by two weeks of behavior tracking and a four-hour, facilitated team effectiveness session including supervisors and employees. A significant positive intervention effect was found for an objective measure of blood pressure at the 12-month follow-up. However, no significant intervention results were found for self-reported general health, safety participation, or safety compliance. These findings suggest that an intervention focused on supervisor support training and a team effectiveness process for planning and problem solving should be further refined and utilized in order to improve employee health with additional research on the beneficial effects on worker safety. PMID:26557703

  12. A Bayesian Nonparametric Approach to Factor Analysis

    DEFF Research Database (Denmark)

    Piatek, Rémi; Papaspiliopoulos, Omiros

    2018-01-01

    This paper introduces a new approach for the inference of non-Gaussian factor models based on Bayesian nonparametric methods. It relaxes the usual normality assumption on the latent factors, widely used in practice, which is too restrictive in many settings. Our approach, on the contrary, does no...

  13. Classification analysis of organization factors related to system safety

    International Nuclear Information System (INIS)

    Liu Huizhen; Zhang Li; Zhang Yuling; Guan Shihua

    2009-01-01

    This paper analyzes the different types of organization factors which influence the system safety. The organization factor can be divided into the interior organization factor and exterior organization factor. The latter includes the factors of political, economical, technical, law, social culture and geographical, and the relationships among different interest groups. The former includes organization culture, communication, decision, training, process, supervision and management and organization structure. This paper focuses on the description of the organization factors. The classification analysis of the organization factors is the early work of quantitative analysis. (authors)

  14. Cost Minimization Analysis of Hypnotic Drug: Target Controlled Inhalation Anesthesia (TCIA Sevoflurane and Target Controlled Infusion (TCI Propofol

    Directory of Open Access Journals (Sweden)

    Made Wiryana

    2016-09-01

    Full Text Available Background: Cost minimization analysis is a pharmaco-economic study used to compare two or more health interventions that have been shown to have the same effect, similar or equivalent. With limited health insurance budget from the Indonesian National Social Security System implementation in 2015, the quality control and the drug cost are two important things that need to be focused. The application of pharmaco-economic study results in the selection and use of drugs more effectively and efficiently. Objective: To determine cost minimization analysis of hypnotic drug between a target controlled inhalation anesthesia (TCIA sevoflurane and a target controlled infusion (TCI propofol in patients underwent a major oncologic surgery in Sanglah General Hospital. Methods: Sixty ASA physical status I-II patients underwent major oncologic surgery were divided into two groups. Group A was using TCIA sevoflurane and group B using TCI propofol. Bispectral index monitor (BIS index was used to evaluate the depth of anesthesia. The statistical tests used are the Shapiro-Wilk test, Lavene test, Mann-Whitney U test and unpaired t-test (α = 0.05. The data analysis used the Statistical Package for Social Sciences (SPSS for Windows. Results: In this study, the rate of drug used per unit time in group A was 0.12 ml sevoflurane per minute (± 0.03 and the group B was 7.25 mg propofol per minute (±0.98. Total cost of hypnotic drug in group A was IDR598.43 (IQR 112.47 per minute, in group B was IDR703.27 (IQR 156.73 per minute (p>0.05. Conclusions: There was no statistically significant difference from the analysis of the drug cost minimization hypnotic drug in a major oncologic surgery using TCIA sevoflurane and TCI propofol.

  15. Using BMDP and SPSS for a Q factor analysis.

    Science.gov (United States)

    Tanner, B A; Koning, S M

    1980-12-01

    While Euclidean distances and Q factor analysis may sometimes be preferred to correlation coefficients and cluster analysis for developing a typology, commercially available software does not always facilitate their use. Commands are provided for using BMDP and SPSS in a Q factor analysis with Euclidean distances.

  16. EXPLORATORY FACTOR ANALYSIS (EFA IN CONSUMER BEHAVIOR AND MARKETING RESEARCH

    Directory of Open Access Journals (Sweden)

    Marcos Pascual Soler

    2012-06-01

    Full Text Available Exploratory Factor Analysis (EFA is one of the most widely used statistical procedures in social research. The main objective of this work is to describe the most common practices used by researchers in the consumer behavior and marketing area. Through a literature review methodology the practices of AFE in five consumer behavior and marketing journals(2000-2010 were analyzed. Then, the choices made by the researchers concerning factor model, retention criteria, rotation, factors interpretation and other relevant issues to factor analysis were analized. The results suggest that researchers routinely conduct analyses using such questionable methods. Suggestions for improving the use of factor analysis and the reporting of results are presented and a checklist (Exploratory Factor Analysis Checklist, EFAC is provided to help editors, reviewers, and authors improve reporting exploratory factor analysis.

  17. Factor analysis of serogroups botanica and aurisina of Leptospira biflexa.

    Science.gov (United States)

    Cinco, M

    1977-11-01

    Factor analysis is performed on serovars of Botanica and Aurisina serogroup of Leptospira biflexa. The results show the arrangement of main factors serovar and serogroup specific, as well as the antigens common with serovars of heterologous serogroups.

  18. Human factors analysis of incident/accident report

    International Nuclear Information System (INIS)

    Kuroda, Isao

    1992-01-01

    Human factors analysis of accident/incident has different kinds of difficulties in not only technical, but also psychosocial background. This report introduces some experiments of 'Variation diagram method' which is able to extend to operational and managemental factors. (author)

  19. Current target industry analysis: Las Vegas Metropolitan Area

    International Nuclear Information System (INIS)

    Boyle, M.R.

    1988-06-01

    This is the second of three reports dealing with the Las Vegas MSA's economic development potential in support of an overall effort to prepare an environmental impact statement for the proposed underground nuclear waste storage facility at Yucca Mountain. The first report provides an assessment of the MSA current business climate for economic growth. This second report draws on that business climate assessment to evaluate the Las Vegas MSA's competitive posture in pursuing business investment in the ''primary'' sector of the economy -- businesses which sell their products or services outside the local marketplace and bring new money back into the area and businesses serving local customers who would otherwise import these products or services from suppliers outside the area. GSO has developed an analytic tool which attempts to model the decision process used by businesses in selecting locations for new or expanded business investment. This computer based model reflects variations in site selection decision making among industries and ownership and management types. The underlying premise of the GSO locational compatibility index (LCI) model is that locational decisions are based more on a process of elimination that on a process of selection. There are many factors, some essential and some desirable, which influence any site selection decision. Multivariate comparative analyses narrow the geographic field to a region, then a group of states, then a state, then a sub-state region, then a community and finally to a specific site. Sometimes these analyses are rational and quantitative. More often, they are at least partially random and intuitive. 2 tabs

  20. Targeted resequencing and analysis of the Diamond-Blackfan anemia disease locus RPS19.

    Directory of Open Access Journals (Sweden)

    Alvaro Martinez Barrio

    2009-07-01

    Full Text Available The Ribosomal protein S19 gene locus (RPS19 has been linked to two kinds of red cell aplasia, Diamond-Blackfan Anemia (DBA and Transient Erythroblastopenia in Childhood (TEC. Mutations in RPS19 coding sequences have been found in 25% of DBA patients, but not in TEC patients. It has been suggested that non-coding RPS19 sequence variants contribute to the considerable clinical variability in red cell aplasia. We therefore aimed at identifying non-coding variations associated with DBA or TEC phenotypes.We targeted a region of 19'980 bp encompassing the RPS19 gene in a cohort of 89 DBA and TEC patients for resequencing. We provide here a catalog of the considerable, previously unrecognized degree of variation in this region. We identified 73 variations (65 SNPs, 8 indels that all are located outside of the RPS19 open reading frame, and of which 67.1% are classified as novel. We hypothesize that specific alleles in non-coding regions of RPS19 could alter the binding of regulatory proteins or transcription factors. Therefore, we carried out an extensive analysis to identify transcription factor binding sites (TFBS. A series of putative interaction sites coincide with detected variants. Sixteen of the corresponding transcription factors are of particular interest, as they are housekeeping genes or show a direct link to hematopoiesis, tumorigenesis or leukemia (e.g. GATA-1/2, PU.1, MZF-1.Specific alleles at predicted TFBSs may alter the expression of RPS19, modify an important interaction between transcription factors with overlapping TFBS or remove an important stimulus for hematopoiesis. We suggest that the detected interactions are of importance for hematopoiesis and could provide new insights into individual response to treatment.

  1. Nonparametric factor analysis of time series

    OpenAIRE

    Rodríguez-Poo, Juan M.; Linton, Oliver Bruce

    1998-01-01

    We introduce a nonparametric smoothing procedure for nonparametric factor analaysis of multivariate time series. The asymptotic properties of the proposed procedures are derived. We present an application based on the residuals from the Fair macromodel.

  2. Analysis of success factors in advertising

    OpenAIRE

    Fedorchak, Oleksiy; Kedebecz, Kristina

    2017-01-01

    The essence of factors of the success of advertising campaigns is investigated. The stages of conducting and stages of evaluation of the effectiveness of advertising campaigns are determined. Also defined goals and objectives of advertising campaigns.

  3. Coupling analysis of the target temperature and thermal stress due to pulsed ion beam

    International Nuclear Information System (INIS)

    Yan Jie; Liu Meng; Lin Jufang; An Li; Long Xinggui

    2013-01-01

    Background: Target temperature has an important effect on the target life for the sealed neutron generator without cooling system. Purpose: To carry out the thermal-mechanical coupling analysis of the film-substrate target bombarded by the pulsed ion beam. Methods: The indirect coupling Finite Element Method (FEM) with a 2-dimensional time-space Gaussian axisymmetric power density as heat source was used to simulate the target temperature and thermal stress fields. Results: The effects of the target temperature and thermal stress fields under difference pulse widths and beam sizes were analyzed in terms of the FEM results. Conclusions: Combining with the temperature requirement and the thermal stress inducing film thermal mechanical destruction effect of the sealed neutron generator film-substrate targets, an optimized pulsed ion beam work status was proposed. (authors)

  4. Beyond typing and grading: target analysis in individualized therapy as a new challenge for tumour pathology.

    Science.gov (United States)

    Kreipe, Hans H; von Wasielewski, Reinhard

    2007-01-01

    In order to bring about its beneficial effects in oncology, targeted therapy depends on accurate target analysis. Whether cells of a tumour will be sensitive to a specific treatment is predicted by the detection of appropriate targets in cancer tissue by immunohistochemistry or molecular methods. In most instances this is performed by histopathologists. Reliability and reproducibility of tissue-based target analysis in histopathology require novel measures of quality assurance by internal and external controls. As a model for external quality assurance in targeted therapy an annual inter-laboratory trial has been set up in Germany applying tissue arrays with up to 60 mammary cancer samples which are tested by participants for expression of HER2/neu and steroid hormone receptors.

  5. Holographic analysis of diffraction structure factors

    International Nuclear Information System (INIS)

    Marchesini, S.; Bucher, J.J.; Shuh, D.K.; Fabris, L.; Press, M.J.; West, M.W.; Hussain, Z.; Mannella, N.; Fadley, C.S.; Van Hove, M.A.; Stolte, W.C.

    2002-01-01

    We combine the theory of inside-source/inside-detector x-ray fluorescence holography and Kossel lines/ x ray standing waves in kinematic approximation to directly obtain the phases of the diffraction structure factors. The influence of Kossel lines and standing waves on holography is also discussed. We obtain partial phase determination from experimental data obtaining the sign of the real part of the structure factor for several reciprocal lattice vectors of a vanadium crystal

  6. Delineation of geochemical anomalies based on stream sediment data utilizing fractal modeling and staged factor analysis

    Science.gov (United States)

    Afzal, Peyman; Mirzaei, Misagh; Yousefi, Mahyar; Adib, Ahmad; Khalajmasoumi, Masoumeh; Zarifi, Afshar Zia; Foster, Patrick; Yasrebi, Amir Bijan

    2016-07-01

    Recognition of significant geochemical signatures and separation of geochemical anomalies from background are critical issues in interpretation of stream sediment data to define exploration targets. In this paper, we used staged factor analysis in conjunction with the concentration-number (C-N) fractal model to generate exploration targets for prospecting Cr and Fe mineralization in Balvard area, SE Iran. The results show coexistence of derived multi-element geochemical signatures of the deposit-type sought and ultramafic-mafic rocks in the NE and northern parts of the study area indicating significant chromite and iron ore prospects. In this regard, application of staged factor analysis and fractal modeling resulted in recognition of significant multi-element signatures that have a high spatial association with host lithological units of the deposit-type sought, and therefore, the generated targets are reliable for further prospecting of the deposit in the study area.

  7. Thermal hydraulics analysis of LIBRA-SP target chamber

    International Nuclear Information System (INIS)

    Mogahed, E.A.

    1996-01-01

    LIBRA-SP is a conceptual design study of an inertially confined 1000 MWe fusion power reactor utilizing self-pinched light ion beams. There are 24 ion beams which are arranged around the reactor cavity. The reaction chamber is an upright cylinder with an inverted conical roof resembling a mushroom, and a pool floor. The vertical sides of the cylinder are occupied by a blanket zone consisting of many perforated rigid HT-9 ferritic steel tubes called PERITs (PEr-forated RIgid Tube). The breeding/cooling material, liquid lead-lithium, flows through the PERITs, providing protection to the reflector/vacuum chamber so as to make it a lifetime component. The neutronics analysis and cavity hydrodynamics calculations are performed to account for the neutron heating and also to determine the effects of vaporization/condensation processes on the surface heat flux. The steady state nuclear heating distribution at the midplane is used for thermal hydraulics calculations. The maximum surface temperature of the HT-9 is chosen to not exceed 625 degree C to avoid drastic deterioration of the metal's mechanical properties. This choice restricts the thermal hydraulics performance of the reaction cavity. The inlet first surface coolant bulk temperature is 370 degree C, and the heat exchanger inlet coolant bulk temperature is 502 degree C. 4 refs., 6 figs., 2 tabs

  8. Analysis of drug adversiting targeted to health professionals

    Directory of Open Access Journals (Sweden)

    Marcela Campos Esqueff Abdalla

    2017-08-01

    Full Text Available The advertising of medicines is the dissemination of the product by the pharmaceutical industry, with emphasis on brand, aiming to promote their prescription and/or purchase. This practice must comply with the legal provisions in effect determined by Brazilian National Surveillance Agency. The present work aimed to analyze advertisements of medicines offered by the industry to health professionals. The capture of advertisements covered physician offices of various specialties, public and private hospitals and magazines directed at health professionals. The analysis of the collected parts involved the verification of legibility and viewing of information required, as well as the compliance with the health legislation that regulates the promotion and advertising of medicines in Brazil – agency’s resolution n. 96/2008. The results showed that no piece meets the health legislation in full. Most industries employs strategies that hinder access to restricted information of use of the medicine, as contra-indications, for example, constituting an obstacle to rational use. It was also observed the presence of indications other than those approved by the agency and use indication for different age groups in the specified product registration. It is obvious the need for a new model controller and more rigid regulator that prioritize above all particular interests, a major importance, that is the society. This must be protected from false advertising and abusive, promoting the rational use of medicines.

  9. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

    Science.gov (United States)

    Lee, Hae Kyung; Bier, Ariel; Cazacu, Simona; Finniss, Susan; Xiang, Cunli; Twito, Hodaya; Poisson, Laila M; Mikkelsen, Tom; Slavin, Shimon; Jacoby, Elad; Yalon, Michal; Toren, Amos; Rempel, Sandra A; Brodie, Chaya

    2013-01-01

    Glioblastomas (GBM), the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs) compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF) as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

  10. MicroRNA-145 is downregulated in glial tumors and regulates glioma cell migration by targeting connective tissue growth factor.

    Directory of Open Access Journals (Sweden)

    Hae Kyung Lee

    Full Text Available Glioblastomas (GBM, the most common and aggressive type of malignant glioma, are characterized by increased invasion into the surrounding brain tissues. Despite intensive therapeutic strategies, the median survival of GBM patients has remained dismal over the last decades. In this study we examined the expression of miR-145 in glial tumors and its function in glioma cells. Using TCGA analysis and real-time PCR we found that the expression of miR-145/143 cluster was downregulated in astrocytic tumors compared to normal brain specimens and in glioma cells and glioma stem cells (GSCs compared to normal astrocytes and neural stem cells. Moreover, the low expression of both miR-145 and miR-143 in GBM was correlated with poor patient prognosis. Transfection of glioma cells with miR-145 mimic or transduction with a lentivirus vector expressing pre-miR 145 significantly decreased the migration and invasion of glioma cells. We identified connective tissue growth factor (CTGF as a novel target of miR-145 in glioma cells; transfection of the cells with this miRNA decreased the expression of CTGF as determined by Western blot analysis and the expression of its 3'-UTR fused to luciferase. Overexpression of a CTGF plasmid lacking the 3'-UTR and administration of recombinant CTGF protein abrogated the inhibitory effect of miR-145 on glioma cell migration. Similarly, we found that silencing of CTGF decreased the migration of glioma cells. CTGF silencing also decreased the expression of SPARC, phospho-FAK and FAK and overexpression of SPARC abrogated the inhibitory effect of CTGF silencing on cell migration. These results demonstrate that miR-145 is downregulated in glial tumors and its low expression in GBM predicts poor patient prognosis. In addition miR-145 regulates glioma cell migration by targeting CTGF which downregulates SPARC expression. Therefore, miR-145 is an attractive therapeutic target for anti-invasive treatment of astrocytic tumors.

  11. Drug target mining and analysis of the Chinese tree shrew for pharmacological testing.

    Directory of Open Access Journals (Sweden)

    Feng Zhao

    Full Text Available The discovery of new drugs requires the development of improved animal models for drug testing. The Chinese tree shrew is considered to be a realistic candidate model. To assess the potential of the Chinese tree shrew for pharmacological testing, we performed drug target prediction and analysis on genomic and transcriptomic scales. Using our pipeline, 3,482 proteins were predicted to be drug targets. Of these predicted targets, 446 and 1,049 proteins with the highest rank and total scores, respectively, included homologs of targets for cancer chemotherapy, depression, age-related decline and cardiovascular disease. Based on comparative analyses, more than half of drug target proteins identified from the tree shrew genome were shown to be higher similarity to human targets than in the mouse. Target validation also demonstrated that the constitutive expression of the proteinase-activated receptors of tree shrew platelets is similar to that of human platelets but differs from that of mouse platelets. We developed an effective pipeline and search strategy for drug target prediction and the evaluation of model-based target identification for drug testing. This work provides useful information for future studies of the Chinese tree shrew as a source of novel targets for drug discovery research.

  12. The regulatory mechanism of fruit ripening revealed by analyses of direct targets of the tomato MADS-box transcription factor RIPENING INHIBITOR

    Science.gov (United States)

    Fujisawa, Masaki; Ito, Yasuhiro

    2013-01-01

    The developmental process of ripening is unique to fleshy fruits and a key factor in fruit quality. The tomato (Solanum lycopersicum) MADS-box transcription factor RIPENING INHIBITOR (RIN), one of the earliest-acting ripening regulators, is required for broad aspects of ripening, including ethylene-dependent and -independent pathways. However, our knowledge of direct RIN target genes has been limited, considering the broad effects of RIN on ripening. In a recent work published in The Plant Cell, we identified 241 direct RIN target genes by chromatin immunoprecipitation coupled with DNA microarray (ChIP-chip) and transcriptome analysis. Functional classification of the targets revealed that RIN participates in the regulation of many biological processes including well-known ripening processes such as climacteric ethylene production and lycopene accumulation. In addition, we found that ethylene is required for the full expression of RIN and several RIN-targeting transcription factor genes at the ripening stage. Here, based on our recently published findings and additional data, we discuss the ripening processes regulated by RIN and the interplay between RIN and ethylene. PMID:23518588

  13. Risk factors for exclusive breastfeeding lasting less than two months-Identifying women in need of targeted breastfeeding support.

    Directory of Open Access Journals (Sweden)

    Karin Cato

    Full Text Available Breastfeeding rates in Sweden are declining, and it is important to identify women at risk for early cessation of exclusive breastfeeding.The aim of this study was to investigate factors associated with exclusive breastfeeding lasting less than two months postpartum.A population-based longitudinal study was conducted at Uppsala University Hospital, Sweden. Six hundred and seventy-nine women were included in this sub-study. Questionnaires were sent at five days, six weeks and six months postpartum, including questions on breastfeeding initiation and duration as well as several other background variables. The main outcome measure was exclusive breastfeeding lasting less than two months postpartum. Multivariable logistic regression analysis was used in order to calculate adjusted Odds Ratios (AOR and 95% Confidence Intervals (95% CI.Seventy-seven percent of the women reported exclusive breastfeeding at two months postpartum. The following variables in the multivariate regression analysis were independently associated with exclusive breastfeeding lasting less than two months postpartum: being a first time mother (AOR 2.15, 95% CI 1.32-3.49, reporting emotional distress during pregnancy (AOR 2.21, 95% CI 1.35-3.62 and giving birth by cesarean section (AOR 2.63, 95% CI 1.34-5.17.Factors associated with shorter exclusive breastfeeding duration were determined. Identification of women experiencing emotional distress during pregnancy, as well as scrutiny of caregiving routines on cesarean section need to be addressed, in order to give individual targeted breastfeeding support and promote longer breastfeeding duration.

  14. Dual DNA binding property of ABA insensitive 3 like factors targeted to promoters responsive to ABA and auxin.

    Science.gov (United States)

    Nag, Ronita; Maity, Manas Kanti; Dasgupta, Maitrayee

    2005-11-01

    The ABA responsive ABI3 and the auxin responsive ARF family of transcription factors bind the CATGCATG (Sph) and TGTCTC core motifs in ABA and auxin response elements (ABRE and AuxRE), respectively. Several evidences indicate ABI3s to act downstream to auxin too. Because DNA binding domain of ABI3s shows significant overlap with ARFs we enquired whether auxin responsiveness through ABI3s could be mediated by their binding to canonical AuxREs. Investigations were undertaken through in vitro gel mobility shift assays (GMSA) using the DNA binding domain B3 of PvAlf (Phaseolus vulgaris ABI3 like factor) and upstream regions of auxin responsive gene GH3 (-267 to -141) and ABA responsive gene Em (-316 to -146) harboring AuxRE and ABRE, respectively. We demonstrate that B3 domain of PvAlf could bind AuxRE only when B3 was associated with its flanking domain B2 (B2B3). Such strict requirement of B2 domain was not observed with ABRE, where B3 could bind with or without being associated with B2. This dual specificity in DNA binding of ABI3s was also demonstrated with nuclear extracts of cultured cells of Arachis hypogea. Supershift analysis of ABRE and AuxRE bound nuclear proteins with antibodies raised against B2B3 domains of PvAlf revealed that ABI3 associated complexes were detectable in association with both cis elements. Competition GMSA confirmed the same complexes to bind ABRE and AuxRE. This dual specificity of ABI3 like factors in DNA binding targeted to natural promoters responsive to ABA and auxin suggests them to have a potential role in conferring crosstalk between these two phytohormones.

  15. Identification of noise in linear data sets by factor analysis

    International Nuclear Information System (INIS)

    Roscoe, B.A.; Hopke, Ph.K.

    1982-01-01

    A technique which has the ability to identify bad data points, after the data has been generated, is classical factor analysis. The ability of classical factor analysis to identify two different types of data errors make it ideally suited for scanning large data sets. Since the results yielded by factor analysis indicate correlations between parameters, one must know something about the nature of the data set and the analytical techniques used to obtain it to confidentially isolate errors. (author)

  16. Exploring Technostress: Results of a Large Sample Factor Analysis

    OpenAIRE

    Jonušauskas, Steponas; Raišienė, Agota Giedrė

    2016-01-01

    With reference to the results of a large sample factor analysis, the article aims to propose the frame examining technostress in a population. The survey and principal component analysis of the sample consisting of 1013 individuals who use ICT in their everyday work was implemented in the research. 13 factors combine 68 questions and explain 59.13 per cent of the answers dispersion. Based on the factor analysis, questionnaire was reframed and prepared to reasonably analyze the respondents’ an...

  17. Identifying target processes for microbial electrosynthesis by elementary mode analysis.

    Science.gov (United States)

    Kracke, Frauke; Krömer, Jens O

    2014-12-30

    Microbial electrosynthesis and electro fermentation are techniques that aim to optimize microbial production of chemicals and fuels by regulating the cellular redox balance via interaction with electrodes. While the concept is known for decades major knowledge gaps remain, which make it hard to evaluate its biotechnological potential. Here we present an in silico approach to identify beneficial production processes for electro fermentation by elementary mode analysis. Since the fundamentals of electron transport between electrodes and microbes have not been fully uncovered yet, we propose different options and discuss their impact on biomass and product yields. For the first time 20 different valuable products were screened for their potential to show increased yields during anaerobic electrically enhanced fermentation. Surprisingly we found that an increase in product formation by electrical enhancement is not necessarily dependent on the degree of reduction of the product but rather the metabolic pathway it is derived from. We present a variety of beneficial processes with product yield increases of maximal 36% in reductive and 84% in oxidative fermentations and final theoretical product yields up to 100%. This includes compounds that are already produced at industrial scale such as succinic acid, lysine and diaminopentane as well as potential novel bio-commodities such as isoprene, para-hydroxybenzoic acid and para-aminobenzoic acid. Furthermore, it is shown that the way of electron transport has major impact on achievable biomass and product yields. The coupling of electron transport to energy conservation could be identified as crucial for most processes. This study introduces a powerful tool to determine beneficial substrate and product combinations for electro-fermentation. It also highlights that the maximal yield achievable by bio electrochemical techniques depends strongly on the actual electron transport mechanisms. Therefore it is of great importance to

  18. International comparison of the factors influencing reimbursement of targeted anti-cancer drugs.

    Science.gov (United States)

    Lim, Carol Sunghye; Lee, Yun-Gyoo; Koh, Youngil; Heo, Dae Seog

    2014-11-29

    Reimbursement policies for anti-cancer drugs vary among countries even though they rely on the same clinical evidence. We compared the pattern of publicly funded drug programs and analyzed major factors influencing the differences. We investigated reimbursement policies for 19 indications with targeted anti-cancer drugs that are used variably across ten countries. The available incremental cost-effectiveness ratio (ICER) data were retrieved for each indication. Based on the comparison between actual reimbursement decisions and the ICERs, we formulated a reimbursement adequacy index (RAI): calculating the proportion of cost-effective decisions, either reimbursement of cost-effective indications or non-reimbursement of cost-ineffective indications, out of the total number of indications for each country. The relationship between RAI and other indices were analyzed, including governmental dependency on health technology assessment, as well as other parameters for health expenditure. All the data used in this study were gathered from sources publicly available online. Japan and France were the most likely to reimburse indications (16/19), whereas Sweden and the United Kingdom were the least likely to reimburse them (5/19 and 6/19, respectively). Indications with high cost-effectiveness values were more likely to be reimbursed (ρ = -0.68, P = 0.001). The three countries with high RAI scores each had a healthcare system that was financed by general taxation. Although reimbursement policies for anti-cancer drugs vary among countries, we found a strong correlation of reimbursements for those indications with lower ICERs. Countries with healthcare systems financed by general taxation demonstrated greater cost-effectiveness as evidenced by reimbursement decisions of anti-cancer drugs.

  19. Ultrasound-targeted hepatic delivery of factor IX in hemophiliac mice.

    Science.gov (United States)

    Anderson, C D; Moisyadi, S; Avelar, A; Walton, C B; Shohet, R V

    2016-06-01

    Ultrasound-targeted microbubble destruction (UTMD) was used to direct the delivery of plasmid and transposase-based vectors encoding human factor IX (hFIX) to the livers of hemophilia B (FIX-/-) mice. The DNA vectors were incorporated into cationic lipid microbubbles, injected intravenously, and transfected into hepatocytes by acoustic cavitation of the bubbles as they transited the liver. Ultrasound parameters were identified that produced transfection of hepatocytes in vivo without substantial damage or bleeding in the livers of the FIX-deficient mice. These mice were treated with a conventional expression plasmid, or one containing a piggyBac transposon construct, and hFIX levels in the plasma and liver were evaluated at multiple time points after UTMD. We detected hFIX in the plasma by western blotting from mice treated with either plasmid during the 12 days after UTMD, and in the hepatocytes of treated livers by immunofluorescence. Reductions in clotting time and improvements in the percentage of FIX activity were observed for both plasmids, conventional (4.15±1.98%), and transposon based (2.70±.75%), 4 to 5 days after UTMD compared with untreated FIX (-/-) control mice (0.92±0.78%) (P=0.001 and P=0.012, respectively). Reduced clotting times persisted for both plasmids 12 days after treatment (reflecting percentage FIX activity of 3.12±1.56%, P=0.02 and 3.08±0.10%, P=0.001, respectively). Clotting times from an additional set of mice treated with pmGENIE3-hFIX were evaluated for long-term effects and demonstrated a persistent reduction in average clotting time 160 days after a single treatment. These data suggest that UTMD could be a minimally invasive, nonviral approach to enhance hepatic FIX expression in patients with hemophilia.

