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Sample records for proinflammatory profile predicts

  1. Gene array analysis of PD-1H overexpressing monocytes reveals a pro-inflammatory profile

    Directory of Open Access Journals (Sweden)

    Preeti Bharaj

    2018-02-01

    Full Text Available We have previously reported that overexpression of Programmed Death -1 Homolog (PD-1H in human monocytes leads to activation and spontaneous secretion of multiple pro inflammatory cytokines. Here we evaluate changes in monocytes gene expression after enforced PD-1H expression by gene array. The results show that there are significant alterations in 51 potential candidate genes that relate to immune response, cell adhesion and metabolism. Genes corresponding to pro-inflammatory cytokines showed the highest upregulation, 7, 3.2, 3.0, 5.8, 4.4 and 3.1 fold upregulation of TNF-α, IL-1 β, IFN-α, γ, λ and IL-27 relative to vector control. The data are in agreement with cytometric bead array analysis showing induction of proinflammatory cytokines, IL-6, IL-1β and TNF-α by PD-1H. Other genes related to inflammation, include transglutaminase 2 (TG2, NF-κB (p65 and p50 and toll like receptors (TLR 3 and 4 were upregulated 5, 4.5 and 2.5 fold, respectively. Gene set enrichment analysis (GSEA also revealed that signaling pathways related to inflammatory response, such as NFκB, AT1R, PYK2, MAPK, RELA, TNFR1, MTOR and proteasomal degradation, were significantly upregulated in response to PD-1H overexpression. We validated the results utilizing a standard inflammatory sepsis model in humanized BLT mice, finding that PD-1H expression was highly correlated with proinflammatory cytokine production. We therefore conclude that PD-1H functions to enhance monocyte activation and the induction of a pro-inflammatory gene expression profile.

  2. Identification of informative features for predicting proinflammatory potentials of engine exhausts.

    Science.gov (United States)

    Wang, Chia-Chi; Lin, Ying-Chi; Lin, Yuan-Chung; Jhang, Syu-Ruei; Tung, Chun-Wei

    2017-08-18

    The immunotoxicity of engine exhausts is of high concern to human health due to the increasing prevalence of immune-related diseases. However, the evaluation of immunotoxicity of engine exhausts is currently based on expensive and time-consuming experiments. It is desirable to develop efficient methods for immunotoxicity assessment. To accelerate the development of safe alternative fuels, this study proposed a computational method for identifying informative features for predicting proinflammatory potentials of engine exhausts. A principal component regression (PCR) algorithm was applied to develop prediction models. The informative features were identified by a sequential backward feature elimination (SBFE) algorithm. A total of 19 informative chemical and biological features were successfully identified by SBFE algorithm. The informative features were utilized to develop a computational method named FS-CBM for predicting proinflammatory potentials of engine exhausts. FS-CBM model achieved a high performance with correlation coefficient values of 0.997 and 0.943 obtained from training and independent test sets, respectively. The FS-CBM model was developed for predicting proinflammatory potentials of engine exhausts with a large improvement on prediction performance compared with our previous CBM model. The proposed method could be further applied to construct models for bioactivities of mixtures.

  3. A predictable Java profile

    DEFF Research Database (Denmark)

    Bøgholm, Thomas; Hansen, Rene Rydhof; Ravn, Anders Peter

    2009-01-01

    A Java profile suitable for development of high integrity embedded systems is presented. It is based on event handlers which are grouped in missions and equipped with respectively private handler memory and shared mission memory. This is a result of our previous work on developing a Java profile......, and is directly inspired by interactions with the Open Group on their on-going work on a safety critical Java profile (JSR-302). The main contribution is an arrangement of the class hierarchy such that the proposal is a generalization of Real-Time Specification for Java (RTSJ). A further contribution...

  4. Adherent Human Alveolar Macrophages Exhibit a Transient Pro-Inflammatory Profile That Confounds Responses to Innate