  20. Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results

    International Nuclear Information System (INIS)

    Baumann, Michael; Krause, Mechthild

    2004-01-01

    Background and purpose: Inhibition of the epidermal growth factor receptor (EGFR) is a fastly developing field in preclinical and clinical cancer research. This review presents the current status of knowledge and discusses radiobiological mechanisms which may underly the efficacy of EGFR inhibitors combined with irradiation. Materials and methods: Preclinical and clinical results on combined targeting of the EGFR and irradiation from the literature and from this laboratory are reviewed. Focus is given to the radiobiological rationale of this approach and to endpoints of experimental radiotherapy. Results: Overexpression of the EGFR is associated with decreased local tumour control after radiotherapy, especially when the overall treatment time is long. Inhibition of the EGFR either alone or in combination with irradiation decreases the growth rate of tumours expressing this receptor. Preclinical data provide proof-of-principle that local tumour control may be improved by combining irradiation with C225 mAb. In a randomised phase III clinical trial, simultaneous irradiation and treatment with the EGFR antibody Cetuximab (Erbitux[reg]; C225) in head and neck cancer patients resulted in significantly improved locoregional tumour control and survival compared to curative irradiation alone. Acute skin reactions increased in the experimental arm. The underlying mechanisms of enhanced radiation effects of combined EGFR inhibition with irradiation and of the partly conflicting results in different studies are poorly understood. There is increasing evidence, that important intertumoral heterogeneity in the response to EGFR inhibition alone and combined with irradiation exists, which appears to be at least partly dependent on specific mutations of the receptor as well as of molecules that are involved in the intracellular signal transduction pathway. Conclusions and outlook: Further investigations at all levels of the translational research chain exploring the mechanisms of

  1. Profiling ethanol-targeted transcription factors in human carcinoma cell-derived embryoid bodies.

    Science.gov (United States)

    Mandal, Chanchal; Halder, Debasish; Chai, Jin Choul; Lee, Young Seek; Jung, Kyoung Hwa; Chai, Young Gyu

    2016-01-15

    Fetal alcohol spectrum disorder is a collective term that represents fetal abnormalities associated with maternal alcohol consumption. Prenatal alcohol exposure and related anomalies are well characterized, but the molecular mechanism behind this phenomenon is not yet understood. Few insights have been gained from genetic and epigenetic studies of fetal alcohol spectrum disorder. Our aim was to profile the important molecular regulators of ethanol-related alterations of the genome. For this purpose, we have analyzed the gene expression pattern of human carcinoma cell-derived embryoid bodies in the absence or presence of ethanol. A cDNA microarray analysis was used to profile mRNA expression in embryoid bodies at day 7 with or without ethanol treatment. A total of 493 differentially expressed genes were identified in response to 50 mM ethanol exposure. Of these, 111 genes were up-regulated, and 382 were down-regulated. Gene ontology term enrichment analysis revealed that these genes are involved in important biological processes: neurological system processes, cognition, behavior, sensory perception of smell, taste and chemical stimuli and synaptic transmission. Similarly, the enrichment of disease-related genes included relevant categories such as neurological diseases, developmental disorders, skeletal and muscular disorders, and connective tissue disorders. Furthermore, we have identified a group of 26 genes that encode transcription factors. We validated the relative gene expression of several transcription factors using quantitative real time PCR. We hope that our study substantially contributes to the understanding of the molecular mechanisms underlying the pathology of alcohol-mediated anomalies and facilitates further research. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Analysis of Increased Information Technology Outsourcing Factors

    Directory of Open Access Journals (Sweden)

    Brcar Franc

    2013-01-01

    Full Text Available The study explores the field of IT outsourcing. The narrow field of research is to build a model of IT outsourcing based on influential factors. The purpose of this research is to determine the influential factors on IT outsourcing expansion. A survey was conducted with 141 large-sized Slovenian companies. Data were statistically analyzed using binary logistic regression. The final model contains five factors: (1 management’s support; (2 knowledge on IT outsourcing; (3 improvement of efficiency and effectiveness; (4 quality improvement of IT services; and (5 innovation improvement of IT. Managers immediately can use the results of this research in their decision-making. Increased performance of each individual organization is to the benefit of the entire society. The examination of IT outsourcing with the methods used is the first such research in Slovenia.

  3. Analysis of the optical scattering characteristics of different types of space targets

    International Nuclear Information System (INIS)

    Han, Yi; Sun, Huayan; Feng, Jianguang; Li, Liang

    2014-01-01

    This paper mainly focused on the measurement, evaluation and potential identification methods of the unresolved space target's photometric characteristics. The bidirectional reflectance distribution function (BRDF) measurement system was introduced first, and then the measurement error of BRDF and its influence on target's optical cross section (OCS) and magnitude were analyzed. Then, different space targets’ OCS and magnitude changing with different factors, such as surface materials and shapes, flying conditions and working states, were analyzed respectively, and some general inclusions of variation laws were deduced. This research can provide references for future studies on space target classification and identification based on the photometric measurement data. (paper)

  4. Fibroblast growth factor receptor (FGFR) alterations in squamous differentiated bladder cancer: a putative therapeutic target for a small subgroup.

    Science.gov (United States)

    Baldia, Philipp H; Maurer, Angela; Heide, Timon; Rose, Michael; Stoehr, Robert; Hartmann, Arndt; Williams, Sarah V; Knowles, Margaret A; Knuechel, Ruth; Gaisa, Nadine T

    2016-11-01

    Although drugable fibroblast growth factor receptor (FGFR) alterations in squamous cell carcinomas (SCC) of various entities are well known, little is known about FGFR modifications in squamous differentiated bladder cancer. Therefore, our study evaluated FGFR1-3 alterations as a putative therapeutic target in this subgroup. We analyzed 73 squamous differentiated bladder cancers (n = 10 pT2, n = 55 pT3, n = 8 pT4) for FGFR1-3 protein expression, FGFR1-3 copy number variations, FGFR3 chromosomal rearrangements (fluorescence in situ hybridization (FISH)) and FGFR3 mutations (SNapShot analysis). Only single cases displayed enhanced protein expression, most frequently FGFR3 overexpression (9.4% (6/64)). FISH showed no amplifications of FGFR1, 2 or 3. Break apart events were only slightly above the cut off in 12.1% (8/66) of cases and no FGFR3-TACC3 rearrangements could be proven by qPCR. FGFR3 mutations (p.S249C) were found in 8.5% (6/71) of tumors and were significantly associated with FGFR3 protein overexpression (p bladder cancer (n = 85), which revealed reduced overall expression of FGFR1 and FGFR2 in tumors compared to normal tissue, while expression of FGFR3 remained high. In the TCGA "squamous-like" subtype FGFR3 mutations were found in 4.9% and correlated with high FGFR3 RNA expression. Mutations of FGFR1 and FGFR2 were less frequent (2.4% and 1.2%). Hence, our comprehensive study provides novel insights into a subgroup of squamous differentiated bladder tumors that hold clues for novel therapeutic regimens and may benefit from FGFR3-targeted therapies.

  5. Warranty claim analysis considering human factors

    International Nuclear Information System (INIS)

    Wu Shaomin

    2011-01-01

    Warranty claims are not always due to product failures. They can also be caused by two types of human factors. On the one hand, consumers might claim warranty due to misuse and/or failures caused by various human factors. Such claims might account for more than 10% of all reported claims. On the other hand, consumers might not be bothered to claim warranty for failed items that are still under warranty, or they may claim warranty after they have experienced several intermittent failures. These two types of human factors can affect warranty claim costs. However, research in this area has received rather little attention. In this paper, we propose three models to estimate the expected warranty cost when the two types of human factors are included. We consider two types of failures: intermittent and fatal failures, which might result in different claim patterns. Consumers might report claims after a fatal failure has occurred, and upon intermittent failures they might report claims after a number of failures have occurred. Numerical examples are given to validate the results derived.

  6. Chiral analysis of baryon form factors

    Energy Technology Data Exchange (ETDEWEB)

    Gail, T.A.

    2007-11-08

    This work presents an extensive theoretical investigation of the structure of the nucleon within the standard model of elementary particle physics. In particular, the long range contributions to a number of various form factors parametrizing the interactions of the nucleon with an electromagnetic probe are calculated. The theoretical framework for those calculations is chiral perturbation theory, the exact low energy limit of Quantum Chromo Dynamics, which describes such long range contributions in terms of a pion-cloud. In this theory, a nonrelativistic leading one loop order calculation of the form factors parametrizing the vector transition of a nucleon to its lowest lying resonance, the {delta}, a covariant calculation of the isovector and isoscalar vector form factors of the nucleon at next to leading one loop order and a covariant calculation of the isoscalar and isovector generalized vector form factors of the nucleon at leading one loop order are performed. In order to perform consistent loop calculations in the covariant formulation of chiral perturbation theory an appropriate renormalization scheme is defined in this work. All theoretical predictions are compared to phenomenology and results from lattice QCD simulations. These comparisons allow for a determination of the low energy constants of the theory. Furthermore, the possibility of chiral extrapolation, i.e. the extrapolation of lattice data from simulations at large pion masses down to the small physical pion mass is studied in detail. Statistical as well as systematic uncertainties are estimated for all results throughout this work. (orig.)

  7. Identification and analysis of potential targets in Streptococcus sanguinis using computer aided protein data analysis.

    Science.gov (United States)

    Chowdhury, Md Rabiul Hossain; Bhuiyan, Md IqbalKaiser; Saha, Ayan; Mosleh, Ivan Mhai; Mondol, Sobuj; Ahmed, C M Sabbir

    2014-01-01

    Streptococcus sanguinis is a Gram-positive, facultative aerobic bacterium that is a member of the viridans streptococcus group. It is found in human mouths in dental plaque, which accounts for both dental cavities and bacterial endocarditis, and which entails a mortality rate of 25%. Although a range of remedial mediators have been found to control this organism, the effectiveness of agents such as penicillin, amoxicillin, trimethoprim-sulfamethoxazole, and erythromycin, was observed. The emphasis of this investigation was on finding substitute and efficient remedial approaches for the total destruction of this bacterium. In this computational study, various databases and online software were used to ascertain some specific targets of S. sanguinis. Particularly, the Kyoto Encyclopedia of Genes and Genomes databases were applied to determine human nonhomologous proteins, as well as the metabolic pathways involved with those proteins. Different software such as Phyre2, CastP, DoGSiteScorer, the Protein Function Predictor server, and STRING were utilized to evaluate the probable active drug binding site with its known function and protein-protein interaction. In this study, among 218 essential proteins of this pathogenic bacterium, 81 nonhomologous proteins were accrued, and 15 proteins that are unique in several metabolic pathways of S. sanguinis were isolated through metabolic pathway analysis. Furthermore, four essentially membrane-bound unique proteins that are involved in distinct metabolic pathways were revealed by this research. Active sites and druggable pockets of these selected proteins were investigated with bioinformatic techniques. In addition, this study also mentions the activity of those proteins, as well as their interactions with the other proteins. Our findings helped to identify the type of protein to be considered as an efficient drug target. This study will pave the way for researchers to develop and discover more effective and specific

  8. Identification and analysis of potential targets in Streptococcus sanguinis using computer aided protein data analysis

    Science.gov (United States)

    Chowdhury, Md Rabiul Hossain; Bhuiyan, Md IqbalKaiser; Saha, Ayan; Mosleh, Ivan MHAI; Mondol, Sobuj; Ahmed, C M Sabbir

    2014-01-01

    Purpose Streptococcus sanguinis is a Gram-positive, facultative aerobic bacterium that is a member of the viridans streptococcus group. It is found in human mouths in dental plaque, which accounts for both dental cavities and bacterial endocarditis, and which entails a mortality rate of 25%. Although a range of remedial mediators have been found to control this organism, the effectiveness of agents such as penicillin, amoxicillin, trimethoprim–sulfamethoxazole, and erythromycin, was observed. The emphasis of this investigation was on finding substitute and efficient remedial approaches for the total destruction of this bacterium. Materials and methods In this computational study, various databases and online software were used to ascertain some specific targets of S. sanguinis. Particularly, the Kyoto Encyclopedia of Genes and Genomes databases were applied to determine human nonhomologous proteins, as well as the metabolic pathways involved with those proteins. Different software such as Phyre2, CastP, DoGSiteScorer, the Protein Function Predictor server, and STRING were utilized to evaluate the probable active drug binding site with its known function and protein–protein interaction. Results In this study, among 218 essential proteins of this pathogenic bacterium, 81 nonhomologous proteins were accrued, and 15 proteins that are unique in several metabolic pathways of S. sanguinis were isolated through metabolic pathway analysis. Furthermore, four essentially membrane-bound unique proteins that are involved in distinct metabolic pathways were revealed by this research. Active sites and druggable pockets of these selected proteins were investigated with bioinformatic techniques. In addition, this study also mentions the activity of those proteins, as well as their interactions with the other proteins. Conclusion Our findings helped to identify the type of protein to be considered as an efficient drug target. This study will pave the way for researchers to

  9. Identification and analysis of potential targets in Streptococcus sanguinis using computer aided protein data analysis

    Directory of Open Access Journals (Sweden)

    Chowdhury MRH

    2014-11-01

    Full Text Available Md Rabiul Hossain Chowdhury,1 Md IqbalKaiser Bhuiyan,2 Ayan Saha,2 Ivan MHAI Mosleh,2 Sobuj Mondol,2 C M Sabbir Ahmed3 1Department of Pharmacy, University of Science and Technology Chittagong, Chittagong, Bangladesh; 2Department of Genetic Engineering and Biotechnology, University of Chittagong, Chittagong, Bangladesh; 3Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna, Bangladesh Purpose: Streptococcus sanguinis is a Gram-positive, facultative aerobic bacterium that is a member of the viridans streptococcus group. It is found in human mouths in dental plaque, which accounts for both dental cavities and bacterial endocarditis, and which entails a mortality rate of 25%. Although a range of remedial mediators have been found to control this organism, the effectiveness of agents such as penicillin, amoxicillin, trimethoprim–sulfamethoxazole, and erythromycin, was observed. The emphasis of this investigation was on finding substitute and efficient remedial approaches for the total destruction of this bacterium. Materials and methods: In this computational study, various databases and online software were used to ascertain some specific targets of S. sanguinis. Particularly, the Kyoto Encyclopedia of Genes and Genomes databases were applied to determine human nonhomologous proteins, as well as the metabolic pathways involved with those proteins. Different software such as Phyre2, CastP, DoGSiteScorer, the Protein Function Predictor server, and STRING were utilized to evaluate the probable active drug binding site with its known function and protein–protein interaction. Results: In this study, among 218 essential proteins of this pathogenic bacterium, 81 nonhomologous proteins were accrued, and 15 proteins that are unique in several metabolic pathways of S. sanguinis were isolated through metabolic pathway analysis. Furthermore, four essentially membrane-bound unique proteins that are involved in distinct metabolic

  10. Design of the solid target structure and the study on the coolant flow distribution in the solid target using the 2-dimensional flow analysis

    International Nuclear Information System (INIS)

    Haga, Katsuhiro; Terada, Atsuhiko; Ishikura, Shuichi; Teshigawara, Makoto; Kinoshita, Hidetaka; Kobayashi, Kaoru; Kaminaga, Masaki; Hino, Ryutaro; Susuki, Akira

    1999-11-01

    A solid target cooled by heavy water is presently under development under the Neutron Science Research Project of the Japan Atomic Energy Research Institute (JAERI). Target plates of several millimeters thickness made of heavy metal are used as the spallation target material and they are put face to face in a row with one to two millimeters gaps in between though which heavy water flows, as the coolant. Based on the design criteria regarding the target plate cooling, the volume percentage of the coolant, and the thermal stress produced in the target plates, we conducted thermal and hydraulic analysis with a one dimensional target plate model. We choosed tungsten as the target material, and decided on various target plate thicknesses. We then calculated the temperature and the thermal stress in the target plates using a two dimensional model, and confirmed the validity of the target plate thicknesses. Based on these analytical results, we proposed a target structure in which forty target plates are divided into six groups and each group is cooled using a single pass of coolant. In order to investigate the relationship between the distribution of the coolant flow, the pressure drop, and the coolant velocity, we conducted a hydraulic analysis using the general purpose hydraulic analysis code. As a result, we realized that an uniform coolant flow distribution can be achieved under a wide range of flow velocity conditions in the target plate cooling channels from 1 m/s to 10 m/s. The pressure drop along the coolant path was 0.09 MPa and 0.17 MPa when the coolant flow velocity was 5 m/s and 7 m/s respectively, which is required to cool the 1.5 MW and 2.5 MW solid targets. (author)

  11. Promotion of seminomatous tumors by targeted overexpression of glial cell line-derived neurotrophic factor in mouse testis

    NARCIS (Netherlands)

    Meng, X.; de rooij, D. G.; Westerdahl, K.; Saarma, M.; Sariola, H.

    2001-01-01

    We show with transgenic mice that targeted overexpression of glial cell line-derived neurotrophic factor (GDNF) in undifferentiated spermatogonia promotes malignant testicular tumors, which express germ-cell markers. The tumors are invasive and contain aneuploid cells, but no distant metastases have

  12. Estimation of Partial Safety Factors and Target Failure Probability Based on Cost Optimization of Rubble Mound Breakwaters

    DEFF Research Database (Denmark)

    Kim, Seung-Woo; Suh, Kyung-Duck; Burcharth, Hans F.

    2010-01-01

    The breakwaters are designed by considering the cost optimization because a human risk is seldom considered. Most breakwaters, however, were constructed without considering the cost optimization. In this study, the optimum return period, target failure probability and the partial safety factors...

  13. An assessment of independent component analysis for detection of military targets from hyperspectral images

    Science.gov (United States)

    Tiwari, K. C.; Arora, M. K.; Singh, D.

    2011-10-01

    Hyperspectral data acquired over hundreds of narrow contiguous wavelength bands are extremely suitable for target detection due to their high spectral resolution. Though spectral response of every material is expected to be unique, but in practice, it exhibits variations, which is known as spectral variability. Most target detection algorithms depend on spectral modelling using a priori available target spectra In practice, target spectra is, however, seldom available a priori. Independent component analysis (ICA) is a new evolving technique that aims at finding out components which are statistically independent or as independent as possible. The technique therefore has the potential of being used for target detection applications. A assessment of target detection from hyperspectral images using ICA and other algorithms based on spectral modelling may be of immense interest, since ICA does not require a priori target information. The aim of this paper is, thus, to assess the potential of ICA based algorithm vis a vis other prevailing algorithms for military target detection. Four spectral matching algorithms namely Orthogonal Subspace Projection (OSP), Constrained Energy Minimisation (CEM), Spectral Angle Mapper (SAM) and Spectral Correlation Mapper (SCM), and four anomaly detection algorithms namely OSP anomaly detector (OSPAD), Reed-Xiaoli anomaly detector (RXD), Uniform Target Detector (UTD) and a combination of Reed-Xiaoli anomaly detector and Uniform Target Detector (RXD-UTD) were considered. The experiments were conducted using a set of synthetic and AVIRIS hyperspectral images containing aircrafts as military targets. A comparison of true positive and false positive rates of target detections obtained from ICA and other algorithms plotted on a receiver operating curves (ROC) space indicates the superior performance of the ICA over other algorithms.

  14. Regression analysis of nuclear plant capacity factors

    International Nuclear Information System (INIS)

    Stocks, K.J.; Faulkner, J.I.

    1980-07-01

    Operating data on all commercial nuclear power plants of the PWR, HWR, BWR and GCR types in the Western World are analysed statistically to determine whether the explanatory variables size, year of operation, vintage and reactor supplier are significant in accounting for the variation in capacity factor. The results are compared with a number of previous studies which analysed only United States reactors. The possibility of specification errors affecting the results is also examined. Although, in general, the variables considered are statistically significant, they explain only a small portion of the variation in the capacity factor. The equations thus obtained should certainly not be used to predict the lifetime performance of future large reactors

  15. An Empirical Analysis of Job Satisfaction Factors.

    Science.gov (United States)

    1987-09-01

    have acknowledged the importance of factors which make the Air Force attractive to its members or conversely, make other employees consider...Maslow’s need hierarchy theory attempts to show that man has five basic categories of needs: physiological, safety, belongingness , esteem, and self...attained until lower-level basic needs are attained. This implies a sort of growth process where optional job environments for given employees are

  16. Dynamic analysis of the Nova Target Chamber to assess alignment errors due to ambient noise

    International Nuclear Information System (INIS)

    McCallen, D.B.; Murray, R.C.

    1984-01-01

    We performed a study to determine the dynamic behavior of the Nova Target Chamber. We conducted a free vibration analysis to determine the natural frequencies of vibration and the corresponding modeshapes of the target chamber. Utilizing the free vibration results, we performed forced vibration analysis to predict the displacements of the chamber due to ambient vibration. The input support motion for the forced vibration analysis was defined by a white noise acceleration spectrum which was based on previous measurements of ground noise near the Nova site. A special purpose computer program was prepared to process the results of the forced vibration analysis. The program yields distances by which the lines of sight of the various laser beams miss the target as a result of ambient vibrations. We also performed additional estimates of miss distance to provide bounds on the results. A description of the finite element model of the chamber, the input spectrum, and the results of the analyses are included

  17. Sentiment analysis enhancement with target variable in Kumar’s Algorithm

    Science.gov (United States)

    Arman, A. A.; Kawi, A. B.; Hurriyati, R.

    2016-04-01

    Sentiment analysis (also known as opinion mining) refers to the use of text analysis and computational linguistics to identify and extract subjective information in source materials. Sentiment analysis is widely applied to reviews discussion that is being talked in social media for many purposes, ranging from marketing, customer service, or public opinion of public policy. One of the popular algorithm for Sentiment Analysis implementation is Kumar algorithm that developed by Kumar and Sebastian. Kumar algorithm can identify the sentiment score of the statement, sentence or tweet, but cannot determine the relationship of the object or target related to the sentiment being analysed. This research proposed solution for that challenge by adding additional component that represent object or target to the existing algorithm (Kumar algorithm). The result of this research is a modified algorithm that can give sentiment score based on a given object or target.

  18. Factors associated with reaching or not reaching target HbA1c after initiation of basal or premixed insulin in patients with type 2 diabetes.

    Science.gov (United States)

    Scheen, A J; Schmitt, H; Jiang, H H; Ivanyi, T

    2017-02-01

    To evaluate factors associated with reaching or not reaching target glycated haemoglobin (HbA 1c ) levels by analysing the respective contributions of fasting hyperglycaemia (FHG), also referred to as basal hyperglycaemia, vs postprandial hyperglycaemia (PHG) before and after initiation of a basal or premixed insulin regimen in patients with type 2 diabetes. This post-hoc analysis of insulin-naïve patients in the DURABLE study randomised to receive either insulin glargine or insulin lispro mix 25 evaluated the percentages of patients achieving a target HbA 1c of <7.0% (<53mmol/mol) per baseline HbA 1c quartiles, and the effect of each insulin regimen on the relative contributions of PHG and FHG to overall hyperglycaemia. Patients had comparable demographic characteristics and similar HbA 1c and FHG values at baseline in each HbA 1c quartile regardless of whether they reached the target HbA 1c . The higher the HbA 1c quartile, the greater was the decrease in HbA 1c , but also the smaller the percentage of patients achieving the target HbA 1c . HbA 1c and FHG decreased more in patients reaching the target, resulting in significantly lower values at endpoint in all baseline HbA 1c quartiles with either insulin treatment. Patients not achieving the target HbA 1c had slightly higher insulin doses, but lower total hypoglycaemia rates. Smaller decreases in FHG were associated with not reaching the target HbA 1c , suggesting a need to increase basal or premixed insulin doses to achieve targeted fasting plasma glucose and improve patient response before introducing more intensive prandial insulin regimens. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  19. Design study and heat transfer analysis of a neutron converter target for medical radioisotope production

    International Nuclear Information System (INIS)

    Masoud Behzad; Sang-In Bak; Seung-Woo Hong; Jong-Seo Chai; Yacine Kadi; Claudio Tenreiro; University of Talca, Talca

    2014-01-01

    A worldwide challenge in the near future will be to find a way of producing radioisotopes in sufficient quantity without relying on research reactors. The motivation for this innovative work on targets lies in the accelerator-based production of radioisotopes using a neutron converter target as in the transmutation by adiabatic resonance crossing concept. Thermal analysis of a multi-channel helium cooled device is performed with the computational fluid dynamics code CFX. Different boundary conditions are taken into account in the simulation process and many important parameters such as maximum allowable solid target temperature as well as uniform inlet velocity and outlet pressure changes in the channels are investigated. The results confirm that the cooling configuration works well; hence such a solid target could be operated safely and may be considered for a prototype target. (author)

  20. A Factor Analysis of the BSRI and the PAQ.

    Science.gov (United States)

    Edwards, Teresa A.; And Others

    Factor analysis of the Bem Sex Role Inventory (BSRI) and the Personality Attributes Questionnaire (PAQ) was undertaken to study the independence of the masculine and feminine scales within each instrument. Both instruments were administered to undergraduate education majors. Analysis of primary first and second order factors of the BSRI indicated…

  1. HER-2 as a Progression Factor and Therapeutic Target in Breast Cancer

    National Research Council Canada - National Science Library

    1999-01-01

    ...). We had observed previously that upon reduction of llER-2 in MCF-7 cells by ribozyme-targeting estradiol lost its ability to induce anchorage- independent colony formation in soft agar of the tumor cell...

  2. Analysis and optimization of the TWINKLE factoring device

    NARCIS (Netherlands)

    Lenstra, A.K.; Shamir, A.; Preneel, B.

    2000-01-01

    We describe an enhanced version of the TWINKLE factoring device and analyse to what extent it can be expected to speed up the sieving step of the Quadratic Sieve and Number Field Sieve factoring al- gorithms. The bottom line of our analysis is that the TWINKLE-assisted factorization of 768-bit

  3. Hierarchical Factoring Based On Image Analysis And Orthoblique Rotations.

    Science.gov (United States)

    Stankov, L

    1979-07-01

    The procedure for hierarchical factoring suggested by Schmid and Leiman (1957) is applied within the framework of image analysis and orthoblique rotational procedures. It is shown that this approach necessarily leads to correlated higher order factors. Also, one can obtain a smaller number of factors than produced by typical hierarchical procedures.

  4. Effectiveness of a selective alcohol prevention program targeting personality risk factors: Results of interaction analyses.

    Science.gov (United States)

    Lammers, Jeroen; Goossens, Ferry; Conrod, Patricia; Engels, Rutger; Wiers, Reinout W; Kleinjan, Marloes

    2017-08-01

    To explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour. A clustered randomized controlled trial, with participants randomly assigned to a 2-session coping skills intervention or a control no-intervention condition. Fifteen secondary schools throughout The Netherlands; 7 schools in the intervention and 8 schools in the control condition. 699 adolescents aged 13-15; 343 allocated to the intervention and 356 to the control condition; with drinking experience and elevated scores in either negative thinking, anxiety sensitivity, impulsivity or sensation seeking. Differential effectiveness of the Preventure program was examined for the personality traits group, education level and gender on past-month binge drinking (main outcome), binge frequency, alcohol use, alcohol frequency and problem drinking, at 12months post-intervention. Preventure is a selective school-based alcohol prevention programme targeting personality risk factors. The comparator was a no-intervention control. Intervention effects were moderated by the personality traits group and by education level. More specifically, significant intervention effects were found on reducing alcohol use within the anxiety sensitivity group (OR=2.14, CI=1.40, 3.29) and reducing binge drinking (OR=1.76, CI=1.38, 2.24) and binge drinking frequency (β=0.24, p=0.04) within the sensation seeking group at 12months post-intervention. Also, lower educated young adolescents reduced binge drinking (OR=1.47, CI=1.14, 1.88), binge drinking frequency (β=0.25, p=0.04), alcohol use (OR=1.32, CI=1.06, 1.65) and alcohol use frequency (β=0.47, p=0.01), but not those in the higher education group. Post hoc latent-growth analyses revealed significant effects on the development of binge drinking (β=-0.19, p=0.02) and binge drinking frequency (β=-0.10, p=0

  5. Analysis of the Neutron Generator and Target for the LSDTS System

    Energy Technology Data Exchange (ETDEWEB)

    Park, Chang Je; Lee, Yong Deok; Song, Jae Hoon; Song, Kee Chan [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2008-11-15

    A preliminary analysis was performed based on the literatures and the patents for the neutron generators and targets for the lead slowing down time spectrometer (LSDTS) system. It was found that local neutron generator did not exhibit enough neutron intensity such as 1E+12 n/s, which is a minimum requirement for the LSDTS system to overcome curium backgrounds. However, a neutron generator implemented with an electron accelerator may provide a higher intensity around 1E+13 n/s and it is required to investigate further including a detail analysis. In addition to the neutron generator, a study on target was performed with the Monte Carlo simulation. In the study, an optimal design of target was suggested to provide a high neutron yield and a better thermal resistance. The suggested target consists several cylindrical plates with a certain cooling gap, which have increasing thickness and increasing radius.

  6. Numerical simulation and experimental study of factors influencing the optical characteristics of a spatial target

    International Nuclear Information System (INIS)

    Zhu Dingqiang; Shen Wentao; Cai Guobiao; Ke Weina

    2013-01-01

    The optical properties of a spatial target are important characteristics for its detection, identification, tracking and interception. A homeostatic model of the temperature and infrared characteristics of the target has been developed considering the radiation of the environmental background. The heat conduction inside the wall and the effect of an internal heat source are included in the model. The reflection characteristics of the target are calculated with bi-directional reflection distribution function (BRDF) models. The temperature and infrared radiation have been measured in the simulating space environment in the ground tests. The comparisons between the theoretical results and experimental data demonstrate a good agreement. Applying the developed model, the influences of several parameters (such as spin frequency, absorptivity/emissivity and thermal conductivity) of the target have been investigated. Highlights: ► A mathematical model was developed to predict the optical characteristics of a spatial target. ► The temperature and infrared radiation are measured in ground tests. ► The simulation results and the test results are consistent. ► The effects of several target parameters were analysed.

  7. Genome-wide analysis of PDX1 target genes in human pancreatic progenitors

    Directory of Open Access Journals (Sweden)

    Xianming Wang

    2018-03-01

    Full Text Available Objective: Homozygous loss-of-function mutations in the gene coding for the homeobox transcription factor (TF PDX1 leads to pancreatic agenesis, whereas heterozygous mutations can cause Maturity-Onset Diabetes of the Young 4 (MODY4. Although the function of Pdx1 is well studied in pre-clinical models during insulin-producing β-cell development and homeostasis, it remains elusive how this TF controls human pancreas development by regulating a downstream transcriptional program. Also, comparative studies of PDX1 binding patterns in pancreatic progenitors and adult β-cells have not been conducted so far. Furthermore, many studies reported the association between single nucleotide polymorphisms (SNPs and T2DM, and it has been shown that islet enhancers are enriched in T2DM-associated SNPs. Whether regions, harboring T2DM-associated SNPs are PDX1 bound and active at the pancreatic progenitor stage has not been reported so far. Methods: In this study, we have generated a novel induced pluripotent stem cell (iPSC line that efficiently differentiates into human pancreatic progenitors (PPs. Furthermore, PDX1 and H3K27ac chromatin immunoprecipitation sequencing (ChIP-seq was used to identify PDX1 transcriptional targets and active enhancer and promoter regions. To address potential differences in the function of PDX1 during development and adulthood, we compared PDX1 binding profiles from PPs and adult islets. Moreover, combining ChIP-seq and GWAS meta-analysis data we identified T2DM-associated SNPs in PDX1 binding sites and active chromatin regions. Results: ChIP-seq for PDX1 revealed a total of 8088 PDX1-bound regions that map to 5664 genes in iPSC-derived PPs. The PDX1 target regions include important pancreatic TFs, such as PDX1 itself, RFX6, HNF1B, and MEIS1, which were activated during the differentiation process as revealed by the active chromatin mark H3K27ac and mRNA expression profiling, suggesting that auto-regulatory feedback regulation

  8. Stromal Activation Associated with Development of Prostate Cancer in Prostate-Targeted Fibroblast Growth Factor 8b Transgenic Mice

    Directory of Open Access Journals (Sweden)

    Teresa D. Elo

    2010-11-01

    Full Text Available Expression of fibroblast growth factor 8 (FGF-8 is commonly increased in prostate cancer. Experimental studies have provided evidence that it plays a role in prostate tumorigenesis and tumor progression. To study how increased FGF-8 affects the prostate, we generated and analyzed transgenic (TG mice expressing FGF-8b under the probasin promoter that targets expression to prostate epithelium. Prostates of the TG mice showed an increased size and changes in stromal and epithelialmorphology progressing fromatypia and prostatic intraepithelial neoplasia (mouse PIN, mPIN lesions to tumors with highly variable phenotype bearing features of adenocarcinoma, carcinosarcoma, and sarcoma. The development of mPIN lesions was preceded by formation of activated stroma containing increased proportion of fibroblastic cells, rich vasculature, and inflammation. The association between advancing stromal and epithelial alterations was statistically significant. Microarray analysis and validation with quantitative polymerase chain reaction revealed that expression of osteopontin and connective tissue growth factor was markedly upregulated in TG mouse prostates compared with wild type prostates. Androgen receptor staining was decreased in transformed epithelium and in hypercellular stroma but strongly increased in the sarcoma-like lesions. In conclusion, our data demonstrate that disruption of FGF signaling pathways by increased epithelial production of FGF-8b leads to strongly activated and atypical stroma, which precedes development of mPIN lesions and prostate cancer with mixed features of adenocarcinoma and sarcoma in the prostates of TG mice. The results suggest that increased FGF-8 in human prostate may also contribute to prostate tumorigenesis by stromal activation.

  9. Modification and analysis of engineering hot spot factor of HFETR

    International Nuclear Information System (INIS)

    Hu Yuechun; Deng Caiyu; Li Haitao; Xu Taozhong; Mo Zhengyu

    2014-01-01

    This paper presents the modification and analysis of engineering hot spot factors of HFETR. The new factors are applied in the fuel temperature analysis and the estimated value of the safety allowable operating power of HFETR. The result shows the maximum cladding temperature of the fuel is lower when the new factor are in utilization, and the safety allowable operating power of HFETR if higher, thus providing the economical efficiency of HFETR. (authors)

  10. A replication of a factor analysis of motivations for trapping

    Science.gov (United States)

    Schroeder, Susan; Fulton, David C.

    2015-01-01

    Using a 2013 sample of Minnesota trappers, we employed confirmatory factor analysis to replicate an exploratory factor analysis of trapping motivations conducted by Daigle, Muth, Zwick, and Glass (1998).  We employed the same 25 items used by Daigle et al. and tested the same five-factor structure using a recent sample of Minnesota trappers. We also compared motivations in our sample to those reported by Daigle et el.

  11. Factor analysis improves the selection of prescribing indicators

    DEFF Research Database (Denmark)

    Rasmussen, Hanne Marie Skyggedal; Søndergaard, Jens; Sokolowski, Ineta

    2006-01-01

    OBJECTIVE: To test a method for improving the selection of indicators of general practitioners' prescribing. METHODS: We conducted a prescription database study including all 180 general practices in the County of Funen, Denmark, approximately 472,000 inhabitants. Principal factor analysis was us...... appropriate and inappropriate prescribing, as revealed by the correlation of the indicators in the first factor. CONCLUSION: Correlation and factor analysis is a feasible method that assists the selection of indicators and gives better insight into prescribing patterns....

  12. Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma—A Review

    Science.gov (United States)

    Siriwardena, Samadarani B. S. M.; Tsunematsu, Takaaki; Qi, Guangying; Ishimaru, Naozumi; Kudo, Yasusei

    2018-01-01

    It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC. PMID:29758011

  13. Target preparation and neutron activation analysis a successful story at IRMM

    CERN Document Server

    Robouch, P; Eguskiza, M; Maguregui, M I; Pommé, S; Ingelbrecht, C

    2002-01-01

    The main task of a target producer is to make well characterized and homogeneous deposits on specific supports. Alpha and/or gamma spectrometry are traditionally used to monitor the quality of actinide deposits. With the increasing demand for enriched stable isotope targets, other analytical techniques, such as ICP-MS and NAA, are needed. This paper presents the application of neutron activation analysis to quality control of 'thin' targets, 'thicker' neutron dosimeters and 'thick' bronze disks prepared by the Reference Materials Unit at the Institute of Reference Materials and Measurements.

  14. Target preparation and neutron activation analysis: a successful story at IRMM

    International Nuclear Information System (INIS)

    Robouch, P.; Arana, G.; Eguskiza, M.; Maguregui, M.I.; Pomme, S.; Ingelbrecht, C.

    2002-01-01

    The main task of a target producer is to make well characterized and homogeneous deposits on specific supports. Alpha and/or gamma spectrometry are traditionally used to monitor the quality of actinide deposits. With the increasing demand for enriched stable isotope targets, other analytical techniques, such as ICP-MS and NAA, are needed. This paper presents the application of neutron activation analysis to quality control of 'thin' targets, 'thicker' neutron dosimeters and 'thick' bronze disks prepared by the Reference Materials Unit at the Institute of Reference Materials and Measurements

  15. Human factor analysis and preventive countermeasures in nuclear power plant

    International Nuclear Information System (INIS)

    Li Ye

    2010-01-01

    Based on the human error analysis theory and the characteristics of maintenance in a nuclear power plant, human factors of maintenance in NPP are divided into three different areas: human, technology, and organization. Which is defined as individual factors, including psychological factors, physiological characteristics, health status, level of knowledge and interpersonal skills; The technical factors including technology, equipment, tools, working order, etc.; The organizational factors including management, information exchange, education, working environment, team building and leadership management,etc The analysis found that organizational factors can directly or indirectly affect the behavior of staff and technical factors, is the most basic human error factor. Based on this nuclear power plant to reduce human error and measures the response. (authors)

  16. Transcriptome-Wide Analysis of Botrytis elliptica Responsive microRNAs and Their Targets in Lilium Regale Wilson by High-Throughput Sequencing and Degradome Analysis

    Directory of Open Access Journals (Sweden)

    Xue Gao

    2017-05-01

    Full Text Available MicroRNAs, as master regulators of gene expression, have been widely identified and play crucial roles in plant-pathogen interactions. A fatal pathogen, Botrytis elliptica, causes the serious folia disease of lily, which reduces production because of the high susceptibility of most cultivated species. However, the miRNAs related to Botrytis infection of lily, and the miRNA-mediated gene regulatory networks providing resistance to B. elliptica in lily remain largely unexplored. To systematically dissect B. elliptica-responsive miRNAs and their target genes, three small RNA libraries were constructed from the leaves of Lilium regale, a promising Chinese wild Lilium species, which had been subjected to mock B. elliptica treatment or B. elliptica infection for 6 and 24 h. By high-throughput sequencing, 71 known miRNAs belonging to 47 conserved families and 24 novel miRNA were identified, of which 18 miRNAs were downreguleted and 13 were upregulated in response to B. elliptica. Moreover, based on the lily mRNA transcriptome, 22 targets for 9 known and 1 novel miRNAs were identified by the degradome sequencing approach. Most target genes for elliptica-responsive miRNAs were involved in metabolic processes, few encoding different transcription factors, including ELONGATION FACTOR 1 ALPHA (EF1a and TEOSINTE BRANCHED1/CYCLOIDEA/PROLIFERATING CELL FACTOR 2 (TCP2. Furthermore, the expression patterns of a set of elliptica-responsive miRNAs and their targets were validated by quantitative real-time PCR. This study represents the first transcriptome-based analysis of miRNAs responsive to B. elliptica and their targets in lily. The results reveal the possible regulatory roles of miRNAs and their targets in B. elliptica interaction, which will extend our understanding of the mechanisms of this disease in lily.

  17. Network based transcription factor analysis of regenerating axolotl limbs

    Directory of Open Access Journals (Sweden)

    Cameron Jo Ann

    2011-03-01

    Full Text Available Abstract Background Studies on amphibian limb regeneration began in the early 1700's but we still do not completely understand the cellular and molecular events of this unique process. Understanding a complex biological process such as limb regeneration is more complicated than the knowledge of the individual genes or proteins involved. Here we followed a systems biology approach in an effort to construct the networks and pathways of protein interactions involved in formation of the accumulation blastema in regenerating axolotl limbs. Results We used the human orthologs of proteins previously identified by our research team as bait to identify the transcription factor (TF pathways and networks that regulate blastema formation in amputated axolotl limbs. The five most connected factors, c-Myc, SP1, HNF4A, ESR1 and p53 regulate ~50% of the proteins in our data. Among these, c-Myc and SP1 regulate 36.2% of the proteins. c-Myc was the most highly connected TF (71 targets. Network analysis showed that TGF-β1 and fibronectin (FN lead to the activation of these TFs. We found that other TFs known to be involved in epigenetic reprogramming, such as Klf4, Oct4, and Lin28 are also connected to c-Myc and SP1. Conclusions Our study provides a systems biology approach to how different molecular entities inter-connect with each other during the formation of an accumulation blastema in regenerating axolotl limbs. This approach provides an in silico methodology to identify proteins that are not detected by experimental methods such as proteomics but are potentially important to blastema formation. We found that the TFs, c-Myc and SP1 and their target genes could potentially play a central role in limb regeneration. Systems biology has the potential to map out numerous other pathways that are crucial to blastema formation in regeneration-competent limbs, to compare these to the pathways that characterize regeneration-deficient limbs and finally, to identify stem

  18. Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Ludwig, Joseph A., E-mail: jaludwig@mdanderson.org; Lamhamedi-Cherradi, Salah-Eddine [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Lee, Ho-Young [Departments of Thoracic Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Naing, Aung [Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States); Benjamin, Robert [Departments of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030 (United States)

    2011-07-26

    The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

  19. Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

    International Nuclear Information System (INIS)

    Ludwig, Joseph A.; Lamhamedi-Cherradi, Salah-Eddine; Lee, Ho-Young; Naing, Aung; Benjamin, Robert

    2011-01-01

    The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R) function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R), in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas

  20. Dual Targeting of the Insulin-Like Growth Factor and Collateral Pathways in Cancer: Combating Drug Resistance

    Directory of Open Access Journals (Sweden)

    Aung Naing

    2011-07-01

    Full Text Available The insulin-like growth factor pathway, regulated by a complex interplay of growth factors, cognate receptors, and binding proteins, is critically important for many of the hallmarks of cancer such as oncogenesis, cell division, growth, and antineoplastic resistance. Naturally, a number of clinical trials have sought to directly abrogate insulin-like growth factor receptor 1 (IGF-1R function and/or indirectly mitigate its downstream mediators such as mTOR, PI3K, MAPK, and others under the assumption that such therapeutic interventions would provide clinical benefit, demonstrable by impaired tumor growth as well as prolonged progression-free and overall survival for patients. Though a small subset of patients enrolled within phase I or II clinical trials revealed dramatic clinical response to IGF-1R targeted therapies (most using monoclonal antibodies to IGF-1R, in toto, the anticancer effect has been underwhelming and unsustained, as even those with marked clinical responses seem to rapidly acquire resistance to IGF-1R targeted agents when used alone through yet to be identified mechanisms. As the IGF-1R receptor is just one of many that converge upon common intracellular signaling cascades, it is likely that effective IGF-1R targeting must occur in parallel with blockade of redundant signaling paths. Herein, we present the rationale for dual targeting of IGF-1R and other signaling molecules as an effective strategy to combat acquired drug resistance by carcinomas and sarcomas.

  1. Factors influencing crime rates: an econometric analysis approach

    Science.gov (United States)

    Bothos, John M. A.; Thomopoulos, Stelios C. A.

    2016-05-01

    The scope of the present study is to research the dynamics that determine the commission of crimes in the US society. Our study is part of a model we are developing to understand urban crime dynamics and to enhance citizens' "perception of security" in large urban environments. The main targets of our research are to highlight dependence of crime rates on certain social and economic factors and basic elements of state anticrime policies. In conducting our research, we use as guides previous relevant studies on crime dependence, that have been performed with similar quantitative analyses in mind, regarding the dependence of crime on certain social and economic factors using statistics and econometric modelling. Our first approach consists of conceptual state space dynamic cross-sectional econometric models that incorporate a feedback loop that describes crime as a feedback process. In order to define dynamically the model variables, we use statistical analysis on crime records and on records about social and economic conditions and policing characteristics (like police force and policing results - crime arrests), to determine their influence as independent variables on crime, as the dependent variable of our model. The econometric models we apply in this first approach are an exponential log linear model and a logit model. In a second approach, we try to study the evolvement of violent crime through time in the US, independently as an autonomous social phenomenon, using autoregressive and moving average time-series econometric models. Our findings show that there are certain social and economic characteristics that affect the formation of crime rates in the US, either positively or negatively. Furthermore, the results of our time-series econometric modelling show that violent crime, viewed solely and independently as a social phenomenon, correlates with previous years crime rates and depends on the social and economic environment's conditions during previous years.

  2. ANALYSIS OF RISK FACTORS ECTOPIC PREGNANCY

    Directory of Open Access Journals (Sweden)

    Budi Santoso

    2017-04-01

    Full Text Available Introduction: Ectopic pregnancy is a pregnancy with extrauterine implantation. This situation is gynecologic emergency that contributes to maternal mortality. Therefore, early recognition, based on identification of the causes of ectopic pregnancy risk factors, is needed. Methods: The design descriptive observational. The samples were pregnant women who had ectopic pregnancy at Maternity Room, Emergency Unit, Dr. Soetomo Hospital, Surabaya, from 1 July 2008 to 1 July 2010. Sampling technique was total sampling using medical records. Result: Patients with ectopic pregnancy were 99 individuals out of 2090 pregnant women who searched for treatment in Dr. Soetomo Hospital. However, only 29 patients were accompanied with traceable risk factors. Discussion:. Most ectopic pregnancies were in the age group of 26-30 years, comprising 32 patients (32.32%, then in age groups of 31–35 years as many as 25 patients (25.25%, 18 patients in age group 21–25 years (18.18%, 17 patients in age group 36–40 years (17.17%, 4 patients in age group 41 years and more (4.04%, and the least was in age group of 16–20 years with 3 patients (3.03%. A total of 12 patients with ectopic pregnancy (41.38% had experience of abortion and 6 patients (20.69% each in groups of patients with ectopic pregnancy who used family planning, in those who used family planning as well as ectopic pregnancy patients with history of surgery. There were 2 patients (6.90% of the group of patients ectopic pregnancy who had history of surgery and history of abortion. The incidence rate of ectopic pregnancy was 4.73%, mostly in the second gravidity (34.34%, whereas the nulliparous have the highest prevalence of 39.39%. Acquired risk factors, i.e. history of operations was 10.34%, patients with family planning 20.69%, patients with history of abortion 41.38%, patients with history of abortion and operation 6.90% patients with family and history of abortion was 20.69%.

  3. Workplace bullying as sensemaking: An analysis of target and actor perspectives on initial hostile interactions

    Czech Academy of Sciences Publication Activity Database

    Zábrodská, Kateřina; Ellwood, C.; Zaemdaar, S.; Mudrák, Jiří

    2016-01-01

    Roč. 22, č. 2 (2016), s. 136-157 ISSN 1475-9551 R&D Projects: GA ČR GPP407/10/P146; GA ČR GA14-02098S Institutional support: RVO:68081740 Keywords : workplace bullying * workplace hostility * sensemaking * target * actor * collective biography * stories Subject RIV: AN - Psychology Impact factor: 0.489, year: 2016

  4. Efficacy of targeted therapy for advanced renal cell carcinoma: A systematic review and meta-analysis of randomized controlled trials

    Directory of Open Access Journals (Sweden)

    Chao Wei

    Full Text Available ABSTRACT We conducted a systematic review and meta-analysis of the literature on the efficacy of the targeted therapies in the treatment of advanced RCC and, via an indirect comparison, to provide an optimal treatment among these agents. A systematic search of Medline, Scopus, Cochrane Library and Clinical Trials unpublished was performed up to Jan 1, 2015 to identify eligible randomized trials. Outcomes of interest assessing a targeted agent included progression free survival (PFS, overall survival (OS and objective response rate (ORR. Thirty eligible randomized controlled studies, total twentyfourth trails (5110 cases and 4626 controls were identified. Compared with placebo and IFN-α, single vascular epithelial growth factor (receptor tyrosine kinase inhibitor and mammalian target of rapamycin agent (VEGF(r-TKI & mTOR inhibitor were associated with improved PFS, improved OS and higher ORR, respectively. Comparing sorafenib combination vs sorafenib, there was no significant difference with regard to PFS and OS, but with a higher ORR. Comparing single or combination VEGF(r-TKI & mTOR inhibitor vs BEV + IFN-α, there was no significant difference with regard to PFS, OS, or ORR. Our network ITC meta-analysis also indicated a superior PFS of axitinib and everolimus compared to sorafenib. Our data suggest that targeted therapy with VEGF(r-TKI & mTOR inhibitor is associated with superior efficacy for treating advanced RCC with improved PFS, OS and higher ORR compared to placebo and IFN-α. In summary, here we give a comprehensive overview of current targeted therapies of advanced RCC that may provide evidence for the adequate targeted therapy selecting.

  5. Partial Safety Factors and Target Reliability Level in Danish Structural Codes

    DEFF Research Database (Denmark)

    Sørensen, John Dalsgaard; Hansen, J. O.; Nielsen, T. A.

    2001-01-01

    The partial safety factors in the newly revised Danish structural codes have been derived using a reliability-based calibration. The calibrated partial safety factors result in the same average reliability level as in the previous codes, but a much more uniform reliability level has been obtained....... The paper describes the code format, the stochastic models and the resulting optimised partial safety factors....

  6. Malware Analysis: From Large-Scale Data Triage to Targeted Attack Recognition (Dagstuhl Seminar 17281)

    OpenAIRE

    Zennou, Sarah; Debray, Saumya K.; Dullien, Thomas; Lakhothia, Arun

    2018-01-01

    This report summarizes the program and the outcomes of the Dagstuhl Seminar 17281, entitled "Malware Analysis: From Large-Scale Data Triage to Targeted Attack Recognition". The seminar brought together practitioners and researchers from industry and academia to discuss the state-of-the art in the analysis of malware from both a big data perspective and a fine grained analysis. Obfuscation was also considered. The meeting created new links within this very diverse community.

  7. Meta-Analysis of PECS with Individuals with ASD: Investigation of Targeted versus Non-Targeted Outcomes, Participant Characteristics, and Implementation Phase

    Science.gov (United States)

    Ganz, Jennifer B.; Davis, John L.; Lund, Emily M.; Goodwyn, Fara D.; Simpson, Richard L.

    2012-01-01

    The Picture Exchange Communication System (PECS) is a widely used picture/icon aided augmentative communication system designed for learners with autism and other developmental disorders. This meta-analysis analyzes the extant empirical literature for PECS relative to targeted (functional communication) and non-targeted concomitant outcomes…

  8. Investigating product development strategy in beverage industry using factor analysis

    Directory of Open Access Journals (Sweden)

    Naser Azad

    2013-03-01

    Full Text Available Selecting a product development strategy that is associated with the company's current service or product innovation, based on customers’ needs and changing environment, plays an important role in increasing demand, increasing market share, increasing sales and profits. Therefore, it is important to extract effective variables associated with product development to improve performance measurement of firms. This paper investigates important factors influencing product development strategies using factor analysis. The proposed model of this paper investigates 36 factors and, using factor analysis, we extract six most influential factors including information sharing, intelligence information, exposure strategy, differentiation, research and development strategy and market survey. The first strategy, partnership, includes five sub-factor including product development partnership, partnership with foreign firms, customers’ perception from competitors’ products, Customer involvement in product development, inter-agency coordination, customer-oriented approach to innovation and transmission of product development change where inter-agency coordination has been considered the most important factor. Internal strengths are the most influential factors impacting the second strategy, intelligence information. The third factor, introducing strategy, introducing strategy, includes four sub criteria and consumer buying behavior is the most influencing factor. Differentiation is the next important factor with five components where knowledge and expertise in product innovation is the most important one. Research and development strategy with four sub-criteria where reducing product development cycle plays the most influential factor and finally, market survey strategy is the last important factor with three factors and finding new market plays the most important role.

  9. Housing price forecastability: A factor analysis

    DEFF Research Database (Denmark)

    Møller, Stig Vinther; Bork, Lasse

    2017-01-01

    We examine U.S. housing price forecastability using principal component analysis (PCA), partial least squares (PLS), and sparse PLS (SPLS). We incorporate information from a large panel of 128 economic time series and show that macroeconomic fundamentals have strong predictive power for future...... movements in housing prices. We find that (S)PLS models systematically dominate PCA models. (S)PLS models also generate significant out-of-sample predictive power over and above the predictive power contained by the price-rent ratio, autoregressive benchmarks, and regression models based on small datasets....

  10. Statistical analysis of target motion in gated lung stereotactic body radiation therapy

    International Nuclear Information System (INIS)

    Zhao Bo; Yang Yong; Li Tianfang; Li Xiang; Heron, Dwight E; Huq, M Saiful

    2011-01-01

    An external surrogate-based respiratory gating technique is a useful method to reduce target margins for the treatment of a moving lung tumor. The success of this technique relies on a good correlation between the motion of the external markers and the internal tumor as well as the repeatability of the respiratory motion. In gated lung stereotactic body radiation therapy (SBRT), the treatment time for each fraction could exceed 30 min due to large fractional dose. Tumor motion may experience pattern changes such as baseline shift during such extended treatment time. The purpose of this study is to analyze tumor motion traces in actual treatment situations and to evaluate the effect of the target baseline shift in gated lung SBRT treatment. Real-time motion data for both the external markers and tumors from 51 lung SBRT treatments with Cyberknife Synchrony technology were analyzed in this study. The treatment time is typically greater than 30 min. The baseline shift was calculated with a rolling average window equivalent to ∼20 s and subtracted from that at the beginning. The magnitude of the baseline shift and its relationship with treatment time were investigated. Phase gating simulation was retrospectively performed on 12 carefully selected treatments with respiratory amplitude larger than 5 mm and regular phases. A customized gating window was defined for each individual treatment. It was found that the baseline shifts are specific to each patient and each fraction. Statistical analysis revealed that more than 69% treatments exhibited increased baseline shifts with the lapse of treatment time. The magnitude of the baseline shift could reach 5.3 mm during a 30 min treatment. Gating simulation showed that tumor excursion was caused mainly by the uncertainties in phase gating simulation and baseline shift, the latter being the primary factor. With a 5 mm gating window, 2 out of 12 treatments in the study group showed significant tumor excursion. Baseline shifts

  11. Genome-Wide Analysis of miRNA targets in Brachypodium and Biomass Energy Crops

    Energy Technology Data Exchange (ETDEWEB)

    Green, Pamela J. [Univ. of Delaware, Newark, DE (United States)

    2015-08-11

    MicroRNAs (miRNAs) contribute to the control of numerous biological processes through the regulation of specific target mRNAs. Although the identities of these targets are essential to elucidate miRNA function, the targets are much more difficult to identify than the small RNAs themselves. Before this work, we pioneered the genome-wide identification of the targets of Arabidopsis miRNAs using an approach called PARE (German et al., Nature Biotech. 2008; Nature Protocols, 2009). Under this project, we applied PARE to Brachypodium distachyon (Brachypodium), a model plant in the Poaceae family, which includes the major food grain and bioenergy crops. Through in-depth global analysis and examination of specific examples, this research greatly expanded our knowledge of miRNAs and target RNAs of Brachypodium. New regulation in response to environmental stress or tissue type was found, and many new miRNAs were discovered. More than 260 targets of new and known miRNAs with PARE sequences at the precise sites of miRNA-guided cleavage were identified and characterized. Combining PARE data with the small RNA data also identified the miRNAs responsible for initiating approximately 500 phased loci, including one of the novel miRNAs. PARE analysis also revealed that differentially expressed miRNAs in the same family guide specific target RNA cleavage in a correspondingly tissue-preferential manner. The project included generation of small RNA and PARE resources for bioenergy crops, to facilitate ongoing discovery of conserved miRNA-target RNA regulation. By associating specific miRNA-target RNA pairs with known physiological functions, the research provides insights about gene regulation in different tissues and in response to environmental stress. This, and release of new PARE and small RNA data sets should contribute basic knowledge to enhance breeding and may suggest new strategies for improvement of biomass energy crops.

  12. Numerical analysis of free surface instabilities in the IFMIF lithium target

    International Nuclear Information System (INIS)

    Gordeev, S.; Heinzel, V.; Moeslang, A.

    2007-01-01

    The International Fusion Materials Facility (IFMIF) facility uses a high speed (10-20 m/s) Lithium (Li) jet flow as a target for two 40 MeV/125 mA deuteron beams. The major function of the Li target is to provide a stable Li jet for the production of an intense neutron flux. For the understanding the lithium jet behaviour and elimination of the free-surface flow instabilities a detailed analysis of the Li jet flow is necessary. Different kinds of instability mechanisms in the liquid jet flow have been evaluated and classified based on analytical and experimental data. Numerical investigations of the target free surface flow have been performed. Previous numerical investigations have shown in principle the suitability of CFD code Star- CD for the simulation of the Li-target flow. The main objective of this study is detailed numerical analysis of instabilities in the Li-jet flow caused by boundary layer relaxation near the nozzle exit, transition to the turbulence flow and back wall curvature. A number of CFD models are developed to investigate the formation of instabilities on the target surface. Turbulence models are validated on the experimental data. Experimental observations have shown that the change of the nozzle geometry at the outlet such as a slight divergence of the nozzle surfaces or nozzle edge defects causes the flow separation and occurrence of longitudinal periodic structures on the free surface with an amplitude up to 5 mm. Target surface fluctuations of this magnitude can lead to the penetration of the deuteron beam in the target structure and cause the local overheating of the back plat. Analysis of large instabilities in the Li-target flow combined with the heat distribution in lithium depending on the free surface shape is performed in this study. (orig.)

  13. 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

  14. Interactions between the R2R3-MYB transcription factor, AtMYB61, and target DNA binding sites.

    Directory of Open Access Journals (Sweden)

    Michael B Prouse

    Full Text Available Despite the prominent roles played by R2R3-MYB transcription factors in the regulation of plant gene expression, little is known about the details of how these proteins interact with their DNA targets. For example, while Arabidopsis thaliana R2R3-MYB protein AtMYB61 is known to alter transcript abundance of a specific set of target genes, little is known about the specific DNA sequences to which AtMYB61 binds. To address this gap in knowledge, DNA sequences bound by AtMYB61 were identified using cyclic amplification and selection of targets (CASTing. The DNA targets identified using this approach corresponded to AC elements, sequences enriched in adenosine and cytosine nucleotides. The preferred target sequence that bound with the greatest affinity to AtMYB61 recombinant protein was ACCTAC, the AC-I element. Mutational analyses based on the AC-I element showed that ACC nucleotides in the AC-I element served as the core recognition motif, critical for AtMYB61 binding. Molecular modelling predicted interactions between AtMYB61 amino acid residues and corresponding nucleotides in the DNA targets. The affinity between AtMYB61 and specific target DNA sequences did not correlate with AtMYB61-driven transcriptional activation with each of the target sequences. CASTing-selected motifs were found in the regulatory regions of genes previously shown to be regulated by AtMYB61. Taken together, these findings are consistent with the hypothesis that AtMYB61 regulates transcription from specific cis-acting AC elements in vivo. The results shed light on the specifics of DNA binding by an important family of plant-specific transcriptional regulators.

  15. Factoring handedness data: I. Item analysis.

    Science.gov (United States)

    Messinger, H B; Messinger, M I

    1995-12-01

    Recently in this journal Peters and Murphy challenged the validity of factor analyses done on bimodal handedness data, suggesting instead that right- and left-handers be studied separately. But bimodality may be avoidable if attention is paid to Oldfield's questionnaire format and instructions for the subjects. Two characteristics appear crucial: a two-column LEFT-RIGHT format for the body of the instrument and what we call Oldfield's Admonition: not to indicate strong preference for handedness item, such as write, unless "... the preference is so strong that you would never try to use the other hand unless absolutely forced to...". Attaining unimodality of an item distribution would seem to overcome the objections of Peters and Murphy. In a 1984 survey in Boston we used Oldfield's ten-item questionnaire exactly as published. This produced unimodal item distributions. With reflection of the five-point item scale and a logarithmic transformation, we achieved a degree of normalization for the items. Two surveys elsewhere based on Oldfield's 20-item list but with changes in the questionnaire format and the instructions, yielded markedly different item distributions with peaks at each extreme and sometimes in the middle as well.

  16. Targeting Tumor Necrosis Factor-α with Adalimumab: Effects on Endothelial Activation and Monocyte Adhesion.

    Directory of Open Access Journals (Sweden)

    Raghav Oberoi

    Full Text Available It is well known that atherosclerotic inflammatory vascular disease is critically driven by oxidized lipids and cytokines. In this regard, tumor necrosis factor (TNF-α is known as a crucial mediator of early pro-atherosclerotic events. Epidemiologic data suggest that blockade of TNF-α has beneficial effects on vascular outcomes in patients with rheumatoid arthritis, however, detailed mechanistic studies are still lacking. This study aims to elucidate effects of TNF-α blockade by adalimumab-which is approved for several inflammatory disorders-on endothelial activation and monocyte adhesion under pro-atherosclerotic conditions.Phorbol myristate acetate (PMA differentiated THP-1 macrophages were stimulated with oxidized low density lipoprotein and subsequent analysis of this conditioned media (oxLDL CM revealed a strong release of TNF-α. The TNF-α rich supernatant led to activation of human umbilical vein endothelial cells (HUVEC as shown by enhanced expression of major adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1, intercellular adhesion molecule-1 (ICAM-1 and E-selectin which was suppressed by the TNF-α inhibitor adalimumab. Accordingly, adalimumab effectively prevented THP-1 monocyte adhesion to endothelial cells under static as well as under flow conditions. Furthermore, adalimumab suppressed endothelial leakage as shown by Evan's blue diffusion across a confluent endothelial monolayer. Of note, after intraperitoneal injection we detected abundant deposition of fluorophore-labelled adalimumab in atherosclerotic plaques of hypercholesterolemic mice.Our results show that adalimumab prevents major inflammatory effects of TNF-α on endothelial activation, endothelial monocyte adhesion, endothelial leakage and therefore extends the therapeutic options of adalimumab to limit vascular inflammation.

  17. Inference of miRNA targets using evolutionary conservation and pathway analysis

    Directory of Open Access Journals (Sweden)

    van Nimwegen Erik

    2007-03-01

    assigns a posterior probability to each putative target site. The results presented here indicate that our general method achieves very good performance in predicting miRNA target sites, providing at the same time insights into the evolution of target sites for individual miRNAs. Moreover, by combining our predictions with pathway analysis, we propose functions of specific miRNAs in nervous system development, inter-cellular communication and cell growth. The complete target site predictions as well as the miRNA/pathway associations are accessible on the ElMMo web server.

  18. Thermal analysis of Ti drive-in target for D-D neutron generation

    International Nuclear Information System (INIS)

    Jung, N.S.; Kim, I.J.; Kim, S.J.; Choi, H.D.

    2008-01-01

    Full text: Thermal analysis was performed for a Ti drive-in target of a D-D neutron generator. Numerical calculation was the only feasible way to obtain the information of the target temperature, since it was very difficult to measure the target temperature during neutron generation due to high voltage being applied to the target. Computational fluid dynamics code CFX-5 was used in this study. In order to define the heat flux term for the thermal analysis, the current profile of the ion beam was measured. The one-dimensional, integrated current profile was measured by using a single slit and a Faraday cup. The measured current profile was transformed into the axially symmetric two-dimensional distribution function by using the Abel inversion, which had the two-dimensional Gaussian function shape. Temperature distribution in the target was calculated at the operating condition. The influence of operational parameters like the ion beam energy, current, coolant mass flow rate and coolant inlet temperature on the target temperature was investigated

  19. Nucleolar targeting of proteins by the tandem array of basic amino acid stretches identified in the RNA polymerase I-associated factor PAF49

    International Nuclear Information System (INIS)

    Ushijima, Ryujiro; Matsuyama, Toshifumi; Nagata, Izumi; Yamamoto, Kazuo

    2008-01-01

    There is accumulating evidence to indicate that the regulation of subnuclear compartmentalization plays important roles in cellular processes. The RNA polymerase I-associated factor PAF49 has been shown to accumulate in the nucleolus in growing cells, but disperse into the nucleoplasm in growth-arrested cells. Serial deletion analysis revealed that amino acids 199-338 were necessary for the nucleolar localization of PAF49. Combinatorial point mutation analysis indicated that the individual basic amino acid stretches (BS) within the central (BS1-4) and the C-terminal (BS5 and 6) regions may cooperatively confer the nucleolar localization of PAF49. Addition of the basic stretches in tandem to a heterologous protein, such as the interferon regulatory factor-3, translocated the tagged protein into the nucleolus, even in the presence of an intrinsic nuclear export sequence. Thus, tandem array of the basic amino acid stretches identified here functions as a dominant nucleolar targeting sequence

  20. Epidermal growth factor receptor targeting of replication competent adenovirus enhances cytotoxicity in bladder cancer

    NARCIS (Netherlands)

    van der Poel, HG; Molenaar, B; van Beusechem, VW; Haisma, HJ; Rodriguez, R; Curiel, DT; Gerritsen, WR

    Purpose: We evaluated the delivery and oncolytic potential of targeted replication competent adenoviruses in bladder cancer lines. Materials and Methods: Seven established human bladder cancer tumor lines (5637, SW800, TCCsup, J82, Scaber, T24 and 253J) were studied for the expression of integrins

  1. Using exploratory factor analysis in personality research: Best-practice recommendations

    Directory of Open Access Journals (Sweden)

    Sumaya Laher

    2010-11-01

    Research purpose: This article presents more objective methods to determine the number of factors, most notably parallel analysis and Velicer’s minimum average partial (MAP. The benefits of rotation are also discussed. The article argues for more consistent use of Procrustes rotation and congruence coefficients in factor analytic studies. Motivation for the study: Exploratory factor analysis is often criticised for not being rigorous and objective enough in terms of the methods used to determine the number of factors, the rotations to be used and ultimately the validity of the factor structure. Research design, approach and method: The article adopts a theoretical stance to discuss the best-practice recommendations for factor analytic research in the field of psychology. Following this, an example located within personality assessment and using the NEO-PI-R specifically is presented. A total of 425 students at the University of the Witwatersrand completed the NEO-PI-R. These responses were subjected to a principal components analysis using varimax rotation. The rotated solution was subjected to a Procrustes rotation with Costa and McCrae’s (1992 matrix as the target matrix. Congruence coefficients were also computed. Main findings: The example indicates the use of the methods recommended in the article and demonstrates an objective way of determining the number of factors. It also provides an example of Procrustes rotation with coefficients of agreement as an indication of how factor analytic results may be presented more rigorously in local research. Practical/managerial implications: It is hoped that the recommendations in this article will have best-practice implications for both researchers and practitioners in the field who employ factor analysis regularly. Contribution/value-add: This article will prove useful to all researchers employing factor analysis and has the potential to set the trend for better use of factor analysis in the South African context.

  2. Numerical analysis of the feasibility of a beam window for TEF target

    International Nuclear Information System (INIS)

    Obayashi, H.; Takei, H.; Iwamoto, H.; Sasa, T.

    2015-01-01

    In the various research activities for ADS (accelerator-driven systems), the construction of the Transmutation Experimental Facility (TEF) is planned within the framework of the J-PARC project as a preceding step before the construction of a pilot ADS. The ADS proposed by JAEA is a tank-type subcritical reactor with a thermal power of 800 MWth which uses lead-bismuth eutectic (LBE) alloy as a target material and a coolant, driven by a 30 MW superconducting proton linac. The beam window of ADS, which separates the proton accelerator and the LBE subcritical core vessel, is exposed to the high-temperature environment induced by the incidence of proton beam. Therefore, the feasibility of the beam window is the most important factor for the realisation of TEF. The objective of this study is to evaluate the feasibility of a designed beam window of TEF target by the numerical analysis with a three-dimensional model. The analysis was performed by considering: (1) the current density and shape of the incident beam, (2) the thermal-fluid behaviour of LBE around the beam window as a function of the flow rate and inlet temperature, (3) the material and the thickness of the beam window, (4) the structural strength of the beam window. In the reference case, the current density and the profile of the proton beam were 20 μA/cm 2 and a Gaussian shape, respectively. The flow rate of LBE and temperature at the inlet were 1 l/s and 350 C. degrees. The material of a beam window was SUS316 stainless steel 2 mm thick. In this reference case, the maximum velocity of LBE and the maximum temperature located at the top of the beam window were about 1.2 m/sec and 477 C. degrees. By increasing the flow rate of LBE up to 4 l/s, the maximum temperature of a beam window was reduced to around 420 C. degrees. The maximum shear stress was 194 MPa, which was observed at the centre on the outside surface of the beam window. The analysed stress in the reference case was lower than the tolerance level

  3. Effective treatment of chemoresistant breast cancer in vitro and in vivo by a factor VII-targeted photodynamic therapy.

    Science.gov (United States)

    Duanmu, J; Cheng, J; Xu, J; Booth, C J; Hu, Z

    2011-04-26

    The purpose of this study was to test a novel, dual tumour vascular endothelial cell (VEC)- and tumour cell-targeting factor VII-targeted Sn(IV) chlorin e6 photodynamic therapy (fVII-tPDT) by targeting a receptor tissue factor (TF) as an alternative treatment for chemoresistant breast cancer using a multidrug resistant (MDR) breast cancer line MCF-7/MDR. The TF expression by the MCF-7/MDR breast cancer cells and tumour VECs in MCF-7/MDR tumours from mice was determined separately by flow cytometry and immunohistochemistry using anti-human or anti-murine TF antibodies. The efficacy of fVII-tPDT was tested in vitro and in vivo and was compared with non-targeted PDT for treatment of chemoresistant breast cancer. The in vitro efficacy was determined by a non-clonogenic assay using crystal violet staining for monolayers, and apoptosis and necrosis were assayed to elucidate the underlying mechanisms. The in vivo efficacy of fVII-tPDT was determined in a nude mouse model of subcutaneous MCF-7/MDR tumour xenograft by measuring tumour volume. To our knowledge, this is the first presentation showing that TF was expressed on tumour VECs in chemoresistant breast tumours from mice. The in vitro efficacy of fVII-tPDT was 12-fold stronger than that of ntPDT for MCF-7/MDR cancer cells, and the mechanism of action involved induction of apoptosis and necrosis. Moreover, fVII-tPDT was effective and safe for the treatment of chemoresistant breast tumours in the nude mouse model. We conclude that fVII-tPDT is effective and safe for the treatment of chemoresistant breast cancer, presumably by simultaneously targeting both the tumour neovasculature and chemoresistant cancer cells. Thus, this dual-targeting fVII-tPDT could also have therapeutic potential for the treatment of other chemoresistant cancers.

  4. Modified unscented Kalman filter using modified filter gain and variance scale factor for highly maneuvering target tracking

    Institute of Scientific and Technical Information of China (English)

    Changyun Liu; Penglang Shui; Gang Wei; Song Li

    2014-01-01

    To improve the low tracking precision caused by lagged filter gain or imprecise state noise when the target highly maneu-vers, a modified unscented Kalman filter algorithm based on the improved filter gain and adaptive scale factor of state noise is pre-sented. In every filter process, the estimated scale factor is used to update the state noise covariance Qk, and the improved filter gain is obtained in the filter process of unscented Kalman filter (UKF) via predicted variance Pk|k-1, which is similar to the standard Kalman filter. Simulation results show that the proposed algorithm provides better accuracy and ability to adapt to the highly maneu-vering target compared with the standard UKF.

  5. Analysis and modeling of localized heat generation by tumor-targeted nanoparticles (Monte Carlo methods)

    Science.gov (United States)

    Sanattalab, Ehsan; SalmanOgli, Ahmad; Piskin, Erhan

    2016-04-01

    We investigated the tumor-targeted nanoparticles that influence heat generation. We suppose that all nanoparticles are fully functionalized and can find the target using active targeting methods. Unlike the commonly used methods, such as chemotherapy and radiotherapy, the treatment procedure proposed in this study is purely noninvasive, which is considered to be a significant merit. It is found that the localized heat generation due to targeted nanoparticles is significantly higher than other areas. By engineering the optical properties of nanoparticles, including scattering, absorption coefficients, and asymmetry factor (cosine scattering angle), the heat generated in the tumor's area reaches to such critical state that can burn the targeted tumor. The amount of heat generated by inserting smart agents, due to the surface Plasmon resonance, will be remarkably high. The light-matter interactions and trajectory of incident photon upon targeted tissues are simulated by MIE theory and Monte Carlo method, respectively. Monte Carlo method is a statistical one by which we can accurately probe the photon trajectories into a simulation area.

  6. TRAC analysis of design basis events for the accelerator production of tritium target/blanket

    International Nuclear Information System (INIS)

    Lin, J.C.; Elson, J.

    1997-01-01

    A two-loop primary cooling system with a residual heat removal system was designed to mitigate the heat generated in the tungsten neutron source rods inside the rungs of the ladders and the shell of the rungs. The Transient Reactor Analysis Code (TRAC) was used to analyze the thermal-hydraulic behavior of the primary cooling system during a pump coastdown transient; a cold-leg, large-break loss-of-coolant accident (LBLOCA); a hot-leg LBLOCA; and a target downcomer LBLOCA. The TRAC analysis results showed that the heat generated in the tungsten neutron source rods can be mitigated by the primary cooling system for the pump coastdown transient and all the LBLOCAs except the target downcomer LBLOCA. For the target downcomer LBLOCA, a cavity flood system is required to fill the cavity with water at a level above the large fixed headers

  7. Exploring Technostress: Results of a Large Sample Factor Analysis

    Directory of Open Access Journals (Sweden)

    Steponas Jonušauskas

    2016-06-01

    Full Text Available With reference to the results of a large sample factor analysis, the article aims to propose the frame examining technostress in a population. The survey and principal component analysis of the sample consisting of 1013 individuals who use ICT in their everyday work was implemented in the research. 13 factors combine 68 questions and explain 59.13 per cent of the answers dispersion. Based on the factor analysis, questionnaire was reframed and prepared to reasonably analyze the respondents’ answers, revealing technostress causes and consequences as well as technostress prevalence in the population in a statistically validated pattern. A key elements of technostress based on factor analysis can serve for the construction of technostress measurement scales in further research.

  8. Economic Analysis of Factors Affecting Technical Efficiency of ...

    African Journals Online (AJOL)

    Economic Analysis of Factors Affecting Technical Efficiency of Smallholders ... socio-economic characteristics which influence technical efficiency in maize production. ... Ministry of Agriculture and livestock, records, books, reports and internet.

  9. Text mining factor analysis (TFA) in green tea patent data

    Science.gov (United States)

    Rahmawati, Sela; Suprijadi, Jadi; Zulhanif

    2017-03-01

    Factor analysis has become one of the most widely used multivariate statistical procedures in applied research endeavors across a multitude of domains. There are two main types of analyses based on factor analysis: Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA). Both EFA and CFA aim to observed relationships among a group of indicators with a latent variable, but they differ fundamentally, a priori and restrictions made to the factor model. This method will be applied to patent data technology sector green tea to determine the development technology of green tea in the world. Patent analysis is useful in identifying the future technological trends in a specific field of technology. Database patent are obtained from agency European Patent Organization (EPO). In this paper, CFA model will be applied to the nominal data, which obtain from the presence absence matrix. While doing processing, analysis CFA for nominal data analysis was based on Tetrachoric matrix. Meanwhile, EFA model will be applied on a title from sector technology dominant. Title will be pre-processing first using text mining analysis.

  10. Examination of thromboxane synthase as a prognostic factor and therapeutic target in non-small cell lung cancer

    LENUS (Irish Health Repository)

    Cathcart, Mary-Clare

    2011-03-09

    Abstract Background Thromboxane synthase (TXS) metabolises prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with a poor prognosis. TXS inhibition induces cell death in-vitro, providing a rationale for therapeutic intervention. We aimed to determine the expression profile of TXS in NSCLC and if it is prognostic and\\/or a survival factor in the disease. Methods TXS expression was examined in human NSCLC and matched controls by western analysis and IHC. TXS metabolite (TXB2) levels were measured by EIA. A 204-patient NSCLC TMA was stained for COX-2 and downstream TXS expression. TXS tissue expression was correlated with clinical parameters, including overall survival. Cell proliferation\\/survival and invasion was examined in NSCLC cells following both selective TXS inhibition and stable TXS over-expression. Results TXS was over-expressed in human NSCLC samples, relative to matched normal controls. TXS and TXB2 levels were increased in protein (p < 0.05) and plasma (p < 0.01) NSCLC samples respectively. TXS tissue expression was higher in adenocarcinoma (p < 0.001) and female patients (p < 0.05). No significant correlation with patient survival was observed. Selective TXS inhibition significantly reduced tumour cell growth and increased apoptosis, while TXS over-expression stimulated cell proliferation and invasiveness, and was protective against apoptosis. Conclusion TXS is over-expressed in NSCLC, particularly in the adenocarcinoma subtype. Inhibition of this enzyme inhibits proliferation and induces apoptosis. Targeting thromboxane synthase alone, or in combination with conventional chemotherapy is a potential therapeutic strategy for NSCLC.

  11. QTL replication and targeted association highlight the nerve growth factor gene for nonverbal communication deficits in autism spectrum disorders.

    Science.gov (United States)

    Lu, A T-H; Yoon, J; Geschwind, D H; Cantor, R M

    2013-02-01

    Autism Spectrum Disorder (ASD) has a heterogeneous etiology that is genetically complex. It is defined by deficits in communication and social skills and the presence of restricted and repetitive behaviors. Genetic analyses of heritable quantitative traits that correlate with ASD may reduce heterogeneity. With this in mind, deficits in nonverbal communication (NVC) were quantified based on items from the Autism Diagnostic Interview Revised. Our previous analysis of 228 families from the Autism Genetics Research Exchange (AGRE) repository reported 5 potential quantitative trait loci (QTL). Here we report an NVC QTL replication study in an independent sample of 213 AGRE families. One QTL was replicated (Panalysis of 476 haplotype blocks with 708 AGRE families using the Family Based Association Test (FBAT). Blocks in two QTL genes were associated with NVC with a P-value of 0.001. Three associated haplotype blocks were intronic to the Nerve Growth Factor (NGF) gene (P=0.001, 0.001, 0.002), and one was intronic to KCND3 (P=0.001). Individual haplotypes within the associated blocks drove the associations (0.003, 0.0004 and 0.0002) for NGF and 0.0001 for KCND3. Using the same methods, these genes were tested for association with NVC in an independent sample of 1517 families from an Autism Genome Project (AGP). NVC was associated with a haplotype in an adjacent NGF block (P=0.0005) and one 46 kb away from the associated block in KCND3 (0.008). These analyses illustrate the value of QTL and targeted association studies for genetically complex disorders such as ASD. NGF is a promising risk gene for NVC deficits.

  12. School programs targeting stress management in children and adolescence: a meta-analysis

    NARCIS (Netherlands)

    Kraag, G.C; Zeegers, M.P.; Kok, G.J.; Hosman, C.M.H.; Huijer Abu-Saad, H.

    2006-01-01

    Introduction This meta-analysis evaluates the effect of school programs targeting stress management or coping skills in school children. Methods Articles were selected through a systematic literature search. Only randomized controlled trials or quasi-experimental studies were included. The

  13. Simulating Serial-Target Antibacterial Drug Synergies Using Flux Balance Analysis

    DEFF Research Database (Denmark)

    Krueger, Andrew S.; Munck, Christian; Dantas, Gautam

    2016-01-01

    Flux balance analysis (FBA) is an increasingly useful approach for modeling the behavior of metabolic systems. However, standard FBA modeling of genetic knockouts cannot predict drug combination synergies observed between serial metabolic targets, even though such synergies give rise to some of t...

  14. Analysis of shots on target and goals scored in soccer matches ...

    African Journals Online (AJOL)

    The aim of this study was to analyse the characteristics and patterns of shots on target and goals scored during the 2012-European Championship. The broadcasted matches were recorded and converted into electronic video files for a computerbased analysis. This quantitative study examined 31 matches of the ...

  15. Doing Televised Rhetorical Analysis as a Means of Promoting College Awareness in a Target Market.

    Science.gov (United States)

    Schnell, Jim

    This paper describes aspects of doing televised rhetorical analysis as they relate to the promotion of college awareness in a particular target market. Considerations in the paper include variables that most professors encounter in their efforts to address the "service" expectations of their employment and how these variables can be…

  16. Targeting tissue factor on tumour cells and angiogenic vascular endothelial cells by factor VII-targeted verteporfin photodynamic therapy for breast cancer in vitro and in vivo in mice

    International Nuclear Information System (INIS)

    Hu, Zhiwei; Rao, Benqiang; Chen, Shimin; Duanmu, Jinzhong

    2010-01-01

    The objective of this study was to develop a ligand-targeted photodynamic therapy (tPDT) by conjugating factor VII (fVII) protein with photosensitiser verteporfin in order to overcome the poor selectivity and enhance the effect of non-targeted PDT (ntPDT) for cancer. fVII is a natural ligand for receptor tissue factor (TF) with high affinity and specificity. The reason for targeting receptor TF for the development of tPDT is that TF is a common but specific target on angiogenic tumour vascular endothelial cells (VEC) and many types of tumour cells, including solid tumours and leukaemia. Murine factor VII protein (mfVII) containing a mutation (Lys341Ala) was covalently conjugated via a cross linker EDC with Veterporfin (VP) that was extracted from liposomal Visudyne, and then free VP was separated by Sephadex G50 spin columns. fVII-tPDT using mfVII-VP conjugate, compared to ntPDT, was tested in vitro for the killing of breast cancer cells and VEGF-stimulated VEC and in vivo for inhibiting the tumour growth of breast tumours in a mouse xenograft model. We showed that: (i) fVII protein could be conjugated with VP without affecting its binding activity; (ii) fVII-tPDT could selectively kill TF-expressing breast cancer cells and VEGF-stimulated angiogenic HUVECs but had no side effects on non-TF expressing unstimulated HUVEC, CHO-K1 and 293 cells; (iii) fVII targeting enhanced the effect of VP PDT by three to four fold; (iii) fVII-tPDT induced significantly stronger levels of apoptosis and necrosis than ntPDT; and (iv) fVII-tPDT had a significantly stronger effect on inhibiting breast tumour growth in mice than ntPDT. We conclude that the fVII-targeted VP PDT that we report here is a novel and effective therapeutic with improved selectivity for the treatment of breast cancer. Since TF is expressed on many types of cancer cells including leukaemic cells and selectively on angiogenic tumour VECs, fVII-tPDT could have broad therapeutic applications for other solid cancers

  17. Sustainable Manufacturing Practices in Malaysian Automotive Industry: Confirmatory Factor Analysis

    OpenAIRE

    Habidin, Nurul Fadly; Zubir, Anis Fadzlin Mohd; Fuz, Nursyazwani Mohd; Latip, Nor Azrin Md; Azman, Mohamed Nor Azhari

    2015-01-01

    Sustainable manufacturing practices (SMPs) have received enormous attention in current years as an effective solution to support the continuous growth and expansion of the automotive manufacturing industry. This reported study was conducted to examine confirmatory factor analysis for SMP such as manufacturing process, supply chain management, social responsibility, and environmental management based on automotive manufacturing industry. The results of confirmatory factor analysis show that fo...

  18. An Analysis of Construction Accident Factors Based on Bayesian Network

    OpenAIRE

    Yunsheng Zhao; Jinyong Pei

    2013-01-01

    In this study, we have an analysis of construction accident factors based on bayesian network. Firstly, accidents cases are analyzed to build Fault Tree method, which is available to find all the factors causing the accidents, then qualitatively and quantitatively analyzes the factors with Bayesian network method, finally determines the safety management program to guide the safety operations. The results of this study show that bad condition of geological environment has the largest posterio...

  19. The Recoverability of P-Technique Factor Analysis

    Science.gov (United States)

    Molenaar, Peter C. M.; Nesselroade, John R.

    2009-01-01

    It seems that just when we are about to lay P-technique factor analysis finally to rest as obsolete because of newer, more sophisticated multivariate time-series models using latent variables--dynamic factor models--it rears its head to inform us that an obituary may be premature. We present the results of some simulations demonstrating that even…

  20. Likelihood-based Dynamic Factor Analysis for Measurement and Forecasting

    NARCIS (Netherlands)

    Jungbacker, B.M.J.P.; Koopman, S.J.

    2015-01-01

    We present new results for the likelihood-based analysis of the dynamic factor model. The latent factors are modelled by linear dynamic stochastic processes. The idiosyncratic disturbance series are specified as autoregressive processes with mutually correlated innovations. The new results lead to

  1. Endothelium-derived vasoactive factors and hypertension: possible roles in pathogenesis and as treatment targets

    DEFF Research Database (Denmark)

    Félétou, Michel; Köhler, Ralf; Vanhoutte, Paul M

    2010-01-01

    Endothelial cells regulate vascular tone by releasing various contracting and relaxing factors including nitric oxide (NO), arachidonic acid metabolites (derived from cyclooxygenases, lipoxygenases, and cytochrome P450 monooxygenases), reactive oxygen species, and vasoactive peptides. Additionally...

  2. Platelet-Derived Growth Factor (PDGF/PDGF Receptors (PDGFR Axis as Target for Antitumor and Antiangiogenic Therapy

    Directory of Open Access Journals (Sweden)

    Anca Maria Cimpean

    2010-03-01

    Full Text Available Angiogenesis in normal and pathological conditions is a multi-step process governed by positive and negative endogenous regulators. Many growth factors are involved in different steps of angiogenesis, like vascular endothelial growth factors (VEGF, fibroblast growth factor (FGF-2 or platelet-derived growth factors (PDGF. From these, VEGF and FGF-2 were extensively investigated and it was shown that they significantly contribute to the induction and progression of angiogenesis. A lot of evidence has been accumulated in last 10 years that supports the contribution of PDGF/PDGFR axis in developing angiogenesis in both normal and tumoral conditions. The crucial role of PDGF-B and PDGFR-β in angiogenesis has been demonstrated by gene targeting experiments, and their expression correlates with increased vascularity and maturation of the vascular wall. PDGF and their receptors were identified in a large variety of human tumor cells. In experimental models it was shown that inhibition of PDGF reduces interstitial fluid pressure in tumors and enhances the effect of chemotherapy. PDGFR have been involved in the cardiovascular development and their loss leads to a disruption in yolk sac blood vessels development. PDGFRβ expression by pericytes is necessary for their recruitment and integration in the wall of tumor vessels. Endothelial cells of tumor-associated blood vessels can express PDGFR. Based on these data, it was suggested the potential benefit of targeting PDGFR in the treatment of solid tumors. The molecular mechanisms of PDGF/PDGFR-mediated angiogenesis are not fully understood, but it was shown that tyrosine kinase inhibitors reduce tumor growth and angiogenesis in experimental xenograft models, and recent data demonstrated their efficacy in chemoresistant tumors. The in vivo effects of PDGFR inhibitors are more complex, based on the cross-talk with other angiogenic factors. In this review, we summarize data regarding the mechanisms and

  3. Analysis of Deregulated microRNAs and Their Target Genes in Gastric Cancer.

    Directory of Open Access Journals (Sweden)

    Simonas Juzėnas

    Full Text Available MicroRNAs (miRNAs are widely studied non-coding RNAs that modulate gene expression. MiRNAs are deregulated in different tumors including gastric cancer (GC and have potential diagnostic and prognostic implications. The aim of our study was to determine miRNA profile in GC tissues, followed by evaluation of deregulated miRNAs in plasma of GC patients. Using available databases and bioinformatics methods we also aimed to evaluate potential target genes of confirmed differentially expressed miRNA and validate these findings in GC tissues.The study included 51 GC patients and 51 controls. Initially, we screened miRNA expression profile in 13 tissue samples of GC and 12 normal gastric tissues with TaqMan low density array (TLDA. In the second stage, differentially expressed miRNAs were validated in a replication cohort using qRT-PCR in tissue and plasma samples. Subsequently, we analyzed potential target genes of deregulated miRNAs using bioinformatics approach, determined their expression in GC tissues and performed correlation analysis with targeting miRNAs.Profiling with TLDA revealed 15 deregulated miRNAs in GC tissues compared to normal gastric mucosa. Replication analysis confirmed that miR-148a-3p, miR-204-5p, miR-223-3p and miR-375 were consistently deregulated in GC tissues. Analysis of GC patients' plasma samples showed significant down-regulation of miR-148a-3p, miR-375 and up-regulation of miR-223-3p compared to healthy subjects. Further, using bioinformatic tools we identified targets of replicated miRNAs and performed disease-associated gene enrichment analysis. Ultimately, we evaluated potential target gene BCL2 and DNMT3B expression by qRT-PCR in GC tissue, which correlated with targeting miRNA expression.Our study revealed miRNA profile in GC tissues and showed that miR-148a-3p, miR-223-3p and miR-375 are deregulated in GC plasma samples, but these circulating miRNAs showed relatively weak diagnostic performance as sole biomarkers

  4. Improved target detection and bearing estimation utilizing fast orthogonal search for real-time spectral analysis

    International Nuclear Information System (INIS)

    Osman, Abdalla; El-Sheimy, Naser; Nourledin, Aboelamgd; Theriault, Jim; Campbell, Scott

    2009-01-01

    The problem of target detection and tracking in the ocean environment has attracted considerable attention due to its importance in military and civilian applications. Sonobuoys are one of the capable passive sonar systems used in underwater target detection. Target detection and bearing estimation are mainly obtained through spectral analysis of received signals. The frequency resolution introduced by current techniques is limited which affects the accuracy of target detection and bearing estimation at a relatively low signal-to-noise ratio (SNR). This research investigates the development of a bearing estimation method using fast orthogonal search (FOS) for enhanced spectral estimation. FOS is employed in this research in order to improve both target detection and bearing estimation in the case of low SNR inputs. The proposed methods were tested using simulated data developed for two different scenarios under different underwater environmental conditions. The results show that the proposed method is capable of enhancing the accuracy for target detection as well as bearing estimation especially in cases of a very low SNR

  5. Interacting with target tracking algorithms in a gaze-enhanced motion video analysis system

    Science.gov (United States)

    Hild, Jutta; Krüger, Wolfgang; Heinze, Norbert; Peinsipp-Byma, Elisabeth; Beyerer, Jürgen

    2016-05-01

    Motion video analysis is a challenging task, particularly if real-time analysis is required. It is therefore an important issue how to provide suitable assistance for the human operator. Given that the use of customized video analysis systems is more and more established, one supporting measure is to provide system functions which perform subtasks of the analysis. Recent progress in the development of automated image exploitation algorithms allow, e.g., real-time moving target tracking. Another supporting measure is to provide a user interface which strives to reduce the perceptual, cognitive and motor load of the human operator for example by incorporating the operator's visual focus of attention. A gaze-enhanced user interface is able to help here. This work extends prior work on automated target recognition, segmentation, and tracking algorithms as well as about the benefits of a gaze-enhanced user interface for interaction with moving targets. We also propose a prototypical system design aiming to combine both the qualities of the human observer's perception and the automated algorithms in order to improve the overall performance of a real-time video analysis system. In this contribution, we address two novel issues analyzing gaze-based interaction with target tracking algorithms. The first issue extends the gaze-based triggering of a target tracking process, e.g., investigating how to best relaunch in the case of track loss. The second issue addresses the initialization of tracking algorithms without motion segmentation where the operator has to provide the system with the object's image region in order to start the tracking algorithm.

  6. Tyrosine dephosphorylation enhances the therapeutic target activity of epidermal growth factor receptor (EGFR) by disrupting its interaction with estrogen receptor (ER).

    Science.gov (United States)

    Ma, Shao; Yin, Ning; Qi, Xiaomei; Pfister, Sandra L; Zhang, Mei-Jie; Ma, Rong; Chen, Guan

    2015-05-30

    Protein-protein interactions can increase or decrease its therapeutic target activity and the determining factors involved, however, are largely unknown. Here, we report that tyrosine-dephosphorylation of epidermal growth factor receptor (EGFR) increases its therapeutic target activity by disrupting its interaction with estrogen receptor (ER). Protein tyrosine phosphatase H1 (PTPH1) dephosphorylates the tyrosine kinase EGFR, disrupts its interaction with the nuclear receptor ER, and increases breast cancer sensitivity to small molecule tyrosine kinase inhibitors (TKIs). These effects require PTPH1 catalytic activity and its interaction with EGFR, suggesting that the phosphatase may increase the sensitivity by dephosphorylating EGFR leading to its dissociation with ER. Consistent with this notion, a nuclear-localization defective ER has a higher EGFR-binding activity and confers the resistance to TKI-induced growth inhibition. Additional analysis show that PTPH1 stabilizes EGFR, stimulates the membranous EGFR accumulation, and enhances the growth-inhibitory activity of a combination therapy of TKIs with an anti-estrogen. Since EGFR and ER both are substrates for PTPH1 in vitro and in intact cells, these results indicate that an inhibitory EGFR-ER protein complex can be switched off through a competitive enzyme-substrate binding. Our results would have important implications for the treatment of breast cancer with targeted therapeutics.

  7. Left ventricular wall motion abnormalities evaluated by factor analysis as compared with Fourier analysis

    International Nuclear Information System (INIS)

    Hirota, Kazuyoshi; Ikuno, Yoshiyasu; Nishikimi, Toshio

    1986-01-01

    Factor analysis was applied to multigated cardiac pool scintigraphy to evaluate its ability to detect left ventricular wall motion abnormalities in 35 patients with old myocardial infarction (MI), and in 12 control cases with normal left ventriculography. All cases were also evaluated by conventional Fourier analysis. In most cases with normal left ventriculography, the ventricular and atrial factors were extracted by factor analysis. In cases with MI, the third factor was obtained in the left ventricle corresponding to wall motion abnormality. Each case was scored according to the coincidence of findings of ventriculography and those of factor analysis or Fourier analysis. Scores were recorded for three items; the existence, location, and degree of asynergy. In cases of MI, the detection rate of asynergy was 94 % by factor analysis, 83 % by Fourier analysis, and the agreement in respect to location was 71 % and 66 %, respectively. Factor analysis had higher scores than Fourier analysis, but this was not significant. The interobserver error of factor analysis was less than that of Fourier analysis. Factor analysis can display locations and dynamic motion curves of asynergy, and it is regarded as a useful method for detecting and evaluating left ventricular wall motion abnormalities. (author)

  8. Efficacy of epidermal growth factor receptor targeting in advanced chordoma: case report and literature review

    Directory of Open Access Journals (Sweden)

    Guiramand Jérôme

    2011-10-01

    Full Text Available Abstract Background Chordomas are very rare low-grade malignant bone tumors that arise from the embryonic rests of the notochord. They are characterized by slow growth and long history with frequent local relapses, and sometimes metastases. While chemotherapy is not efficient, imatinib has shown antitumor activity. Case presentation We report on a 76-year-old patient with EGFR-overexpressing advanced chordoma that progressed on imatinib and subsequently responded to erlotinib during 12 months. Conclusions We report the fourth case of advanced chordoma treated with an EGFR inhibitor. We also review the literature concerning the rationale and potential of EGFR targeting in chordoma.

  9. Strategies for enhancing the implementation of school-based policies or practices targeting risk factors for chronic disease.

    Science.gov (United States)

    Wolfenden, Luke; Nathan, Nicole K; Sutherland, Rachel; Yoong, Sze Lin; Hodder, Rebecca K; Wyse, Rebecca J; Delaney, Tessa; Grady, Alice; Fielding, Alison; Tzelepis, Flora; Clinton-McHarg, Tara; Parmenter, Benjamin; Butler, Peter; Wiggers, John; Bauman, Adrian; Milat, Andrew; Booth, Debbie; Williams, Christopher M

    2017-11-29

    consulted with experts in the field to identify other relevant research. 'Implementation' was defined as the use of strategies to adopt and integrate evidence-based health interventions and to change practice patterns within specific settings. We included any trial (randomised or non-randomised) conducted at any scale, with a parallel control group that compared a strategy to implement policies or practices to address diet, physical activity, overweight or obesity, tobacco or alcohol use by school staff to 'no intervention', 'usual' practice or a different implementation strategy. Citation screening, data extraction and assessment of risk of bias was performed by review authors in pairs. Disagreements between review authors were resolved via consensus, or if required, by a third author. Considerable trial heterogeneity precluded meta-analysis. We narratively synthesised trial findings by describing the effect size of the primary outcome measure for policy or practice implementation (or the median of such measures where a single primary outcome was not stated). We included 27 trials, 18 of which were conducted in the USA. Nineteen studies employed randomised controlled trial (RCT) designs. Fifteen trials tested strategies to implement healthy eating policies, practice or programs; six trials tested strategies targeting physical activity policies or practices; and three trials targeted tobacco policies or practices. Three trials targeted a combination of risk factors. None of the included trials sought to increase the implementation of interventions to delay initiation or reduce the consumption of alcohol. All trials examined multi-strategic implementation strategies and no two trials examined the same combinations of implementation strategies. The most common implementation strategies included educational materials, educational outreach and educational meetings. For all outcomes, the overall quality of evidence was very low and the risk of bias was high for the majority of

  10. Virtual diplomacy: an analysis of the structure of the target audiences

    Directory of Open Access Journals (Sweden)

    V. V. Verbytska

    2016-03-01

    Full Text Available In the context of the global information society the communication processes, especially at the international level, become more important.  The effectiveness of communication depends primarily on its focus, i.e. on defining clearly the target audience which it should focus on. Virtual diplomacy, as a kind of political communication at the international level, is no exception.  The novelty, rapid development and dissemination of this phenomenon require profound analysis and elaboration of effective utilization strategies, including studying its recipients and target audiences. Purpose: identification, structuring and analysis of the recipients of virtual diplomacy as the audiences of international political communication. The study uses such research methods, as system analysis, structural functionalism, dialectics and synergy, comparison, critical analysis. Main results of the research: 1. The study examined the specifics of political communication in the context of the development of the global information society at the international level. 2. It also analyzed the recipients of virtual diplomacy as a kind of political communication at the international level. 3. The study highlighted the key target groups in the global Internet network based on the tasks performed by virtual diplomacy. 4. It proved the effectiveness of cooperation with each target group in the framework of virtual diplomacy. 5. It described the specifics of the work with each target group in the context of virtual diplomacy. Practical implications: The article may be useful for writing scientific theoretical studies, tests, essays and term papers, for designing special courses in universities in the sphere of international relations and international information. It can also be a guide for the authorities carrying out diplomatic activities and international information cooperation. Findings: In the context of the establishment of the global information society political

  11. System for automatic x-ray-image analysis, measurement, and sorting of laser fusion targets

    International Nuclear Information System (INIS)

    Singleton, R.M.; Perkins, D.E.; Willenborg, D.L.

    1980-01-01

    This paper describes the Automatic X-Ray Image Analysis and Sorting (AXIAS) system which is designed to analyze and measure x-ray images of opaque hollow microspheres used as laser fusion targets. The x-ray images are first recorded on a high resolution film plate. The AXIAS system then digitizes and processes the images to accurately measure the target parameters and defects. The primary goals of the AXIAS system are: to provide extremely accurate and rapid measurements, to engineer a practical system for a routine production environment and to furnish the capability of automatically measuring an array of images for sorting and selection

  12. Confirmatory factor analysis reveals a latent cognitive structure common to bipolar disorder, schizophrenia, and normal controls.

    Science.gov (United States)

    Schretlen, David J; Peña, Javier; Aretouli, Eleni; Orue, Izaskun; Cascella, Nicola G; Pearlson, Godfrey D; Ojeda, Natalia

    2013-06-01

    We sought to determine whether a single hypothesized latent factor structure would characterize cognitive functioning in three distinct groups. We assessed 576 adults (340 community controls, 126 adults with bipolar disorder, and 110 adults with schizophrenia) using 15 measures derived from nine cognitive tests. Confirmatory factor analysis (CFA) was conducted to examine the fit of a hypothesized six-factor model. The hypothesized factors included attention, psychomotor speed, verbal memory, visual memory, ideational fluency, and executive functioning. The six-factor model provided an excellent fit for all three groups [for community controls, root mean square error of approximation (RMSEA) schizophrenia, RMSEA = 0.06 and CFI = 0.98]. Alternate models that combined fluency with processing speed or verbal and visual memory reduced the goodness of fit. Multi-group CFA results supported factor invariance across the three groups. Confirmatory factor analysis supported a single six-factor structure of cognitive functioning among patients with schizophrenia or bipolar disorder and community controls. While the three groups clearly differ in level of performance, they share a common underlying architecture of information processing abilities. These cognitive factors could provide useful targets for clinical trials of treatments that aim to enhance information processing in persons with neurological and neuropsychiatric disorders. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. An analysis of health promotion materials for Dutch truck drivers: Off target and too complex?

    Science.gov (United States)

    Boeijinga, Anniek; Hoeken, Hans; Sanders, José

    2017-01-01

    Despite various health promotion initiatives, unfavorable figures regarding Dutch truck drivers' eating behaviors, exercise behaviors, and absenteeism have not improved. The aim was to obtain a better understanding of the low level of effectiveness of current health interventions for Dutch truck drivers by examining to what extent these are tailored to the target group's particular mindset (focus of content) and health literacy skills (presentation of content). The article analyzes 21 health promotion materials for Dutch truck drivers using a two-step approach: (a) an analysis of the materials' focus, guided by the Health Action Process Approach; and (b) an argumentation analysis, guided by pragma-dialectics. The corpus analysis revealed: (a) a predominant focus on the motivation phase; and (b) in line with the aim of motivating the target group, a consistent use of pragmatic arguments, which were typically presented in an implicit way. The results indicate that existing health promotion materials for Dutch truck drivers are not sufficiently tailored to the target group's mindset and health literacy skills. Recommendations are offered to develop more tailored/effective health interventions targeting this high-risk, underserved occupational group.

  14. TargetVue: Visual Analysis of Anomalous User Behaviors in Online Communication Systems.

    Science.gov (United States)

    Cao, Nan; Shi, Conglei; Lin, Sabrina; Lu, Jie; Lin, Yu-Ru; Lin, Ching-Yung

    2016-01-01

    Users with anomalous behaviors in online communication systems (e.g. email and social medial platforms) are potential threats to society. Automated anomaly detection based on advanced machine learning techniques has been developed to combat this issue; challenges remain, though, due to the difficulty of obtaining proper ground truth for model training and evaluation. Therefore, substantial human judgment on the automated analysis results is often required to better adjust the performance of anomaly detection. Unfortunately, techniques that allow users to understand the analysis results more efficiently, to make a confident judgment about anomalies, and to explore data in their context, are still lacking. In this paper, we propose a novel visual analysis system, TargetVue, which detects anomalous users via an unsupervised learning model and visualizes the behaviors of suspicious users in behavior-rich context through novel visualization designs and multiple coordinated contextual views. Particularly, TargetVue incorporates three new ego-centric glyphs to visually summarize a user's behaviors which effectively present the user's communication activities, features, and social interactions. An efficient layout method is proposed to place these glyphs on a triangle grid, which captures similarities among users and facilitates comparisons of behaviors of different users. We demonstrate the power of TargetVue through its application in a social bot detection challenge using Twitter data, a case study based on email records, and an interview with expert users. Our evaluation shows that TargetVue is beneficial to the detection of users with anomalous communication behaviors.

  15. Hot-spot analysis for drug discovery targeting protein-protein interactions.

    Science.gov (United States)

    Rosell, Mireia; Fernández-Recio, Juan

    2018-04-01

    Protein-protein interactions are important for biological processes and pathological situations, and are attractive targets for drug discovery. However, rational drug design targeting protein-protein interactions is still highly challenging. Hot-spot residues are seen as the best option to target such interactions, but their identification requires detailed structural and energetic characterization, which is only available for a tiny fraction of protein interactions. Areas covered: In this review, the authors cover a variety of computational methods that have been reported for the energetic analysis of protein-protein interfaces in search of hot-spots, and the structural modeling of protein-protein complexes by docking. This can help to rationalize the discovery of small-molecule inhibitors of protein-protein interfaces of therapeutic interest. Computational analysis and docking can help to locate the interface, molecular dynamics can be used to find suitable cavities, and hot-spot predictions can focus the search for inhibitors of protein-protein interactions. Expert opinion: A major difficulty for applying rational drug design methods to protein-protein interactions is that in the majority of cases the complex structure is not available. Fortunately, computational docking can complement experimental data. An interesting aspect to explore in the future is the integration of these strategies for targeting PPIs with large-scale mutational analysis.

  16. iTAR: a web server for identifying target genes of transcription factors using ChIP-seq or ChIP-chip data.

    Science.gov (United States)

    Yang, Chia-Chun; Andrews, Erik H; Chen, Min-Hsuan; Wang, Wan-Yu; Chen, Jeremy J W; Gerstein, Mark; Liu, Chun-Chi; Cheng, Chao

    2016-08-12

    Chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) or microarray hybridization (ChIP-chip) has been widely used to determine the genomic occupation of transcription factors (TFs). We have previously developed a probabilistic method, called TIP (Target Identification from Profiles), to identify TF target genes using ChIP-seq/ChIP-chip data. To achieve high specificity, TIP applies a conservative method to estimate significance of target genes, with the trade-off being a relatively low sensitivity of target gene identification compared to other methods. Additionally, TIP's output does not render binding-peak locations or intensity, information highly useful for visualization and general experimental biological use, while the variability of ChIP-seq/ChIP-chip file formats has made input into TIP more difficult than desired. To improve upon these facets, here we present are fined TIP with key extensions. First, it implements a Gaussian mixture model for p-value estimation, increasing target gene identification sensitivity and more accurately capturing the shape of TF binding profile distributions. Second, it enables the incorporation of TF binding-peak data by identifying their locations in significant target gene promoter regions and quantifies their strengths. Finally, for full ease of implementation we have incorporated it into a web server ( http://syslab3.nchu.edu.tw/iTAR/ ) that enables flexibility of input file format, can be used across multiple species and genome assembly versions, and is freely available for public use. The web server additionally performs GO enrichment analysis for the identified target genes to reveal the potential function of the corresponding TF. The iTAR web server provides a user-friendly interface and supports target gene identification in seven species, ranging from yeast to human. To facilitate investigating the quality of ChIP-seq/ChIP-chip data, the web server generates the chart of the

  17. MicroRNA and cellular targets profiling reveal miR-217 and miR-576-3p as proviral factors during Oropouche infection.

    Directory of Open Access Journals (Sweden)

    Victor Emmanuel Viana Geddes

    2018-05-01

    Full Text Available Oropouche Virus is the etiological agent of an arbovirus febrile disease that affects thousands of people and is widespread throughout Central and South American countries. Although isolated in 1950's, still there is scarce information regarding the virus biology and its prevalence is likely underestimated. In order to identify and elucidate interactions with host cells factors and increase the understanding about the Oropouche Virus biology, we performed microRNA (miRNA and target genes screening in human hepatocarcinoma cell line HuH-7. Cellular miRNAs are short non-coding RNAs that regulates gene expression post-transcriptionally and play key roles in several steps of viral infections. The large scale RT-qPCR based screening found 13 differentially expressed miRNAs in Oropouche infected cells. Further validation confirmed that miR-217 and miR-576-3p were 5.5 fold up-regulated at early stages of virus infection (6 hours post-infection. Using bioinformatics and pathway enrichment analysis, we predicted the cellular targets genes for miR-217 and miR-576-3p. Differential expression analysis of RNA from 95 selected targets revealed genes involved in innate immunity modulation, viral release and neurological disorder outcomes. Further analysis revealed the gene of decapping protein 2 (DCP2, a previous known restriction factor for bunyaviruses transcription, as a miR-217 candidate target that is progressively down-regulated during Oropouche infection. Our analysis also showed that activators genes involved in innate immune response through IFN-β pathway, as STING (Stimulator of Interferon Genes and TRAF3 (TNF-Receptor Associated Factor 3, were down-regulated as the infection progress. Inhibition of miR-217 or miR-576-3p restricts OROV replication, decreasing viral RNA (up to 8.3 fold and virus titer (3 fold. Finally, we showed that virus escape IFN-β mediated immune response increasing the levels of cellular miR-576-3p resulting in a decreasing of

  18. Analysis of related risk factors for pancreatic fistula after pancreaticoduodenectomy

    Directory of Open Access Journals (Sweden)

    Qi-Song Yu

    2016-08-01

    Full Text Available Objective: To explore the related risk factors for pancreatic fistula after pancreaticoduodenectomy to provide a theoretical evidence for effectively preventing the occurrence of pancreatic fistula. Methods: A total of 100 patients who were admitted in our hospital from January, 2012 to January, 2015 and had performed pancreaticoduodenectomy were included in the study. The related risk factors for developing pancreatic fistula were collected for single factor and Logistic multi-factor analysis. Results: Among the included patients, 16 had pancreatic fistula, and the total occurrence rate was 16% (16/100. The single-factor analysis showed that the upper abdominal operation history, preoperative bilirubin, pancreatic texture, pancreatic duct diameter, intraoperative amount of bleeding, postoperative hemoglobin, and application of somatostatin after operation were the risk factors for developing pancreatic fistula (P<0.05. The multi-factor analysis showed that the upper abdominal operation history, the soft pancreatic texture, small pancreatic duct diameter, and low postoperative hemoglobin were the dependent risk factors for developing pancreatic fistula (OR=4.162, 6.104, 5.613, 4.034, P<0.05. Conclusions: The occurrence of pancreatic fistula after pancreaticoduodenectomy is closely associated with the upper abdominal operation history, the soft pancreatic texture, small pancreatic duct diameter, and low postoperative hemoglobin; therefore, effective measures should be taken to reduce the occurrence of pancreatic fistula according to the patients’ own conditions.

  19. Environmental Performance in Countries Worldwide: Determinant Factors and Multivariate Analysis

    Directory of Open Access Journals (Sweden)

    Isabel Gallego-Alvarez

    2014-11-01

    Full Text Available The aim of this study is to analyze the environmental performance of countries and the variables that can influence it. At the same time, we performed a multivariate analysis using the HJ-biplot, an exploratory method that looks for hidden patterns in the data, obtained from the usual singular value decomposition (SVD of the data matrix, to contextualize the countries grouped by geographical areas and the variables relating to environmental indicators included in the environmental performance index. The sample used comprises 149 countries of different geographic areas. The findings obtained from the empirical analysis emphasize that socioeconomic factors, such as economic wealth and education, as well as institutional factors represented by the style of public administration, in particular control of corruption, are determinant factors of environmental performance in the countries analyzed. In contrast, no effect on environmental performance was found for factors relating to the internal characteristics of a country or political factors.

  20. Smoking among American adolescents: a risk and protective factor analysis.

    Science.gov (United States)

    Scal, Peter; Ireland, Marjorie; Borowsky, Iris Wagman

    2003-04-01

    Cigarette smoking remains a substantial threat to the current and future health of America's youth. The purpose of this study was to identify the risk and protective factors for cigarette smoking among US adolescents. Data from the National Longitudinal Study of Adolescent Health was used, comparing the responses of all non-smokers at Time 1 for their ability to predict the likelihood of smoking at Time 2, one year later. Data was stratified into four gender by grade group cohorts. Cross-cutting risk factors for smoking among all four cohorts were: using alcohol, marijuana, and other illicit drugs; violence involvement; having had sex; having friends who smoke and learning problems. Having a higher grade point average and family connectedness were protective across all cohorts. Other gender and grade group specific risk and protective factors were identified. The estimated probability of initiating smoking decreased by 19.2% to 54.1% both in situations of high and low risk as the number of protective factors present increased. Of the factors that predict or protect against smoking some are influential across all gender and grade group cohorts studied, while others are specific to gender and developmental stage. Prevention efforts that target both the reduction of risk factors and enhancement of protective factors at the individual, family, peer group and community are likely to reduce the likelihood of smoking initiation.

  1. Hierarchical axon targeting of Drosophila olfactory receptor neurons specified by the proneural transcription factors Atonal and Amos.

    Science.gov (United States)

    Okumura, Misako; Kato, Tomoko; Miura, Masayuki; Chihara, Takahiro

    2016-01-01

    Sensory information is spatially represented in the brain to form a neural map. It has been suggested that axon-axon interactions are important for neural map formation; however, the underlying mechanisms are not fully understood. We used the Drosophila antennal lobe, the first olfactory center in the brain, as a model for studying neural map formation. Olfactory receptor neurons (ORNs) expressing the same odorant receptor target their axons to a single glomerulus out of approximately 50 glomeruli in the antennal lobe. Previous studies have showed that the axons of Atonal ORNs, specified by Atonal, a basic helix-loop-helix (bHLH) transcription factor, pioneer antennal lobe formation; however, the details remain to be elucidated. Here, we show that genetic ablation of Atonal ORNs affects antennal lobe structure and axon targeting of Amos ORNs, another type of ORN specified by the bHLH transcription factor Amos. During development, Atonal ORNs reach the antennal lobe and form the axon commissure before Amos ORNs. We also found that N-cadherin knockdown specifically in Atonal ORNs disrupts the glomerular boundary in the whole antennal lobe. Our results suggest that Atonal ORNs function as pioneer axons. Thus, correct axon targeting of Atonal ORNs is essential for formation of the whole antennal lobe. © 2015 The Molecular Biology Society of Japan and Wiley Publishing Asia Pty Ltd.

  2. Can the Growth/Differentiation Factor-15 Be a Surrogate Target in Chronic Heart Failure Biomarker-Guided Therapy?

    Directory of Open Access Journals (Sweden)

    Alexander E. Berezin

    2017-03-01

    Full Text Available Heart failure (HF biomarker-guided therapy is a promising method, which directs to the improvement of clinical status, attenuation of admission/readmission to the hospital and reduction in mortality rate. Many biological markers, like inflammatory cytokines, are under consideration as a surrogate target for HF treatment, while there are known biomarkers with established predictive value, such as natriuretic peptides. However, discovery of new biomarkers reflecting various underlying mechanisms of HF and appearing to be surrogate targets for biomarker-guided therapy is fairly promising. Nowadays, growth/differentiation factor 15 (GDF-15 is suggested a target biomarker for HF treatment. Although elevated level of GDF-15 is associated with HF development, progression, and prognosis, there is no represented evidence regarding the direct comparison of this biomarker with other clinical risk predictors and biomarkers. Moreover, GDF-15 might serve as a contributor to endothelial progenitor cells (EPC dysfunction by inducing EPC death/autophagy and limiting their response to angiopoetic and reparative effects. The short communication was discussed whether GDF-15 is good molecular target for HF biomarker-guided therapy.

  3. Preparation and preclinical evaluation of (177)Lu-nimotuzumab targeting epidermal growth factor receptor overexpressing tumors

    Czech Academy of Sciences Publication Activity Database

    Beckford, Denis R.; Eigner, Sebastian; Eigner-Henke, Kateřina; Lebeda, Ondřej; Melichar, František; Beran, Miloš

    2012-01-01

    Roč. 39, č. 1 (2012), s. 3-13 ISSN 0969-8051 R&D Projects: GA MŠk 2B06165 Institutional research plan: CEZ:AV0Z10480505 Keywords : Radioimmunotherapy * Nimotuzumab * (177)Lu * Monoclonal antibody Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 2.517, year: 2012

  4. Genome-wide strategies identify downstream target genes of chick connective tissue-associated transcription factors.

    Science.gov (United States)

    Orgeur, Mickael; Martens, Marvin; Leonte, Georgeta; Nassari, Sonya; Bonnin, Marie-Ange; Börno, Stefan T; Timmermann, Bernd; Hecht, Jochen; Duprez, Delphine; Stricker, Sigmar

    2018-03-29

    Connective tissues support organs and play crucial roles in development, homeostasis and fibrosis, yet our understanding of their formation is still limited. To gain insight into the molecular mechanisms of connective tissue specification, we selected five zinc-finger transcription factors - OSR1, OSR2, EGR1, KLF2 and KLF4 - based on their expression patterns and/or known involvement in connective tissue subtype differentiation. RNA-seq and ChIP-seq profiling of chick limb micromass cultures revealed a set of common genes regulated by all five transcription factors, which we describe as a connective tissue core expression set. This common core was enriched with genes associated with axon guidance and myofibroblast signature, including fibrosis-related genes. In addition, each transcription factor regulated a specific set of signalling molecules and extracellular matrix components. This suggests a concept whereby local molecular niches can be created by the expression of specific transcription factors impinging on the specification of local microenvironments. The regulatory network established here identifies common and distinct molecular signatures of limb connective tissue subtypes, provides novel insight into the signalling pathways governing connective tissue specification, and serves as a resource for connective tissue development. © 2018. Published by The Company of Biologists Ltd.

  5. Roles of the Nfu Fe–S targeting factors in the trypanosome mitochondrion

    Czech Academy of Sciences Publication Activity Database

    Benz, C.; Kovářová, Julie; Králová-Hromadová, Ivica; Pierik, A. J.; Lukeš, Julius

    2016-01-01

    Roč. 46, č. 10 (2016), s. 641-651 ISSN 0020-7519 EU Projects: European Commission(XE) 316304 - MODBIOLIN Institutional support: RVO:60077344 Keywords : Trypanosoma brucei * Nfu1 * iron–sulphur cluster * Fe–S Mitochondrion Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.730, year: 2016

  6. Preclinical evaluation of radiolabelled nimotuzumab, a promising monoclonal antibody targeting the epidermal growth factor receptor

    Czech Academy of Sciences Publication Activity Database

    Bárta, P.; Lázníčková, A.; Lázníček, M.; Beckford, Denis R.; Beran, Miloš

    2013-01-01

    Roč. 56, č. 5 (2013), s. 280-288 ISSN 0362-4803 Grant - others:GA ČR(CZ) GAP304/10/1738 Institutional support: RVO:61389005 Keywords : radiopharmaceutical * 177Lu * 131I * nimotuzumab * EGFR * preclinical biodistribution Subject RIV: FR - Pharmacology ; Medidal Chemistry Impact factor: 1.187, year: 2013

  7. Targets in the microenvironment of rectal cancer : A focus on angiogenic growth factors and chemokines

    NARCIS (Netherlands)

    Tamas, Karin Rita

    2015-01-01

    Cancer cells interact with each other, and with cells of the tumor microenvironment. This coincides with the production of numerous soluble factors which can stimulate cancer cell growth and migration. In addition the tumor microenvironment can facilitate cancer cells to escape the effect of

  8. Multiple Targets for Novel Therapy of FSGS Associated with Circulating Permeability Factor

    Directory of Open Access Journals (Sweden)

    Virginia J. Savin

    2017-01-01

    Full Text Available A plasma component is responsible for altered glomerular permeability in patients with focal segmental glomerulosclerosis. Evidence includes recurrence after renal transplantation, remission after plasmapheresis, proteinuria in infants of affected mothers, transfer of proteinuria to experimental animals, and impaired glomerular permeability after exposure to patient plasma. Therapy may include decreasing synthesis of the injurious agent, removing or blocking its interaction with cells, or blocking signaling or enhancing cell defenses to restore the permeability barrier and prevent progression. Agents that may prevent the synthesis of the permeability factor include cytotoxic agents or aggressive chemotherapy. Extracorporeal therapies include plasmapheresis, immunoadsorption with protein A or anti-immunoglobulin, or lipopheresis. Oral or intravenous galactose also decreases Palb activity. Studies of glomeruli have shown that several strategies prevent the action of FSGS sera. These include blocking receptor-ligand interactions, modulating cell reactions using indomethacin or eicosanoids 20-HETE or 8,9-EET, and enhancing cytoskeleton and protein interactions using calcineurin inhibitors, glucocorticoids, or rituximab. We have identified cardiotrophin-like cytokine factor 1 (CLCF-1 as a candidate for the permeability factor. Therapies specific to CLCF-1 include potential use of cytokine receptor-like factor (CRLF-1 and inhibition of Janus kinase 2. Combined therapy using multiple modalities offers therapy to reverse proteinuria and prevent scarring.

  9. Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy

    NARCIS (Netherlands)

    Bremer, Edwin

    2013-01-01

    The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective

  10. Human Factors in High-Tech Writing: Targeting the Right Tool for Professional Development.

    Science.gov (United States)

    Rehling, Louise

    1996-01-01

    Presents a method, based on a human factors approach, for helping individuals choose training in a new text technology that suits them. Offers a self-assessment questionnaire ranking preferences among firms, industries, techniques, roles, purposes for writing; then matches those preferences to typical expectations for each of several new text…

  11. Fasting-induced adipose factor/angiopoietin-like protein 4: a potential target for dyslipidemia?

    NARCIS (Netherlands)

    Zandbergen, F.J.; Dijk, van S.; Müller, M.R.; Kersten, A.H.

    2006-01-01

    Recently, several proteins with homology to angiopoietins have been discovered. Three members of this new group, designated angiopoietin-like proteins (ANGPTLs), have been linked to regulation of energy metabolism. This review will focus on the fasting-induced adipose factor (FIAF)/ANGPTL4 as an

  12. Minimizing driver errors: examining factors leading to failed target tracking and detection.

    Science.gov (United States)

    2013-06-01

    Driving a motor vehicle is a common practice for many individuals. Although driving becomes : repetitive and a very habitual task, errors can occur that lead to accidents. One factor that can be a : cause for such errors is a lapse in attention or a ...

  13. Endoplasmic Reticulum-Associated Degradation Factor ERLIN2: Oncogenic Roles and Molecular Targeting of Breast Cancer

    Science.gov (United States)

    2013-06-01

    S Hong, KG Park, IK Lee, CS Choi, RW Hanson, HS Choi and SH Koo. Regulation of hepatic gluconeogenesis by an ER-bound tran- scription factor...cytoplasmic free Ca2+ without generation of inositol phos- phates in NG115-401L neuronal cells. Bio- chem J 1988; 253: 81-86. [17] Y Sagara and G

  14. Confirmatory factor analysis applied to the Force Concept Inventory

    Science.gov (United States)

    Eaton, Philip; Willoughby, Shannon D.

    2018-06-01

    In 1995, Huffman and Heller used exploratory factor analysis to draw into question the factors of the Force Concept Inventory (FCI). Since then several papers have been published examining the factors of the FCI on larger sets of student responses and understandable factors were extracted as a result. However, none of these proposed factor models have been verified to not be unique to their original sample through the use of independent sets of data. This paper seeks to confirm the factor models proposed by Scott et al. in 2012, and Hestenes et al. in 1992, as well as another expert model proposed within this study through the use of confirmatory factor analysis (CFA) and a sample of 20 822 postinstruction student responses to the FCI. Upon application of CFA using the full sample, all three models were found to fit the data with acceptable global fit statistics. However, when CFA was performed using these models on smaller sample sizes the models proposed by Scott et al. and Eaton and Willoughby were found to be far more stable than the model proposed by Hestenes et al. The goodness of fit of these models to the data suggests that the FCI can be scored on factors that are not unique to a single class. These scores could then be used to comment on how instruction methods effect the performance of students along a single factor and more in-depth analyses of curriculum changes may be possible as a result.

  15. CFD Analysis of the Active Part of the HYPER Spallation Target

    International Nuclear Information System (INIS)

    Nam-il Tak; Chungho Cho; Tae-Yung Song

    2006-01-01

    KAERI (Korea Atomic Energy Research Institute) is developing an accelerator driven system (ADS) named HYPER (HYbrid Power Extraction Reactor) for a transmutation of long-lived nuclear wastes. One of the challenging tasks for the HYPER system is to design a large spallation target having a beam power of 15∼25 MW. The present paper focuses on the thermal-hydraulic performance of the active part of the HYPER target. Computational fluid dynamics (CFD) analysis was performed using a commercial code CFX 5.7.1. Several advanced turbulence models with different grid structures were applied. The CFX results show the significant impact of the turbulence model on the window temperature. It is concluded that experimental verifications are very important for the design of the HYPER target. (authors)

  16. Accurate Analysis of Target Characteristic in Bistatic SAR Images: A Dihedral Corner Reflectors Case.

    Science.gov (United States)

    Ao, Dongyang; Li, Yuanhao; Hu, Cheng; Tian, Weiming

    2017-12-22

    The dihedral corner reflectors are the basic geometric structure of many targets and are the main contributions of radar cross section (RCS) in the synthetic aperture radar (SAR) images. In stealth technologies, the elaborate design of the dihedral corners with different opening angles is a useful approach to reduce the high RCS generated by multiple reflections. As bistatic synthetic aperture sensors have flexible geometric configurations and are sensitive to the dihedral corners with different opening angles, they specially fit for the stealth target detections. In this paper, the scattering characteristic of dihedral corner reflectors is accurately analyzed in bistatic synthetic aperture images. The variation of RCS with the changing opening angle is formulated and the method to design a proper bistatic radar for maximizing the detection capability is provided. Both the results of the theoretical analysis and the experiments show the bistatic SAR could detect the dihedral corners, under a certain bistatic angle which is related to the geometry of target structures.

  17. Detection of Moving Targets Based on Doppler Spectrum Analysis Technique for Passive Coherent Radar

    Directory of Open Access Journals (Sweden)

    Zhao Yao-dong

    2013-06-01

    Full Text Available A novel method of moving targets detection taking Doppler spectrum analysis technique for Passive Coherent Radar (PCR is provided. After dividing the receiving signals into segments as pulse series, it utilizes the technique of pulse compress and Doppler processing to detect and locate the targets. Based on the algorithm for Pulse-Doppler (PD radar, the equipollence between continuous and pulsed wave in match filtering is proved and details of this method are introduced. To compare it with the traditional method of Cross-Ambiguity Function (CAF calculation, the relationship and mathematical modes of them are analyzed, with some suggestions on parameters choosing. With little influence to the gain of targets, the method can greatly promote the processing efficiency. The validity of the proposed method is demonstrated by offline processing real collected data sets and simulation results.

  18. Blood pressure variability predicts cardiovascular events independently of traditional cardiovascular risk factors and target organ damage

    DEFF Research Database (Denmark)

    Vishram, Julie K K; Dahlöf, Björn; Devereux, Richard B

    2015-01-01

    ). METHODS: In 8505 patients randomized to losartan vs. atenolol-based treatment in the LIFE study, we tested whether BP variability assessed as SD and range for BP6-24months measured at 6, 12, 18 and 24 months of treatment was associated with target organ damage (TOD) defined by LVH on ECG and urine albumin......BACKGROUND: Assessment of antihypertensive treatment is normally based on the mean value of a number of blood pressure (BP) measurements. However, it is uncertain whether high in-treatment visit-to-visit BP variability may be harmful in hypertensive patients with left ventricular hypertrophy (LVH.......05), but MI was not. CONCLUSION: In LIFE patients, higher in-treatment BP6-24months variability was independently of mean BP6-24months associated with later CEP and stroke, but not with MI or TOD after 24 months....

  19. Re-Factoring Glycolytic Genes for Targeted Engineering of Catabolism in Gram-Negative Bacteria

    DEFF Research Database (Denmark)

    Sánchez-Pascuala, Alberto; Nikel, Pablo I.; de Lorenzo, Víctor

    2018-01-01

    the potential applications of such a portable tool for targeted pathway engineering, in the present protocol we describe how the genes encoding all the enzymes of the linear EMP route have been individually recruited from the genome of E. coli K-12, edited in silico to remove their endogenous regulatory signals......The Embden-Meyerhof-Parnas (EMP) pathway is widely accepted to be the biochemical standard of glucose catabolism. The well-characterized glycolytic route of Escherichia coli, based on the EMP catabolism, is an example of an intricate pathway in terms of genomic organization of the genes involved...... and patterns of gene expression and regulation. This intrinsic genetic and metabolic complexity renders it difficult to engineer glycolytic activities and transfer them onto other microbial cell factories, thus limiting the biotechnological potential of bacterial hosts that lack the route. Taking into account...

  20. Deterministic and stochastic analysis of alternative climate targets under differentiated cooperation regimes

    International Nuclear Information System (INIS)

    Loulou, Richard; Labriet, Maryse; Kanudia, Amit

    2009-01-01

    This article analyzes the feasibility of attaining a variety of climate targets during the 21st century, under alternative cooperation regimes by groups of countries. Five climate targets of increasing severity are analyzed, following the EMF-22 experiment. Each target is attempted under two cooperation regimes, a First Best scenario where all countries fully cooperate from 2012 on, and a Second Best scenario where the World is partitioned into three groups, and each group of countries enters the cooperation at a different date, and implement emission abatement actions in a progressive manner, once in the coalition. The resulting ten combinations are simulated via the ETSAP-TIAM technology based, integrated assessment model. In addition to the 10 separate case analyses, the article proposes a probabilistic treatment of three targets under the First Best scenario, and shows that the three forcing targets may in fact be interpreted as a single target on global temperature change, while assuming that the climate sensitivity C s is uncertain. It is shown that such an interpretation is possible only if the probability distribution of C s is carefully chosen. The analysis of the results shows that the lowest forcing level is unattainable unless immediate coordinated action is undertaken by all countries, and even so only at a high global cost. The middle and the high forcing levels are feasible at affordable global costs, even under the Second Best scenario. Another original contribution of this article is to explain why certain combinations of technological choices are made by the model, and in particular why the climate target clearly supersedes the usually accepted objective of improving energy efficiency. The analysis shows that under some climate targets, it is not optimal to improve energy efficiency, but rather to take advantage of certain technologies that help to reach the climate objective, but that happen to be less energy efficient than even the technologies

  1. Design, construction, and analysis of specific zinc finger nucleases for microphthalmia - associate transcription factor

    Directory of Open Access Journals (Sweden)

    Wenwen Wang

    2012-08-01

    Full Text Available This work studied the design, construction, and cleavage analysis of zinc finger nucleases (ZFNs that could cut the specific sequences within microphthalmia - associate transcription factor (mitfa of zebra fish. The target site and ZFPs were selected and designed with zinc finger tools, while the ZFPs were synthesized using DNAWorks and two-step PCR. The ZFNs were constructed, expressed, purified, and analyzed in vitro. As expected, the designed ZFNs could create a double-stand break (DSB at the target site in vitro. The DNAWorks, two-step PCR, and an optimized process of protein expression were firstly induced in the construction of ZFNs successfully, which was an effective and simplified protocol. These results could be useful for further application of ZFNs - mediated gene targeting.

  2. Brain derived neurotrophic factor mediated learning, fear acquisition and extinction as targets for developing novel treatments for anxiety

    Directory of Open Access Journals (Sweden)

    Karina Soares de Oliveira

    Full Text Available ABSTRACT Anxiety and obsessive-compulsive related disorders are highly prevalent and disabling disorders for which there are still treatment gaps to be explored. Fear is a core symptom of these disorders and its learning is highly dependent on the activity of the neurotrophin brain-derived neurotrophic factor (BDNF. Should BDNF-mediated fear learning be considered a target for the development of novel treatments for anxiety and obsessive-compulsive related disorders? We review the evidence that suggests that BDNF expression is necessary for the acquisition of conditioned fear, as well as for the recall of its extinction. We describe the findings related to fear learning and genetic/epigenetic manipulation of Bdnf expression in animals and BDNF allelic variants in humans. Later, we discuss how manipulation of BDNF levels represents a promising potential treatment target that may increase the benefits of therapies that extinguish previously conditioned fear.

  3. Seismic analysis of fuel and target assemblies at a production reactor

    International Nuclear Information System (INIS)

    Braverman, J.I.; Wang, Y.K.

    1991-01-01

    This paper describes the unique modeling and analysis considerations used to assess the seismic adequacy of the fuel and target assemblies in a production reactor at Savannah River Site. This confirmatory analysis was necessary to provide assurance that the reactor can operate safely during a seismic event and be brought to a safe shutdown condition. The plant which was originally designed in the 1950's required to be assessed to more current seismic criteria. The design of the reactor internals and the magnitude of the structural responses enabled the use of a linear elastic dynamic analysis. A seismic analysis was performed using a finite element model consisting of the fuel and target assemblies, reactor tank, and a portion of the concrete structure supporting the reactor tank. The effects of submergence of the fuel and target assemblies in the water contained within the reactor tank can have a significant effect on their seismic response. Thus, the model included hydrodynamic fluid coupling effects between the assemblies and the reactor tank. Fluid coupling mass terms were based on formulations for solid bodies immersed in incompressible and frictionless fluids. The potential effects of gap conditions were also assessed in this evaluation. 5 refs., 6 figs., 1 tab

  4. The effects of Risk Factor-Targeted Lifestyle Counselling Intervention on working-age stroke patients' adherence to lifestyle change.

    Science.gov (United States)

    Oikarinen, Anne; Engblom, Janne; Kääriäinen, Maria; Kyngäs, Helvi

    2017-09-01

    Since a history of stroke or transient ischaemic attack is a major risk factor for a recurrent event, lifestyle counselling during the hospital phase is an essential component of treatment and may increase the probability of lifestyle change. To study the effect of risk factor-targeted lifestyle counselling intervention on working-age stroke patients' adherence to lifestyle changes. A quasi-experimental, nonequivalent control group pretest-post-test design. Stroke patients in an acute neurological unit were divided into a control group (n = 75) receiving standard counselling and an experimental group (n = 75) receiving risk factor-targeted counselling. Lifestyle data and clinical outcomes were collected at hospital between January 2010 and October 2011, while data on adherence to lifestyle changes 3, 6, and 12 months after discharge. The baseline lifestyle habits did not differ significantly other than in alcohol behaviour. Both groups increased their intake, but the intervention group to a lesser degree. However, the experimental group significantly lost their weight for the first 3 and 6 months; at 3 months reduction in cigarette consumption and at 6 months significant increases in smoking cessation were also achieved. All improved some of their lifestyle habits. Intervention was associated with support from nurses as well as from family and friends. Adherence scores were higher in the experimental group. Some short-term advantages in lifestyle habits due to the intervention were noted. Participants in both groups improved some of their lifestyle habits. © 2016 Nordic College of Caring Science.

  5. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis.

    Science.gov (United States)

    Yang, Tieshan; Yao, Qian; Cao, Fei; Liu, Qianqian; Liu, Binlei; Wang, Xiu-Hong

    Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs), which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF-1α protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis.

  6. A BRDF-BPDF database for the analysis of Earth target reflectances

    Science.gov (United States)

    Breon, Francois-Marie; Maignan, Fabienne

    2017-01-01

    Land surface reflectance is not isotropic. It varies with the observation geometry that is defined by the sun, view zenith angles, and the relative azimuth. In addition, the reflectance is linearly polarized. The reflectance anisotropy is quantified by the bidirectional reflectance distribution function (BRDF), while its polarization properties are defined by the bidirectional polarization distribution function (BPDF). The POLDER radiometer that flew onboard the PARASOL microsatellite remains the only space instrument that measured numerous samples of the BRDF and BPDF of Earth targets. Here, we describe a database of representative BRDFs and BPDFs derived from the POLDER measurements. From the huge number of data acquired by the spaceborne instrument over a period of 7 years, we selected a set of targets with high-quality observations. The selection aimed for a large number of observations, free of significant cloud or aerosol contamination, acquired in diverse observation geometries with a focus on the backscatter direction that shows the specific hot spot signature. The targets are sorted according to the 16-class International Geosphere-Biosphere Programme (IGBP) land cover classification system, and the target selection aims at a spatial representativeness within the class. The database thus provides a set of high-quality BRDF and BPDF samples that can be used to assess the typical variability of natural surface reflectances or to evaluate models. It is available freely from the PANGAEA website (PANGAEA.864090" target="_blank">doi:10.1594/PANGAEA.864090). In addition to the database, we provide a visualization and analysis tool based on the Interactive Data Language (IDL). It allows an interactive analysis of the measurements and a comparison against various BRDF and BPDF analytical models. The present paper describes the input data, the selection principles, the database format, and the analysis tool

  7. Involvement of pro-inflammatory cytokines and growth factors in the pathogenesis of Dupuytren's contracture: a novel target for a possible future therapeutic strategy?

    Science.gov (United States)

    Bianchi, Enrica; Taurone, Samanta; Bardella, Lia; Signore, Alberto; Pompili, Elena; Sessa, Vincenzo; Chiappetta, Caterina; Fumagalli, Lorenzo; Di Gioia, Cira; Pastore, Francesco S; Scarpa, Susanna; Artico, Marco

    2015-10-01

    Dupuytren's contracture (DC) is a benign fibro-proliferative disease of the hand causing fibrotic nodules and fascial cords which determine debilitating contracture and deformities of fingers and hands. The present study was designed to characterize pro-inflammatory cytokines and growth factors involved in the pathogenesis, progression and recurrence of this disease, in order to find novel targets for alternative therapies and strategies in controlling DC. The expression of pro-inflammatory cytokines and of growth factors was detected by immunohistochemistry in fibrotic nodules and normal palmar fascia resected respectively from patients affected by DC and carpal tunnel syndrome (CTS; as negative controls). Reverse transcription (RT)-PCR analysis and immunofluorescence were performed to quantify the expression of transforming growth factor (TGF)-β1, interleukin (IL)-1β and vascular endothelial growth factor (VEGF) by primary cultures of myofibroblasts and fibroblasts isolated from Dupuytren's nodules. Histological analysis showed high cellularity and high proliferation rate in Dupuytren's tissue, together with the presence of myofibroblastic isotypes; immunohistochemical staining for macrophages was completely negative. In addition, a strong expression of TGF-β1, IL-1β and VEGF was evident in the extracellular matrix and in the cytoplasm of fibroblasts and myofibroblasts in Dupuytren's nodular tissues, as compared with control tissues. These results were confirmed by RT-PCR and by immunofluorescence in pathological and normal primary cell cultures. These preliminary observations suggest that TGF-β1, IL-1β and VEGF may be considered potential therapeutic targets in the treatment of Dupuytren's disease (DD). © 2015 Authors; published by Portland Press Limited.

  8. Analysis of the thermomechanical behavior of the IFMIF bayonet target assembly under design loading scenarios

    Energy Technology Data Exchange (ETDEWEB)

    Bernardi, D., E-mail: davide.bernardi@enea.it [ENEA Brasimone, Camugnano, BO (Italy); Arena, P.; Bongiovì, G.; Di Maio, P.A. [Dipartimento di Energia, Ingegneria dell’Informazione e Modelli Matematici, Università di Palermo, Viale delle Scienze, Palermo (Italy); Frisoni, M. [ENEA Bologna, Via Martiri di Monte Sole 4, Bologna (Italy); Miccichè, G.; Serra, M. [ENEA Brasimone, Camugnano, BO (Italy)

    2015-10-15

    In the framework of the IFMIF Engineering Validation and Engineering Design Activities (IFMIF/EVEDA) phase, ENEA is responsible for the design of the European concept of the IFMIF lithium target system which foresees the possibility to periodically replace only the most irradiated and thus critical component (i.e., the backplate) while continuing to operate the rest of the target for a longer period (the so-called bayonet backplate concept). In this work, the results of the steady state thermomechanical analysis of the IFMIF bayonet target assembly under two different design loading scenarios (a “hot” scenario and a “cold” scenario) are briefly reported highlighting the relevant indications obtained with respect to the fulfillment of the design requirements. In particular, the analyses have shown that in the hot scenario the temperatures reached in the target assembly are within the material acceptable limits while in the cold scenario transition below the ductile to brittle transition temperature (DBTT) cannot be excluded. Moreover, results indicate that the contact between backplate and high flux test module is avoided and that the overall structural integrity of the system is assured in both scenarios. However, stress linearization analysis reveals that ITER Structural Design Criteria for In-vessel Components (SDC-IC) design rules are not always met along the selected paths at backplate middle plane section in the hot scenario, thus suggesting the need of a revision of the backplate design or a change of the operating conditions.

  9. Thermal analysis of LEU modified Cintichem target irradiated in TRIGA reactor

    International Nuclear Information System (INIS)

    Catana, A; Toma, C.

    2009-01-01

    Actions conceived during last years at international level for conversion of Molybdenum fabrication process from HEU to LEU targets utilization created opportunities for INR to get access to information and participating to international discussions under IAEA auspices. Concrete steps for developing fission Molybdenum technology were facilitated. Institute of Nuclear Research bringing together a number of conditions like suitable irradiation possibilities, direct communication between reactor and hot cell facility, handling capacity of high radioactive sources, and simultaneously the existence of an expanding internal market, decided to undertake the necessary steps in order to produce fission molybdenum. Over the course of last years of efforts in this direction we developed the steps for fission Molybdenum technology development based on modified Cintichem process in accordance with the Argonne National Laboratory proved methodology. Progress made by INR to heat transfer computations of annular target using is presented. An advanced thermal-hydraulic analysis was performed to estimate the heat removal capability for an enriched uranium (LEU) foil annular target irradiated in TRIGA reactor core. As a result, the present analysis provides an upper limit estimate of the LEU-foil and external target surface temperatures during irradiation in TRIGA 14 MW reactor. (authors)

  10. Radiation inactivation analysis of enzymes. Effect of free radical scavengers on apparent target sizes

    International Nuclear Information System (INIS)

    Eichler, D.C.; Solomonson, L.P.; Barber, M.J.; McCreery, M.J.; Ness, G.C.

    1987-01-01

    In most cases the apparent target size obtained by radiation inactivation analysis corresponds to the subunit size or to the size of a multimeric complex. In this report, we examined whether the larger than expected target sizes of some enzymes could be due to secondary effects of free radicals. To test this proposal we carried out radiation inactivation analysis on Escherichia coli DNA polymerase I, Torula yeast glucose-6-phosphate dehydrogenase, Chlorella vulgaris nitrate reductase, and chicken liver sulfite oxidase in the presence and absence of free radical scavengers (benzoic acid and mannitol). In the presence of free radical scavengers, inactivation curves are shifted toward higher radiation doses. Plots of scavenger concentration versus enzyme activity showed that the protective effect of benzoic acid reached a maximum at 25 mM then declined. Mannitol alone had little effect, but appeared to broaden the maximum protective range of benzoic acid relative to concentration. The apparent target size of the polymerase activity of DNA polymerase I in the presence of free radical scavengers was about 40% of that observed in the absence of these agents. This is considerably less than the minimum polypeptide size and may reflect the actual size of the polymerase functional domain. Similar effects, but of lesser magnitude, were observed for glucose-6-phosphate dehydrogenase, nitrate reductase, and sulfite oxidase. These results suggest that secondary damage due to free radicals generated in the local environment as a result of ionizing radiation can influence the apparent target size obtained by this method

  11. Silver nanoparticles inhibit the function of hypoxia-inducible factor-1 and target genes: insight into the cytotoxicity and antiangiogenesis

    Directory of Open Access Journals (Sweden)

    Yang T

    2016-12-01

    Full Text Available Tieshan Yang,1 Qian Yao,1 Fei Cao,1 Qianqian Liu,1 Binlei Liu,2 Xiu-Hong Wang1 1Laboratory for Biomedical Photonics, Institute of Laser Engineering, Beijing University of Technology, 2Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China Abstract: Hypoxia-inducible factor-1 (HIF-1 is a transcription factor that is activated upon exposure to hypoxic stress. It modulates a number of cellular responses including proliferation, apoptosis, angiogenesis, and metabolism by activating a panel of target genes in response to hypoxia. The HIF-1 level is often upregulated in the hypoxic microenvironment of solid tumors, which contributes to cancer treatment failure. Here we report that silver nanoparticles (AgNPs, which are widely used as an antimicrobial agent, are an effective inhibitor of HIF-1. AgNPs inhibited the activation of a HIF-dependent reporter construct after the cells were exposed to hypoxic conditions or treated with cobalt chloride, a hypoxia mimetic agent. The AgNPs also interfered with the accumulation of HIF-1α protein and the induction of the endogenous HIF target genes, VEGF-A and GLUT1. Since both HIF-1 and vascular endothelial growth factor-A play an important role in angiogenesis, AgNPs also inhibited angiogenesis in vitro. Our data reveal a new mechanism of how AgNPs act on cellular function, that is, they disrupt HIF signaling pathway. This finding provides a novel insight into how AgNPs can inhibit cancer cell growth and angiogenesis. Keywords: silver nanoparticles (AgNPs, hypoxia-inducible factor, transcriptional activity, vascular endothelial growth factor-A, angiogenesis

  12. Confirmatory factor analysis of the female sexual function index.

    Science.gov (United States)

    Opperman, Emily A; Benson, Lindsay E; Milhausen, Robin R

    2013-01-01

    The Female Sexual Functioning Index (Rosen et al., 2000 ) was designed to assess the key dimensions of female sexual functioning using six domains: desire, arousal, lubrication, orgasm, satisfaction, and pain. A full-scale score was proposed to represent women's overall sexual function. The fifth revision to the Diagnostic and Statistical Manual (DSM) is currently underway and includes a proposal to combine desire and arousal problems. The objective of this article was to evaluate and compare four models of the Female Sexual Functioning Index: (a) single-factor model, (b) six-factor model, (c) second-order factor model, and (4) five-factor model combining the desire and arousal subscales. Cross-sectional and observational data from 85 women were used to conduct a confirmatory factor analysis on the Female Sexual Functioning Index. Local and global goodness-of-fit measures, the chi-square test of differences, squared multiple correlations, and regression weights were used. The single-factor model fit was not acceptable. The original six-factor model was confirmed, and good model fit was found for the second-order and five-factor models. Delta chi-square tests of differences supported best fit for the six-factor model validating usage of the six domains. However, when revisions are made to the DSM-5, the Female Sexual Functioning Index can adapt to reflect these changes and remain a valid assessment tool for women's sexual functioning, as the five-factor structure was also supported.

  13. Factors affecting ambulance utilization for asthma attack treatment: understanding where to target interventions.

    Science.gov (United States)

    Raun, L H; Ensor, K B; Campos, L A; Persse, D

    2015-05-01

    Asthma is a serious, sometimes fatal condition, in which attacks vary in severity, potentially requiring emergency medical services (EMS) ambulance treatment. A portion of asthma attacks requiring EMS ambulance treatment may be prevented with improved education and access to care. The aim of this study was to identify areas of the city with high rates of utilization of EMS ambulance for treatment, and the demographics, socio-economic status, and time of day associated with these rates, to better target future interventions to prevent emergencies and reduce cost. A cross-sectional study was conducted on individuals in Houston, TX (USA) requiring ambulance treatment for asthma attacks from 2004 to 2011. 12,155 EMS ambulance-treated asthma attack cases were linked to census tracts. High rate treatment areas were identified with geospatial mapping. Census tract demographic characteristics of these high rate areas were compared with the remainder of the city using logistic regression. The association between case level demographics and the time of day of asthma attack within the high rate area was also assessed with logistic regression. EMS ambulance-treated high rate areas were identified and found to have a utilization incidence rate over six times higher per 100,000 people than the remainder of the city. There is an increased risk of location in this high rate area with a census tract level increase of percent of population: earning less than $10,000 yearly income (RR 1.21, 1.16-1.26), which is black (RR 1.08, 1.07-1.10), which is female (RR 1.34, 1.20-1.49) and have obtained less than a high school degree (RR 1.02, 1.01-1.03). Within the high rate area, case level data indicates an increased risk of requiring an ambulance after normal doctor office hours for men compared with women (RR 1.13, 1.03-1.22), for black compared with Hispanic ethnicity (RR 1.31, 1.08-1.59), or for adults (less than 41 and greater than 60) compared with children. Interventions to prevent

  14. Allocating the Fixed Resources and Setting Targets in Integer Data Envelopment Analysis

    Directory of Open Access Journals (Sweden)

    Kobra Gholami

    2013-11-01

    Full Text Available Data envelopment analysis (DEA is a non-parametric approach to evaluate a set of decision making units (DMUs consuming multiple inputs to produce multiple outputs. Formally, DEA use to estimate the efficiency score into the empirical efficient frontier. Also, DEA can be used to allocate resources and set targets for future forecast. The data are continuous in the standard DEA model whereas there are many problems in the real life that data must be integer such as number of employee, machinery, expert and so on. Thus in this paper we propose an approach to allocate fixed resources and set fixed targets with selective integer assumption that is based on an integer data envelopment analysis (IDEA approach for the first time. The major aim in this approach is preserving the efficiency score of DMUs. We use the concept of benchmarking to reach this aim. The numerical example gets to illustrate the applicability of the proposed method.

  15. MEANING OF TARGET AMBIGUITY FACTOR IN INTELLECTUAL TECHNOLOGIES OF SCIENTIFIC SEARCH

    Directory of Open Access Journals (Sweden)

    V. M. Коleshko

    2008-01-01

    Full Text Available The main peculiar feature of an intellectual system orientated to formulation of original scientific hypothesis, non-trivial technical solutions is an initial target ambiguity of creative search. Process concerning creation of new knowledge in such system presuppose chaotic steps directed on hypothesis synthesis and their improvement, cancellation of non-productive searching methods and advancement of new scientific theories. Formation of new knowledge which generally has random character at the initial stage gradually becomes more ordered, motivated to obtain a concrete result due to development of searching process. Both components of the intellectual medium (a human being and a machine have so to speak an equilibrium in their actions, actively interacting and supplementing each other in the most creative procedures of hypothesis synthesis. Role difference resides in that a computer provides its formal logical and information resource for solution selection, and a researcher is assigned to carry out an additional task that is to take decisions about correctness of scientific hypothesis

  16. Chenodeoxycholic Acid Reduces Hypoxia Inducible Factor-1α Protein and Its Target Genes.

    Directory of Open Access Journals (Sweden)

    Yunwon Moon

    Full Text Available This study evaluated HIF-1α inhibitors under different hypoxic conditions, physiological hypoxia (5% O2 and severe hypoxia (0.1% O2. We found that chenodeoxy cholic acid (CDCA reduced the amount of HIF-1α protein only under physiological hypoxia but not under severe hypoxia without decreasing its mRNA level. By using a proteasome inhibitor MG132 and a translation inhibitor cyclohexamide, we showed that CDCA reduced HIF-1α protein by decreasing its translation but not by enhancing its degradation. The following findings indicated that farnesoid X receptor (FXR, a CDCA receptor and its target gene, Small heterodimer partner (SHP are not involved in this effect of CDCA. Distinctly from CDCA, MG132 prevented SHP and an exogenous FXR agonist, GW4064 from reducing HIF-1α protein. Furthermore a FXR antagonist, guggulsterone failed to prevent CDCA from decreasing HIF-1α protein. Furthermore, guggulsterone by itself reduced HIF-1α protein even in the presence of MG132. These findings suggested that CDCA and guggulsterone reduced the translation of HIF-1α in a mechanism which FXR and SHP are not involved. This study reveals novel therapeutic functions of traditional nontoxic drugs, CDCA and guggulsterone, as inhibitors of HIF-1α protein.

  17. Modulation of the Endocannabinoid System: Vulnerability Factor and New Treatment Target for Stimulant Addiction.

    Directory of Open Access Journals (Sweden)

    Stéphanie eOlière

    2013-09-01

    Full Text Available Cannabis is one of the most widely used illicit substance among users of stimulants such as cocaine and amphetamine. Interestingly, recent accumulating evidence points toward the involvement of the endocannabinoid system (ECBS in the neurobiological processes related to stimulant addiction. This article presents an up-to-date review with deep-insights into the pivotal role of the ECBS in the neurobiology of stimulant addiction and the effects of its modulation on addictive behaviors. The aims of this article are to: 1 review the role of cannabis use and ECBS modulation in the neurobiological substrates of psychostimulant addiction and 2 evaluate the potential of cannabinoid-based pharmacological strategies to treat stimulant addiction. A growing number of studies support a critical role of the ECBS and its modulation by synthetic or natural cannabinoid in various neurobiological and behavioral aspects of stimulants addiction. Thus, cannabinoids modulate brain reward systems closely involved in stimulants addiction, and provide further evidence that the cannabinoid system could be explored as a potential drug discovery target for treating addiction across different classes of stimulants.

  18. Re-Factoring Glycolytic Genes for Targeted Engineering of Catabolism in Gram-Negative Bacteria.

    Science.gov (United States)

    Sánchez-Pascuala, Alberto; Nikel, Pablo I; de Lorenzo, Víctor

    2018-01-01

    The Embden-Meyerhof-Parnas (EMP) pathway is widely accepted to be the biochemical standard of glucose catabolism. The well-characterized glycolytic route of Escherichia coli, based on the EMP catabolism, is an example of an intricate pathway in terms of genomic organization of the genes involved and patterns of gene expression and regulation. This intrinsic genetic and metabolic complexity renders it difficult to engineer glycolytic activities and transfer them onto other microbial cell factories, thus limiting the biotechnological potential of bacterial hosts that lack the route. Taking into account the potential applications of such a portable tool for targeted pathway engineering, in the present protocol we describe how the genes encoding all the enzymes of the linear EMP route have been individually recruited from the genome of E. coli K-12, edited in silico to remove their endogenous regulatory signals, and synthesized de novo following a standard (i.e., GlucoBrick) that facilitates their grouping in the form of functional modules that can be combined at the user's will. This novel genetic tool allows for the à la carte implementation or boosting of EMP pathway activities into different Gram-negative bacteria. The potential of the GlucoBrick platform is further illustrated by engineering novel glycolytic activities in the most representative members of the Pseudomonas genus (Pseudomonas putida and Pseudomonas aeruginosa).

  19. The control of male fertility by spermatid-specific factors: searching for contraceptive targets from spermatozoon's head to tail

    Science.gov (United States)

    Chen, Su-Ren; Batool, Aalia; Wang, Yu-Qian; Hao, Xiao-Xia; Chang, Chawn-Shang; Cheng, C Yan; Liu, Yi-Xun

    2016-01-01

    Male infertility due to abnormal spermatozoa has been reported in both animals and humans, but its pathogenic causes, including genetic abnormalities, remain largely unknown. On the other hand, contraceptive options for men are limited, and a specific, reversible and safe method of male contraception has been a long-standing quest in medicine. Some progress has recently been made in exploring the effects of spermatid-specifical genetic factors in controlling male fertility. A comprehensive search of PubMed for articles and reviews published in English before July 2016 was carried out using the search terms ‘spermiogenesis failure', ‘globozoospermia', ‘spermatid-specific', ‘acrosome', ‘infertile', ‘manchette', ‘sperm connecting piece', ‘sperm annulus', ‘sperm ADAMs', ‘flagellar abnormalities', ‘sperm motility loss', ‘sperm ion exchanger' and ‘contraceptive targets'. Importantly, we have opted to focus on articles regarding spermatid-specific factors. Genetic studies to define the structure and physiology of sperm have shown that spermatozoa appear to be one of the most promising contraceptive targets. Here we summarize how these spermatid-specific factors regulate spermiogenesis and categorize them according to their localization and function from spermatid head to tail (e.g., acrosome, manchette, head-tail conjunction, annulus, principal piece of tail). In addition, we emphatically introduce small-molecule contraceptives, such as BRDT and PPP3CC/PPP3R2, which are currently being developed to target spermatogenic-specific proteins. We suggest that blocking the differentiation of haploid germ cells, which rarely affects early spermatogenic cell types and the testicular microenvironment, is a better choice than spermatogenic-specific proteins. The studies described here provide valuable information regarding the genetic and molecular defects causing male mouse infertility to improve our understanding of the importance of spermatid

  20. Countermeasure development for Rift Valley fever: deletion, modification or targeting of major virulence factor NSs.

    Science.gov (United States)

    Lihoradova, Olga; Ikegami, Tetsuro

    2014-01-01

    Rift Valley fever (RVF) is a mosquito-borne zoonotic disease characterized by a high rate of abortion in ruminants, and febrile illness, hemorrhagic fever, retinitis and encephalitis in humans. RVF is caused by the RVF virus (RVFV), belonging to the genus Phlebovirus of the family Bunyaviridae . RVFV encodes a major virulence factor, NSs , which is dispensable for viral replication, yet required for evasion of host innate immune responses. RVFV NSs inhibits host gene upregulation at the transcriptional level, while promoting viral translation in the cytoplasm. In this article, we summarize the virology and pathology of RVF, and countermeasure development for RVF, with emphasis on NSs function and applications.

  1. Targeted delivery of polyamidoamine-paclitaxel conjugate functionalized with anti-human epidermal growth factor receptor 2 trastuzumab

    Directory of Open Access Journals (Sweden)

    Ma P

    2015-03-01

    Full Text Available Pengkai Ma,1 Xuemei Zhang,1 Ling Ni,2 Jinming Li,2 Fengpu Zhang,1 Zheng Wang,1 Shengnan Lian,1 Kaoxiang Sun1 1School of Pharmacy, Yantai University, Yantai, Shandong Province, People’s Republic of China; 2State Key Laboratory of Long-acting and Targeting Drug Delivery System, Yantai, Shandong Province, People’s Republic of China Background: Antibody-dendrimer conjugates have the potential to improve the targeting and release of chemotherapeutic drugs at the tumor site while reducing adverse side effects caused by drug accumulation in healthy tissues. In this study, trastuzumab (TMAB, which binds to human epidermal growth factor receptor 2 (HER2, was used as a targeting agent in a TMAB-polyamidoamine (PAMAM conjugate carrying paclitaxel (PTX specifically to cells overexpressing HER2. Methods: TMAB was covalently linked to a PAMAM dendrimer via bifunctional polyethylene glycol (PEG. PTX was conjugated to PAMAM using succinic anhydride as a cross-linker, yielding TMAB-PEG-PAMAM-PTX. Dynamic light scattering and transmission electron microscopy were used to characterize the conjugates. The cellular uptake and in vivo biodistribution were studied by fluorescence microscopy, flow cytometry, and Carestream In Vivo FX, respectively. Results: Nuclear magnetic resonance spectroscopy demonstrated that PEG, PTX, fluorescein isothiocyanate, and cyanine7 were conjugated to PAMAM. Ultraviolet-visible spectroscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis demonstrated that TMAB was conjugated to PEG-PAMAM. Dynamic light scattering and transmission electron microscopy measurements revealed that the different conjugates ranged in size between 10 and 35 nm and had a spherical shape. In vitro cellular uptake demonstrated that the TMAB-conjugated PAMAM was taken up by HER2-overexpressing BT474 cells more efficiently than MCF-7 cells that expressed lower levels of HER2. Co-localization experiments indicated that TMAB-conjugated PAMAM was

  2. Analysis and Simulation of Multi-target Echo Signals from a Phased Array Radar

    OpenAIRE

    Jia Zhen; Zhou Rui

    2017-01-01

    The construction of digital radar simulation systems has been a research hotspot of the radar field. This paper focuses on theoretical analysis and simulation of multi-target echo signals produced in a phased array radar system, and constructs an array antenna element and a signal generation environment. The antenna element is able to simulate planar arrays and optimizes these arrays by adding window functions. And the signal environment can model and simulate radar transmission signals, rada...

  3. Methodological Approach to Company Cash Flows Target-Oriented Forecasting Based on Financial Position Analysis

    OpenAIRE

    Sergey Krylov

    2012-01-01

    The article treats a new methodological approach to the company cash flows target-oriented forecasting based on its financial position analysis. The approach is featured to be universal and presumes application of the following techniques developed by the author: financial ratio values correction techniques and correcting cash flows techniques. The financial ratio values correction technique assumes to analyze and forecast company financial position while the correcting cash flows technique i...

  4. Targeting khat or targeting Somalis? A discourse analysis of project evaluations on khat abuse among Somali immigrants in Scandinavia

    Directory of Open Access Journals (Sweden)

    Nordgren Johan

    2015-09-01

    Full Text Available BACKGROUND – In Denmark, Norway and Sweden, the use of the psychoactive plant khat is widely seen as a social and health problem exclusively affecting the Somali immigrant population. Several projects by governmental and municipal bodies and agencies have been initiated to reduce khat use and abuse within this target population.

  5. Myeloid cell leukemia-1 (Mc1-1 is a candidate target gene of hypoxia-inducible factor-1 (HIF-1 in the testis

    Directory of Open Access Journals (Sweden)

    Palladino Michael A

    2012-12-01

    Full Text Available Abstract Background Spermatic cord torsion can lead to testis ischemia (I and subsequent ischemia-reperfusion (I/R causing germ cell-specific apoptosis. Previously, we demonstrated that the hypoxia-inducible factor-1 (HIF-1 transcription factor, a key regulator of physiological responses to hypoxia, is abundant in Leydig cells in normoxic and ischemic testes. We hypothesize that testicular HIF-1 activates the expression of antiapoptotic target genes to protect Leydig cells from apoptosis. In silico analysis of testis genes containing a consensus hypoxia response element (HRE, 5’-RCGTG-3’ identified myeloid cell leukemia-1 (Mcl-1 as a potential HIF-1 target gene. The purpose of this study was to determine whether HIF-1 shows DNA-binding activity in normoxic and ischemic testes and whether Mcl-1 is a target gene of testicular HIF-1. Methods The testicular HIF-1 DNA-binding capacity was analyzed in vitro using a quantitative enzyme-linked immunosorbent assay (ELISA and electrophoretic mobility shift assays (EMSA. MCL-1 protein expression was evaluated by immunoblot analysis and immunohistochemistry. The binding of testicular HIF-1 to the Mcl-1 gene was examined via chromatin immunoprecipitation (ChIP analysis. Results The ELISA and EMSA assays demonstrated that testicular HIF-1 from normoxic and ischemic testes binds DNA equally strongly, suggesting physiological roles for HIF-1 in the normoxic testis, unlike most tissues in which HIF-1 is degraded under normoxic conditions and is only activated by hypoxia. MCL-1 protein was determined to be abundant in both normoxic and ischemic testes and expressed in Leydig cells. In a pattern identical to that of HIF-1 expression, the steady-state levels of MCL-1 were not significantly affected by I or I/R and MCL-1 co-localized with HIF-1α in Leydig cells. Chromatin immunoprecipitation (ChIP analysis using a HIF-1 antibody revealed sequences enriched for the Mcl-1 promoter. Conclusions The results

  6. Risk Factors for Suicide Ideation Among Adolescents: Five-Year National Data Analysis.

    Science.gov (United States)

    Im, Yeojin; Oh, Won-Oak; Suk, Minhyun

    2017-06-01

    This study identified risk factors for suicide ideation among adolescents through a secondary analysis using data collected over five years from the 5th-9th Korea Youth Risk Behavior Survey. We analyzed 370,568 students' responses to questions about suicidality. The risk factors for suicide ideation included demographic characteristics, such as gender (girls), low grades, low economic status, and not living with one or both parents. Behavioral and mental health risk factors affecting suicide ideation were depression, low sleep satisfaction, high stress, alcohol consumption, smoking, and sexual activity. Health care providers should particularly target adolescents manifesting the above risk factors when developing suicide prevention programs for them. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Clinicopathological Analysis of Factors Related to Colorectal Tumor Perforation

    OpenAIRE

    Medina-Arana, Vicente; Martínez-Riera, Antonio; Delgado-Plasencia, Luciano; Rodríguez-González, Diana; Bravo-Gutiérrez, Alberto; Álvarez-Argüelles, Hugo; Alarcó-Hernández, Antonio; Salido-Ruiz, Eduardo; Fernández-Peralta, Antonia M.; González-Aguilera, Juan J.

    2015-01-01

    Abstract Colorectal tumor perforation is a life-threatening complication of this disease. However, little is known about the anatomopathological factors or pathophysiologic mechanisms involved. Pathological and immunohistochemical analysis of factors related with tumoral neo-angiogenesis, which could influence tumor perforation are assessed in this study. A retrospective study of patients with perforated colon tumors (Group P) and T4a nonperforated (controls) was conducted between 2001 and 20...

  8. Analysis of Key Factors Driving Japan’s Military Normalization

    Science.gov (United States)

    2017-09-01

    no change to our policy of not giving in to terrorism.”40 Though the prime minister was democratically supported, Koizumi’s leadership style took...of the key driving factors of Japan’s normalization. The areas of prime ministerial leadership , regional security threats, alliance issues, and...analysis of the key driving factors of Japan’s normalization. The areas of prime ministerial leadership , regional security threats, alliance issues, and

  9. Systematic analysis of neutron yields from thick targets bombarded by heavy ions and protons with moving source model

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Takashi; Kurosawa, Tadahiro; Nakamura, Takashi E-mail: nakamura@cyric.tohoku.ac.jp

    2002-03-21

    A simple phenomenological analysis using the moving source model has been performed on the neutron energy spectra produced by bombarding thick targets with high energy heavy ions which have been systematically measured at the Heavy-Ion Medical Accelerator (HIMAC) facility (located in Chiba, Japan) of the National Institute of Radiological Sciences (NIRS). For the bombardment of both heavy ions and protons in the energy region of 100-500 MeV per nucleon, the moving source model incorporating the knock-on process could be generally successful in reproducing the measured neutron spectra within a factor of two margin of accuracy. This phenomenological analytical equation is expressed having several parameters as functions of atomic number Z{sub p}, mass number A{sub p}, energy per nucleon E{sub p} for projectile, and atomic number Z{sub T}, mass number A{sub T} for target. By inputting these basic data for projectile and target into this equation we can easily estimate the secondary neutron energy spectra at an emission angle of 0-90 deg. for bombardment with heavy ions and protons in the aforementioned energy region. This method will be quite useful to estimate the neutron source term in the neutron shielding design of high energy proton and heavy ion accelerators.

  10. Factor analysis of the contextual fine motor questionnaire in children.

    Science.gov (United States)

    Lin, Chin-Kai; Meng, Ling-Fu; Yu, Ya-Wen; Chen, Che-Kuo; Li, Kuan-Hua

    2014-02-01

    Most studies treat fine motor as one subscale in a developmental test, hence, further factor analysis of fine motor has not been conducted. In fact, fine motor has been treated as a multi-dimensional domain from both clinical and theoretical perspectives, and therefore to know its factors would be valuable. The aim of this study is to analyze the internal consistency and factor validity of the Contextual Fine Motor Questionnaire (CFMQ). Based on the ecological observation and literature, the Contextual Fine Motor Questionnaire (CFMQ) was developed and includes 5 subscales: Pen Control, Tool Use During Handicraft Activities, the Use of Dining Utensils, Connecting and Separating during Dressing and Undressing, and Opening Containers. The main purpose of this study is to establish the factorial validity of the CFMQ through conducting this factor analysis study. Among 1208 questionnaires, 904 were successfully completed. Data from the children's CFMQ submitted by primary care providers was analyzed, including 485 females (53.6%) and 419 males (46.4%) from grades 1 to 5, ranging in age from 82 to 167 months (M=113.9, SD=16.3). Cronbach's alpha was used to measure internal consistency and explorative factor analysis was applied to test the five factor structures within the CFMQ. Results showed that Cronbach's alpha coefficient of the CFMQ for 5 subscales ranged from .77 to .92 and all item-total correlations with corresponding subscales were larger than .4 except one item. The factor loading of almost all items classified to their factor was larger than .5 except 3 items. There were five factors, explaining a total of 62.59% variance for the CFMQ. In conclusion, the remaining 24 items in the 5 subscales of the CFMQ had appropriate internal consistency, test-retest reliability and construct validity. Copyright © 2013 Elsevier Ltd. All rights reserved.

  11. Microinvasion of liver metastases from colorectal cancer: predictive factors and application for determining clinical target volume

    International Nuclear Information System (INIS)

    Qian, Yang; Zeng, Zhao-Chong; Ji, Yuan; Xiao, Yin-Ping

    2015-01-01

    This study evaluates the microscopic characteristics of liver metastases from colorectal cancer (LMCRC) invasion and provides a reference for expansion from gross tumor volume (GTV) to clinical targeting volume (CTV). Data from 129 LMCRC patients treated by surgical resection at our hospital between January 2008 and September 2009 were collected for study. Tissue sections used for pathology and clinical data were reviewed. Patient information used for the study included gender, age, original tumor site, number of tumors, tumor size, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 199 (CA199), synchronous or metachronous liver metastases, and whether patients received chemotherapy. The distance of liver microinvasion from the tumor boundary was measured microscopically by two senior pathologists. Of 129 patients evaluated, 81 (62.8 %) presented microinvasion distances from the tumor boundary ranging between 1.0 − 7.0 mm. A GTV-to-CTV expansion of 5, 6.7, or 7.0 mm was required to provide a 95, 99, or 100 % probability, respectively, of obtaining clear resection margins by microscopic observation. The extent of invasion was not related to gender, age, synchronous or metachronous liver metastases, tumor size, CA199 level, or chemotherapy. The extent of invasion was related to original tumor site, CEA level, and number of tumors. A scoring system was established based on the latter three positive predictors. Using this system, an invasion distance less than 3 mm was measured in 93.4 % of patients with a score of ≤1 point, but in only 85.7 % of patients with a score of ≤2 points. The extent of tumor invasion in our LMCRC patient cohort correlated with original tumor site, CEA level, and number of tumors. These positive predictors may potentially be used as a scoring system for determining GTV-to-CTV expansion

  12. Targeting modifiable risk factors in age-related macular degeneration in optometric practice in Sweden

    Directory of Open Access Journals (Sweden)

    Martin L

    2017-04-01

    patients. Targeted education and implementation strategies may be needed. Keywords: age-related macular degeneration, diet, smoking, nutritional supplements

  13. Using Factor Analysis to Identify Topic Preferences Within MBA Courses

    Directory of Open Access Journals (Sweden)

    Earl Chrysler

    2003-02-01

    Full Text Available This study demonstrates the role of a principal components factor analysis in conducting a gap analysis as to the desired characteristics of business alumni. Typically, gap analyses merely compare the emphases that should be given to areas of inquiry with perceptions of actual emphases. As a result, the focus is upon depth of coverage. A neglected area in need of investigation is the breadth of topic dimensions and their differences between the normative (should offer and the descriptive (actually offer. The implications of factor structures, as well as traditional gap analyses, are developed and discussed in the context of outcomes assessment.

  14. Molecular targeting of growth factor receptor-bound 2 (Grb2) as an anti-cancer strategy.

    Science.gov (United States)

    Dharmawardana, Pathirage G; Peruzzi, Benedetta; Giubellino, Alessio; Burke, Terrence R; Bottaro, Donald P

    2006-01-01

    Growth factor receptor-bound 2 (Grb2) is a ubiquitously expressed adapter protein that provides a critical link between cell surface growth factor receptors and the Ras signaling pathway. As such, it has been implicated in the oncogenesis of several important human malignancies. In addition to this function, research over the last decade has revealed other fundamental roles for Grb2 in cell motility and angiogenesis--processes that also contribute to tumor growth, invasiveness and metastasis. This functional profile makes Grb2 a high priority target for anti-cancer drug development. Knowledge of Grb2 protein structure, its component Src homology domains and their respective structure-function relationships has facilitated the rapid development of sophisticated drug candidates that can penetrate cells, bind Grb2 with high affinity and potently antagonize Grb2 signaling. These novel compounds offer considerable promise in our growing arsenal of rationally designed anti-cancer therapeutics.

  15. Analysis of IFR driver fuel hot channel factors

    International Nuclear Information System (INIS)

    Ku, J.Y.; Chang, L.K.; Mohr, D.

    1994-01-01

    Thermal-hydraulic uncertainty factors for Integral Fast Reactor (IFR) driver fuels have been determined based primarily on the database obtained from the predecessor fuels used in the IFR prototype, Experimental Breeder Reactor II. The uncertainty factors were applied to the channel factors (HCFs) analyses to obtain separate overall HCFs for fuel and cladding for steady-state analyses. A ''semistatistical horizontal method'' was used in the HCFs analyses. The uncertainty factor of the fuel thermal conductivity dominates the effects considered in the HCFs analysis; the uncertainty in fuel thermal conductivity will be reduced as more data are obtained to expand the currently limited database for the IFR ternary metal fuel (U-20Pu-10Zr). A set of uncertainty factors to be used for transient analyses has also been derived

  16. Interactive analysis of human error factors in NPP operation events

    International Nuclear Information System (INIS)

    Zhang Li; Zou Yanhua; Huang Weigang

    2010-01-01

    Interactive of human error factors in NPP operation events were introduced, and 645 WANO operation event reports from 1999 to 2008 were analyzed, among which 432 were found relative to human errors. After classifying these errors with the Root Causes or Causal Factors, and then applying SPSS for correlation analysis,we concluded: (1) Personnel work practices are restricted by many factors. Forming a good personnel work practices is a systematic work which need supports in many aspects. (2)Verbal communications,personnel work practices, man-machine interface and written procedures and documents play great roles. They are four interaction factors which often come in bundle. If some improvements need to be made on one of them,synchronous measures are also necessary for the others.(3) Management direction and decision process, which are related to management,have a significant interaction with personnel factors. (authors)

  17. Analysis of IFR driver fuel hot channel factors

    International Nuclear Information System (INIS)

    Ku, J.Y.; Chang, L.K.; Mohr, D.

    2004-01-01

    Thermal-hydraulic uncertainty factors for Integral Fast Reactor (IFR) driver fuels have been determined based primarily on the database obtained from the predecessor fuels used in the IFR prototype. Experimental Breeder Reactor II. The uncertainty factors were applied to the hot channel factors (HCFs) analyses to obtain separate overall HCFs for fuel and cladding for steady-state analyses. A 'semistatistical horizontal method' was used in the HCFs analyses. The uncertainty factor of the fuel thermal conductivity dominates the effects considered in the HCFs analysis; the uncertainty in fuel thermal conductivity will be reduced as more data are obtained to expand the currently limited database for the IFR ternary metal fuel (U-20Pu-10Zr). A set of uncertainty factors to be used for transient analyses has also been derived. (author)

  18. Confirmatory Factor Analysis of the Procrastination Assessment Scale for Students

    Directory of Open Access Journals (Sweden)

    Ronald D. Yockey

    2015-10-01

    Full Text Available The relative fit of one- and two-factor models of the Procrastination Assessment Scale for Students (PASS was investigated using confirmatory factor analysis on an ethnically diverse sample of 345 participants. The results indicated that although the two-factor model provided better fit to the data than the one-factor model, neither model provided optimal fit. However, a two-factor model which accounted for common item theme pairs used by Solomon and Rothblum in the creation of the scale provided good fit to the data. In addition, a significant difference by ethnicity was also found on the fear of failure subscale of the PASS, with Whites having significantly lower scores than Asian Americans or Latino/as. Implications of the results are discussed and recommendations made for future work with the scale.

  19. Two Expectation-Maximization Algorithms for Boolean Factor Analysis

    Czech Academy of Sciences Publication Activity Database

    Frolov, A. A.; Húsek, Dušan; Polyakov, P.Y.

    2014-01-01

    Roč. 130, 23 April (2014), s. 83-97 ISSN 0925-2312 R&D Projects: GA ČR GAP202/10/0262 Grant - others:GA MŠk(CZ) ED1.1.00/02.0070; GA MŠk(CZ) EE.2.3.20.0073 Program:ED Institutional research plan: CEZ:AV0Z10300504 Keywords : Boolean Factor analysis * Binary Matrix factorization * Neural networks * Binary data model * Dimension reduction * Bars problem Subject RIV: IN - Informatics, Computer Science Impact factor: 2.083, year: 2014

  20. Who uses apps in health promotion? A target group analysis of leaders.

    Science.gov (United States)

    Bregenzer, Anita; Wagner-Hartl, Verena; Jiménez, Paul

    2017-11-01

    User characteristics should be considered when designing features for e-health or m-health applications, as the developed solution should aim to support this specific target group. This study explores the effect of user characteristics (personality, health state, stress/recovery state, leadership behavior) on the interest and likelihood of using an app for health promotion activities at the workplace. Leaders are a key factor for the success of workplace health promotion; therefore, the target group of this study are leaders. The data of 412 leaders were collected in an online study. Hierarchical multiple linear regression analyses were conducted for four outcome criteria ("personal health," "contacting," "leadership feedback" and "corporate key figures"). The findings showed that neuroticism, physical health and health-promoting leadership were important predictors for using an app for monitoring personal health and getting in social contact about health issues. The stress/recovery state was significantly related to the feature of getting in social contact.

  1. Transcription factors as targets for improving Aspergillus niger as cell factory

    DEFF Research Database (Denmark)

    Poulsen, Lars; Bruno, K.S.; Thykær, Jette

    for gene knockout. The resulting mutants were first exposed to screening experiments including morphological studies and investigation of acid profile and protease activity. Among others an interesting finding was that one mutant had an oxalic acid overproducing phenotype (OOP). In the screening...... experiments the OOP mutant showed a 30 % (± 5%) increase in oxalic acid titer. The OOP mutant was further characterized in 2L scale bioreactors, and a 90 % (±30%) increase of the overall yield coefficient of oxalic acid on glucose was seen. Further data on the OOP mutant will be presented and results from......). In the present study the effect of modulation of transcription factors in Aspergillus niger, which is an industrially important micro-organism used in various processes including organic acid and enzyme production, was investigated. The strategy described in this work focuses on regulation connected to p...

  2. Variation in Veteran Identity as a Factor in Veteran-Targeted Interventions.

    Science.gov (United States)

    Hack, Samantha M; DeForge, Bruce R; Lucksted, Alicia

    2017-07-01

    The sociocultural identities that people self-assign or accept influence their interpersonal interactions and decision making. Identity-based interventions attempt to influence individuals by associating healthy behaviors with in-group membership. Outreach and educational efforts aimed at veterans may rely on "typical" veteran identity stereotypes. However, as discussed in this Open Forum, there is evidence that veteran identity is not monolithic but rather fluctuates on the basis of personal characteristics and individual military service experiences. Overall, the impact of veteran identity on veterans' health behaviors and use of health care is not known and has been understudied. A major limiting factor is the lack of a standardized measure of veteran identity that can assess variations in salience, prominence, and emotional valence.

  3. Workplace Innovation: Exploratory and Confirmatory Factor Analysis for Construct Validation

    Directory of Open Access Journals (Sweden)

    Wipulanusat Warit

    2017-06-01

    Full Text Available Workplace innovation enables the development and improvement of products, processes and services leading simultaneously to improvement in organisational performance. This study has the purpose of examining the factor structure of workplace innovation. Survey data, extracted from the 2014 APS employee census, comprising 3,125 engineering professionals in the Commonwealth of Australia’s departments were analysed using exploratory factor analysis (EFA and confirmatory factor analysis (CFA. EFA returned a two-factor structure explaining 69.1% of the variance of the construct. CFA revealed that a two-factor structure was indicated as a validated model (GFI = 0.98, AGFI = 0.95, RMSEA = 0.08, RMR = 0.02, IFI = 0.98, NFI = 0.98, CFI = 0.98, and TLI = 0.96. Both factors showed good reliability of the scale (Individual creativity: α = 0.83, CR = 0.86, and AVE = 0.62; Team Innovation: α = 0.82, CR = 0.88, and AVE = 0.61. These results confirm that the two factors extracted for characterising workplace innovation included individual creativity and team innovation.

  4. Ranking insurance firms using AHP and Factor Analysis

    Directory of Open Access Journals (Sweden)

    Mohammad Khodaei Valahzaghard

    2013-03-01

    Full Text Available Insurance industry includes a significant part of economy and it is important to learn more about the capabilities of different firms, which are active in this industry. In this paper, we present an empirical study to rank the insurance firms using analytical hierarchy process as well as factor analysis. The study considers four criteria including capital adequacy, quality of earning, quality of cash flow and quality of firms’ assets. The results of the implementation of factor analysis (FA have been verified using Kaiser-Meyer-Olkin (KMO=0.573 and Bartlett's Chi-Square (443.267 P-value=0.000 tests. According to the results FA, the first important factor, capital adequacy, represents 21.557% of total variance, the second factor, quality of income, represents 20.958% of total variance. In addition, the third factor, quality of cash flow, represents 19.417% of total variance and the last factor, quality of assets, represents 18.641% of total variance. The study has also used analytical hierarchy process (AHP to rank insurance firms. The results of our survey indicate that capital adequacy (0.559 is accounted as the most important factor followed by quality of income (0.235, quality of cash flow (0.144 and quality of assets (0.061. The results of AHP are consistent with the results of FA, which somewhat validates the overall study.

  5. Identification of MALT1 as both a prognostic factor and a potential therapeutic target of regorafenib in cholangiocarcinoma patients.

    Science.gov (United States)

    Yeh, Chun-Nan; Chang, Yu-Chan; Su, Yeu; Shin-Shian Hsu, Dennis; Cheng, Chi-Tung; Wu, Ren-Chin; Chung, Yi-Hsiu; Chiang, Kun-Chun; Yeh, Ta-Sen; Lu, Meng-Lun; Liu, Chun-Yu; Mu-Hsin Chang, Peter; Chen, Ming-Han; Huang, Chi-Ying F; Hsiao, Michael; Chen, Ming-Huang

    2017-12-26

    Intrahepatic cholangiocarcinoma (CCA) is an aggressive cancer that lacks an effective targeted therapy. Here, we assessed the therapeutic efficacy of regorafenib in CCA, as well as elucidated its underlying mechanism. We first demonstrated that regorafenib not only inhibited growth but also induced apoptosis in human CCA cells. Subsequently, we used in silico approaches to identify MALT1 (Mucosa-associated lymphoid tissue protein 1), which plays an important role in activating NF-κB, as a potential target of regorafenib. Overexpression of Elk-1, but not Ets-1, in HuCCT1 cells markedly reduced their sensitivity to regorafenib, which might be attributed to a significant increase in MALT1 levels. Our results further demonstrated that this drug drastically inhibited MALT1 expression by suppressing the Raf/Erk/Elk-1 pathway. The efficacy of regorafenib in decreasing in vivo CCA growth was confirmed in animal models. Regorafenib efficacy was observed in two MALT1-positive CCA patients who failed to respond to several other lines of therapy. Finally, MALT1 was also identified as an independent poor prognostic factor for patients with intrahepatic CCA. In conclusion, our study identified MALT1 to be a downstream mediator of the Raf/Erk/Elk-1 pathway and suggested that MALT1 may be a new therapeutic target for successful treatment of CCA by regorafenib.

  6. The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1.

    Science.gov (United States)

    Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

    2016-12-02

    Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. The transcription factor Prep1 controls hepatic insulin sensitivity and gluconeogenesis by targeting nuclear localization of FOXO1

    International Nuclear Information System (INIS)

    Kulebyakin, Konstantin; Penkov, Dmitry; Blasi, Francesco; Akopyan, Zhanna; Tkachuk, Vsevolod

    2016-01-01

    Liver plays a key role in controlling body carbohydrate homeostasis by switching between accumulation and production of glucose and this way maintaining constant level of glucose in blood. Increased blood glucose level triggers release of insulin from pancreatic β-cells. Insulin represses hepatic glucose production and increases glucose accumulation. Insulin resistance is the main cause of type 2 diabetes and hyperglycemia. Currently thiazolidinediones (TZDs) targeting transcriptional factor PPARγ are used as insulin sensitizers for treating patients with type 2 diabetes. However, TZDs are reported to be associated with cardiovascular and liver problems and stimulate obesity. Thus, it is necessary to search new approaches to improve insulin sensitivity. A promising candidate is transcriptional factor Prep1, as it was shown earlier it could affect insulin sensitivity in variety of insulin-sensitive tissues. The aim of the present study was to evaluate a possible involvement of transcriptional factor Prep1 in control of hepatic glucose accumulation and production. We created mice with liver-specific Prep1 knockout and discovered that hepatocytes derived from these mice are much more sensitive to insulin, comparing to their WT littermates. Incubation of these cells with 100 nM insulin results in almost complete inhibition of gluconeogenesis, while in WT cells this repression is only partial. However, Prep1 doesn't affect gluconeogenesis in the absence of insulin. Also, we observed that nuclear content of gluconeogenic transcription factor FOXO1 was greatly reduced in Prep1 knockout hepatocytes. These findings suggest that Prep1 may control hepatic insulin sensitivity by targeting FOXO1 nuclear stability. - Highlights: • A novel model of liver-specific Prep1 knockout is established. • Ablation of Prep1 in hepatocytes increases insulin sensitivity. • Prep1 controls hepatic insulin sensitivity by regulating localization of FOXO1. • Prep1 regulates

  8. A factor analysis to find critical success factors in retail brand

    Directory of Open Access Journals (Sweden)

    Naser Azad

    2013-03-01

    Full Text Available The present exploratory study aims to find critical components of retail brand among some retail stores. The study seeks to build a brand name in retail level and looks to find important factors affecting it. Customer behavior is largely influenced when the first retail customer experience is formed. These factors have direct impacts on customer experience and satisfaction in retail industry. The proposed study performs an empirical investigation on two well-known retain stores located in city of Tehran, Iran. Using a sample of 265 people from regular customers, the study uses factor analysis and extracts four main factors including related brand, product benefits, customer welfare strategy and corporate profits using the existing 31 factors in the literature.

  9. Ensemble Sensitivity Analysis of a Severe Downslope Windstorm in Complex Terrain: Implications for Forecast Predictability Scales and Targeted Observing Networks

    Science.gov (United States)

    2013-09-01

    observations, linear regression finds the straight line that explains the linear relationship of the sample. This line is given by the equation y = mx + b...SENSITIVITY ANALYSIS OF A SEVERE DOWNSLOPE WINDSTORM IN COMPLEX TERRAIN: IMPLICATIONS FOR FORECAST PREDICTABILITY SCALES AND TARGETED OBSERVING...SENSITIVITY ANALYSIS OF A SEVERE DOWNSLOPE WINDSTORM IN COMPLEX TERRAIN: IMPLICATIONS FOR FORECAST PREDICTABILITY SCALES AND TARGETED OBSERVING NETWORKS

  10. Md-miR156ab and Md-miR395 Target WRKY Transcription Factors to Influence Apple Resistance to Leaf Spot Disease.

    Science.gov (United States)

    Zhang, Qiulei; Li, Yang; Zhang, Yi; Wu, Chuanbao; Wang, Shengnan; Hao, Li; Wang, Shengyuan; Li, Tianzhong

    2017-01-01

    MicroRNAs (miRNAs) are key regulators of gene expression that post-transcriptionally regulate transcription factors involved in plant physiological activities. Little is known about the effects of miRNAs in disease resistance in apple ( Malus × domestica ). We globally profiled miRNAs in the apple cultivar Golden Delicious (GD) infected or not with the apple leaf spot fungus Alternaria alternaria f. sp. mali (ALT1), and identified 58 miRNAs that exhibited more than a 2-fold upregulation upon ALT1 infection. We identified a pair of miRNAs that target protein-coding genes involved in the defense response against fungal pathogens; Md-miR156ab targets a novel WRKY transcription factor, MdWRKYN1, which harbors a TIR and a WRKY domain. Md-miR395 targets another transcription factor, MdWRKY26, which contains two WRKY domains. Real-time PCR analysis showed that Md-miR156ab and Md-miR395 levels increased, while MdWRKYN1 and MdWRKY26 expression decreased in ALT1-inoculated GD leaves; furthermore, the overexpression of Md-miR156ab and Md-miR395 resulted in a significant reduction in MdWRKYN1 and MdWRKY26 expression. To investigate whether these miRNAs and their targets play a crucial role in plant defense, we overexpressed MdWRKYN1 or knocked down Md-miR156ab activity, which in both cases enhanced the disease resistance of the plants by upregulating the expression of the WRKY-regulated pathogenesis-related (PR) protein-encoding genes MdPR3-1, MdPR3-2, MdPR4, MdPR5, MdPR10-1 , and MdPR10-2 . In a similar analysis, we overexpressed MdWRKY26 or suppressed Md-miR395 activity, and found that many PR protein-encoding genes were also regulated by MdWRKY26 . In GD, ALT-induced Md-miR156ab and Md-miR395 suppress MdWRKYN1 and MdWRKY26 expression, thereby decreasing the expression of some PR genes, and resulting in susceptibility to ALT1.

  11. An analysis of possible off target effects following CAS9/CRISPR targeted deletions of neuropeptide gene enhancers from the mouse genome.

    Science.gov (United States)

    Hay, Elizabeth Anne; Khalaf, Abdulla Razak; Marini, Pietro; Brown, Andrew; Heath, Karyn; Sheppard, Darrin; MacKenzie, Alasdair

    2017-08-01

    We have successfully used comparative genomics to identify putative regulatory elements within the human genome that contribute to the tissue specific expression of neuropeptides such as galanin and receptors such as CB1. However, a previous inability to rapidly delete these elements from the mouse genome has prevented optimal assessment of their function in-vivo. This has been solved using CAS9/CRISPR genome editing technology which uses a bacterial endonuclease called CAS9 that, in combination with specifically designed guide RNA (gRNA) molecules, cuts specific regions of the mouse genome. However, reports of "off target" effects, whereby the CAS9 endonuclease is able to cut sites other than those targeted, limits the appeal of this technology. We used cytoplasmic microinjection of gRNA and CAS9 mRNA into 1-cell mouse embryos to rapidly generate enhancer knockout mouse lines. The current study describes our analysis of the genomes of these enhancer knockout lines to detect possible off-target effects. Bioinformatic analysis was used to identify the most likely putative off-target sites and to design PCR primers that would amplify these sequences from genomic DNA of founder enhancer deletion mouse lines. Amplified DNA was then sequenced and blasted against the mouse genome sequence to detect off-target effects. Using this approach we were unable to detect any evidence of off-target effects in the genomes of three founder lines using any of the four gRNAs used in the analysis. This study suggests that the problem of off-target effects in transgenic mice have been exaggerated and that CAS9/CRISPR represents a highly effective and accurate method of deleting putative neuropeptide gene enhancer sequences from the mouse genome. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Immune checkpoint inhibitors and targeted therapies for metastatic melanoma: A network meta-analysis.

    Science.gov (United States)

    Pasquali, Sandro; Chiarion-Sileni, Vanna; Rossi, Carlo Riccardo; Mocellin, Simone

    2017-03-01

    Immune checkpoint inhibitors and targeted therapies, two new class of drugs for treatment of metastatic melanoma, have not been compared in randomized controlled trials (RCT). We quantitatively summarized the evidence and compared immune and targeted therapies in terms of both efficacy and toxicity. A comprehensive search for RCTs of immune checkpoint inhibitors and targeted therapies was conducted to August 2016. Using a network meta-analysis approach, treatments were compared with each other and ranked based on their effectiveness (as measured by the impact on progression-free survival [PFS]) and acceptability (the inverse of high grade toxicity). Twelve RCTs enrolling 6207 patients were included. Network meta-analysis generated 15 comparisons. Combined BRAF and MEK inhibitors were associated with longer PFS as compared to anti-CTLA4 (HR: 0.22; 95% confidence interval [CI]: 0.12-0.41) and anti-PD1 antibodies alone (HR: 0.38; CI: 0.20-0.72). However, anti-PD1 monoclonal antibodies were less toxic than anti-CTLA4 monoclonal antibodies (RR: 0.65; CI: 0.40-0.78) and their combination significantly increased toxicity compared to either single agent anti-CTLA4 (RR: 2.06; CI: 1.45-2.93) or anti-PD1 monoclonal antibodies (RR: 3.67; CI: 2.27-5.96). Consistently, ranking analysis suggested that the combination of targeted therapies is the most effective strategy, whereas single agent anti-PD1 antibodies have the best acceptability. The GRADE level of evidence quality for these findings was moderate to low. The simultaneous inhibition of BRAF and MEK appears the most effective treatment for melanomas harboring BRAF V600 mutation, although anti-PD1 antibodies appear to be less toxic. Further research is needed to increase the quality of evidence. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Targeting Hypoxia-Inducible Factor 1α in a New Orthotopic Model of Glioblastoma Recapitulating the Hypoxic Tumor Microenvironment.

    Science.gov (United States)

    Nigim, Fares; Cavanaugh, Jill; Patel, Anoop P; Curry, William T; Esaki, Shin-ichi; Kasper, Ekkehard M; Chi, Andrew S; Louis, David N; Martuza, Robert L; Rabkin, Samuel D; Wakimoto, Hiroaki

    2015-07-01

    Tissue hypoxia and necrosis represent pathophysiologic and histologic hallmarks of glioblastoma (GBM). Although hypoxia inducible factor 1α (HIF-1α) plays crucial roles in the malignant phenotypes of GBM, developing HIF-1α-targeted agents has been hampered by the lack of a suitable preclinical model that recapitulates the complex biology of clinical GBM. We present a new GBM model, MGG123, which was established from a recurrent human GBM. Orthotopic xenografting of stem-like MGG123 cells reproducibly generated lethal tumors that were characterized by foci of palisading necrosis, hypervascularity, and robust stem cell marker expression. Perinecrotic neoplastic cells distinctively express HIF-1α and are proliferative in both xenografts and the patient tissue. The xenografts contain scattered hypoxic foci that were consistently greater than 50 μm distant from blood vessels, indicating intratumoral heterogeneity of oxygenation. Hypoxia enhanced HIF-1α expression in cultured MGG123 cells, which was abrogated by the HIF-1α inhibitors digoxin or ouabain. In vivo, treatment of orthotopic MGG123 xenografts with digoxin decreased HIF-1α expression, vascular endothelial growth factor mRNA levels, and CD34-positive vasculature within the tumors, and extended survival of mice bearing the aggressive MGG123 GBM. This preclinical tumor model faithfully recapitulates the GBM-relevant hypoxic microenvironment and stemness and is a suitable platform for studying disease biology and developing hypoxia-targeted agents.

  14. Critical analysis of the potential for therapeutic targeting of mammalian target of rapamycin (mTOR in gastric cancer

    Directory of Open Access Journals (Sweden)

    Inokuchi M

    2014-04-01

    Full Text Available Mikito Inokuchi,1 Keiji Kato,1 Kazuyuki Kojima,2 Kenichi Sugihara1 1Department of Surgical Oncology, 2Department of Minimally Invasive Surgery, Tokyo Medical and Dental University, Tokyo, Japan Abstract: Multidisciplinary treatment including chemotherapy has become the global standard of care for patients with metastatic gastric cancer (mGC; nonetheless, survival remains poor. Although many molecular-targeted therapies have been developed for various cancers, only anti-HER2 treatment has produced promising results in patients with mGC. Mammalian target of rapamycin (mTOR plays a key role in cell proliferation, antiapoptosis, and metastasis in signaling pathways from the tyrosine kinase receptor, and its activation has been demonstrated in gastric cancer (GC cells. This review discusses the clinical relevance of mTOR in GC and examines its potential as a therapeutic target in patients with mGC. Preclinical studies in animal models suggest that suppression of the mTOR pathway inhibits the proliferation of GC cells and delays tumor progression. The mTOR inhibitor everolimus has been evaluated as second- or third-line treatment in clinical trials. Adverse events were well tolerated although the effectiveness of everolimus alone was limited. Everolimus is now being evaluated in combination with chemotherapy in Phase III clinical studies in this subgroup of patients. Two Phase III studies include exploratory biomarker research designed to evaluate the predictive value of the expression or mutation of molecules related to the Akt/mTOR signaling pathway. These biomarker studies may lead to the realization of targeted therapy for selected patients with mGC in the future. Keywords: gastric cancer, mTOR, everolimus

  15. In-silico Metabolome Target Analysis Towards PanC-based Antimycobacterial Agent Discovery.

    Science.gov (United States)

    Khoshkholgh-Sima, Baharak; Sardari, Soroush; Izadi Mobarakeh, Jalal; Khavari-Nejad, Ramezan Ali

    2015-01-01

    Mycobacterium tuberculosis, the main cause of tuberculosis (TB), has still remained a global health crisis especially in developing countries. Tuberculosis treatment is a laborious and lengthy process with high risk of noncompliance, cytotoxicity adverse events and drug resistance in patient. Recently, there has been an alarming rise of drug resistant in TB. In this regard, it is an unmet need to develop novel antitubercular medicines that target new or more effective biochemical pathways to prevent drug resistant Mycobacterium. Integrated study of metabolic pathways through in-silico approach played a key role in antimycobacterial design process in this study. Our results suggest that pantothenate synthetase (PanC), anthranilate phosphoribosyl transferase (TrpD) and 3-isopropylmalate dehydratase (LeuD) might be appropriate drug targets. In the next step, in-silico ligand analysis was used for more detailed study of chemical tractability of targets. This was helpful to identify pantothenate synthetase (PanC, Rv3602c) as the best target for antimycobacterial design procedure. Virtual library screening on the best ligand of PanC was then performed for inhibitory ligand design. At the end, five chemical intermediates showed significant inhibition of Mycobacterium bovis with good selectivity indices (SI) ≥10 according to Tuberculosis Antimicrobial Acquisition & Coordinating Facility of US criteria for antimycobacterial screening programs.

  16. Identification of Cell Surface Targets through Meta-analysis of Microarray Data

    Directory of Open Access Journals (Sweden)

    Henry Haeberle

    2012-07-01

    Full Text Available High-resolution image guidance for resection of residual tumor cells would enable more precise and complete excision for more effective treatment of cancers, such as medulloblastoma, the most common pediatric brain cancer. Numerous studies have shown that brain tumor patient outcomes correlate with the precision of resection. To enable guided resection with molecular specificity and cellular resolution, molecular probes that effectively delineate brain tumor boundaries are essential. Therefore, we developed a bioinformatics approach to analyze micro-array datasets for the identification of transcripts that encode candidate cell surface biomarkers that are highly enriched in medulloblastoma. The results identified 380 genes with greater than a two-fold increase in the expression in the medulloblastoma compared with that in the normal cerebellum. To enrich for targets with accessibility for extracellular molecular probes, we further refined this list by filtering it with gene ontology to identify genes with protein localization on, or within, the plasma membrane. To validate this meta-analysis, the top 10 candidates were evaluated with immunohistochemistry. We identified two targets, fibrillin 2 and EphA3, which specifically stain medulloblastoma. These results demonstrate a novel bioinformatics approach that successfully identified cell surface and extracellular candidate markers enriched in medulloblastoma versus adjacent cerebellum. These two proteins are high-value targets for the development of tumor-specific probes in medulloblastoma. This bioinformatics method has broad utility for the identification of accessible molecular targets in a variety of cancers and will enable probe development for guided resection.

  17. Analysis on Target Detection and Classification in LTE Based Passive Forward Scattering Radar

    Directory of Open Access Journals (Sweden)

    Raja Syamsul Azmir Raja Abdullah

    2016-09-01

    Full Text Available The passive bistatic radar (PBR system can utilize the illuminator of opportunity to enhance radar capability. By utilizing the forward scattering technique and procedure into the specific mode of PBR can provide an improvement in target detection and classification. The system is known as passive Forward Scattering Radar (FSR. The passive FSR system can exploit the peculiar advantage of the enhancement in forward scatter radar cross section (FSRCS for target detection. Thus, the aim of this paper is to show the feasibility of passive FSR for moving target detection and classification by experimental analysis and results. The signal source is coming from the latest technology of 4G Long-Term Evolution (LTE base station. A detailed explanation on the passive FSR receiver circuit, the detection scheme and the classification algorithm are given. In addition, the proposed passive FSR circuit employs the self-mixing technique at the receiver; hence the synchronization signal from the transmitter is not required. The experimental results confirm the passive FSR system’s capability for ground target detection and classification. Furthermore, this paper illustrates the first classification result in the passive FSR system. The great potential in the passive FSR system provides a new research area in passive radar that can be used for diverse remote monitoring applications.

  18. Analysis on Target Detection and Classification in LTE Based Passive Forward Scattering Radar.

    Science.gov (United States)

    Raja Abdullah, Raja Syamsul Azmir; Abdul Aziz, Noor Hafizah; Abdul Rashid, Nur Emileen; Ahmad Salah, Asem; Hashim, Fazirulhisyam

    2016-09-29

    The passive bistatic radar (PBR) system can utilize the illuminator of opportunity to enhance radar capability. By utilizing the forward scattering technique and procedure into the specific mode of PBR can provide an improvement in target detection and classification. The system is known as passive Forward Scattering Radar (FSR). The passive FSR system can exploit the peculiar advantage of the enhancement in forward scatter radar cross section (FSRCS) for target detection. Thus, the aim of this paper is to show the feasibility of passive FSR for moving target detection and classification by experimental analysis and results. The signal source is coming from the latest technology of 4G Long-Term Evolution (LTE) base station. A detailed explanation on the passive FSR receiver circuit, the detection scheme and the classification algorithm are given. In addition, the proposed passive FSR circuit employs the self-mixing technique at the receiver; hence the synchronization signal from the transmitter is not required. The experimental results confirm the passive FSR system's capability for ground target detection and classification. Furthermore, this paper illustrates the first classification result in the passive FSR system. The great potential in the passive FSR system provides a new research area in passive radar that can be used for diverse remote monitoring applications.

  19. Expression analysis of miRNA and target mRNAs in esophageal cancer

    Energy Technology Data Exchange (ETDEWEB)

    Meng, X.R. [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China); Lu, P. [Gastrointestinal Surgery Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Mei, J.Z.; Liu, G.J. [Medical Oncology Department, People' s Hospital of Zhengzhou, Zhengzhou (China); Fan, Q.X. [Oncology Department, The First Affiliated Hospital of Zhengzhou University, Zhengzhou (China)

    2014-08-01

    We aimed to investigate miRNAs and related mRNAs through a network-based approach in order to learn the crucial role that they play in the biological processes of esophageal cancer. Esophageal squamous-cell carcinoma (ESCC) and adenocarcinoma (EAC)-related miRNA and gene expression data were downloaded from the Gene Expression Omnibus database, and differentially expressed miRNAs and genes were selected. Target genes of differentially expressed miRNAs were predicted and their regulatory networks were constructed. Differentially expressed miRNA analysis selected four miRNAs associated with EAC and ESCC, among which hsa-miR-21 and hsa-miR-202 were shared by both diseases. hsa-miR-202 was reported for the first time to be associated with esophageal cancer in the present study. Differentially expressed miRNA target genes were mainly involved in cancer-related and signal-transduction pathways. Functional categories of these target genes were related to transcriptional regulation. The results may indicate potential target miRNAs and genes for future investigations of esophageal cancer.

  20. Analysis and Visualization Tool for Targeted Amplicon Bisulfite Sequencing on Ion Torrent Sequencers.

    Directory of Open Access Journals (Sweden)

    Stephan Pabinger

    Full Text Available Targeted sequencing of PCR amplicons generated from bisulfite deaminated DNA is a flexible, cost-effective way to study methylation of a sample at single CpG resolution and perform subsequent multi-target, multi-sample comparisons. Currently, no platform specific protocol, support, or analysis solution is provided to perform targeted bisulfite sequencing on a Personal Genome Machine (PGM. Here, we present a novel tool, called TABSAT, for analyzing targeted bisulfite sequencing data generated on Ion Torrent sequencers. The workflow starts with raw sequencing data, performs quality assessment, and uses a tailored version of Bismark to map the reads to a reference genome. The pipeline visualizes results as lollipop plots and is able to deduce specific methylation-patterns present in a sample. The obtained profiles are then summarized and compared between samples. In order to assess the performance of the targeted bisulfite sequencing workflow, 48 samples were used to generate 53 different Bisulfite-Sequencing PCR amplicons from each sample, resulting in 2,544 amplicon targets. We obtained a mean coverage of 282X using 1,196,822 aligned reads. Next, we compared the sequencing results of these targets to the methylation level of the corresponding sites on an Illumina 450k methylation chip. The calculated average Pearson correlation coefficient of 0.91 confirms the sequencing results with one of the industry-leading CpG methylation platforms and shows that targeted amplicon bisulfite sequencing provides an accurate and cost-efficient method for DNA methylation studies, e.g., to provide platform-independent confirmation of Illumina Infinium 450k methylation data. TABSAT offers a novel way to analyze data generated by Ion Torrent instruments and can also be used with data from the Illumina MiSeq platform. It can be easily accessed via the Platomics platform, which offers a web-based graphical user interface along with sample and parameter storage

  1. Targeting Fibroblast Growth Factor 23 Signaling with Antibodies and Inhibitors, Is There a Rationale?

    Directory of Open Access Journals (Sweden)

    Seiji Fukumoto

    2018-02-01

    Full Text Available Fibroblast growth factor 23 (FGF23 is a phosphotropic hormone mainly produced by bone. FGF23 reduces serum phosphate by suppressing intestinal phosphate absorption through reducing 1,25-dihydroxyvitamin D and proximal tubular phosphate reabsorption. Excessive actions of FG23 result in several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemic rickets (XLH and tumor-induced osteomalacia. While neutral phosphate and active vitamin D are standard therapies for child patients with XLH, these medications have several limitations both in their effects and adverse events. Several approaches that inhibit FGF23 actions including anti-FGF23 antibodies and inhibitors of FGF signaling have been shown to improve phenotypes of model mice for FG23-related hypophosphatemic diseases. In addition, clinical trials indicated that a humanized anti-FGF23 antibody increased serum phosphate and improved quality of life in patients with XLH. Furthermore, circulatory FGF23 is high in patients with chronic kidney disease (CKD. Many epidemiological studies indicated the association between high FGF23 levels and various adverse events especially in patients with CKD. However, it is not known whether the inhibition of FGF23 activities in patients with CKD is beneficial for these patients. In this review, recent findings concerning the modulation of FGF23 activities are discussed.

  2. Targeted selected reaction monitoring mass spectrometric immunoassay for insulin-like growth factor 1.

    Directory of Open Access Journals (Sweden)

    Eric E Niederkofler

    Full Text Available Insulin-like growth factor 1 (IGF1 is an important biomarker of human growth disorders that is routinely analyzed in clinical laboratories. Mass spectrometry-based workflows offer a viable alternative to standard IGF1 immunoassays, which utilize various pre-analytical preparation strategies. In this work we developed an assay that incorporates a novel sample preparation method for dissociating IGF1 from its binding proteins. The workflow also includes an immunoaffinity step using antibody-derivatized pipette tips, followed by elution, trypsin digestion, and LC-MS/MS separation and detection of the signature peptides in a selected reaction monitoring (SRM mode. The resulting quantitative mass spectrometric immunoassay (MSIA exhibited good linearity in the range of 1 to 1,500 ng/mL IGF1, intra- and inter-assay precision with CVs of less than 10%, and lowest limits of detection of 1 ng/mL. The linearity and recovery characteristics of the assay were also established, and the new method compared to a commercially available immunoassay using a large cohort of human serum samples. The IGF1 SRM MSIA is well suited for use in clinical laboratories.

  3. Reg IV is a direct target of intestinal transcriptional factor CDX2 in gastric cancer.

    Directory of Open Access Journals (Sweden)

    Yutaka Naito

    Full Text Available REG4, which encodes Reg IV protein, is a member of the calcium-dependent lectin superfamily and potent activator of the epidermal growth factor receptor/Akt/activator protein-1 signaling pathway. Several human cancers overexpress Reg IV, and Reg IV expression is associated with intestinal phenotype differentiation. However, regulation of REG4 transcription remains unclear. In the present study, we investigated whether CDX2 regulates Reg IV expression in gastric cancer (GC cells. Expression of Reg IV and CDX2 was analyzed by Western blot and quantitative reverse transcription-polymerase chain reaction in 9 GC cell lines and 2 colon cancer cell lines. The function of the 5'-flanking region of the REG4 gene was characterized by luciferase assay. In 9 GC cell lines, endogenous Reg IV and CDX2 expression were well correlated. Using an estrogen receptor-regulated form of CDX2, rapid induction of Reg IV expression was observed in HT-29 cells. Reporter gene assays revealed an important role in transcription for consensus CDX2 DNA binding elements in the 5'-flanking region of the REG4 gene. Chromatin immunoprecipitation assays showed that CDX2 binds directly to the 5'-flanking region of REG4. These results indicate that CDX2 protein directly regulates Reg IV expression.

  4. Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

    Directory of Open Access Journals (Sweden)

    Nadia Belmellat

    2017-11-01

    Full Text Available Tumor necrosis factor-alpha (TNF-α blockade is an effective treatment for rheumatoid arthritis (RA and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept.

  5. Familial risk factors in social anxiety disorder: calling for a family-oriented approach for targeted prevention and early intervention.

    Science.gov (United States)

    Knappe, Susanne; Beesdo-Baum, Katja; Wittchen, Hans-Ulrich

    2010-12-01

    Within the last decade, social anxiety disorder (SAD) has been identified as a highly prevalent and burdensome disorder. Both the characterization of its symptomatology and effective treatment options are widely documented. Studies particularly indicate that SAD aggregates in families and has its onset in early adolescence. Given the family as an important context for children's cognitive, emotional and behavioural development, familial risk factors could be expected to significantly contribute to the reliable detection of populations at risk for SAD. Reviewing studies on familial risk factors for SAD argues for the importance of parental psychopathology and unfavourable family environment, but also denotes to several shortcomings such as cross-sectional designs, short follow-up periods, diverging methodologies and the focus on isolated factors. Using a prospective longitudinal study that covers the high-risk period for SAD, including a broader spectrum of putative risk factors may help to overcome many of the methodological limitations. This review sets out to develop a more family-oriented approach for predicting the onset and maintenance of SAD that may be fruitful to derive targeted prevention and early intervention in SAD.

  6. Cancer risk factors in Korean news media: a content analysis.

    Science.gov (United States)

    Kye, Su Yeon; Kwon, Jeong Hyun; Kim, Yong-Chan; Shim, Minsun; Kim, Jee Hyun; Cho, Hyunsoon; Jung, Kyu Won; Park, Keeho

    2015-01-01

    Little is known about the news coverage of cancer risk factors in Korea. This study aimed to examine how the news media encompasses a wide array of content regarding cancer risk factors and related cancer sites, and investigate whether news coverage of cancer risk factors is congruent with the actual prevalence of the disease. A content analysis was conducted on 1,138 news stories covered during a 5-year period between 2008 and 2012. The news stories were selected from nationally representative media in Korea. Information was collected about cancer risk factors and cancer sites. Of various cancer risk factors, occupational and environmental exposures appeared most frequently in the news. Breast cancer was mentioned the most in relation to cancer sites. Breast, cervical, prostate, and skin cancer were overrepresented in the media in comparison to incidence and mortality cases, whereas lung, thyroid, liver, and stomach cancer were underrepresented. To our knowledge, this research is the first investigation dealing with news coverage about cancer risk factors in Korea. The study findings show occupational and environmental exposures are emphasized more than personal lifestyle factors; further, more prevalent cancers in developed countries have greater media coverage, not reflecting the realities of the disease. The findings may help health journalists and other health storytellers to develop effective ways to communicate cancer risk factors.

  7. Landslides geotechnical analysis. Qualitative assessment by valuation factors

    Science.gov (United States)

    Cuanalo Oscar, Sc D.; Oliva Aldo, Sc D.; Polanco Gabriel, M. E.

    2012-04-01

    In general, a landslide can cause a disaster when it is combined a number of factors such as an extreme event related to a geological phenomenon, vulnerable elements exposed in a specific geographic area, and the probability of loss and damage evaluated in terms of lives and economic assets, in a certain period of time. This paper presents the qualitative evaluation of slope stability through of Valuation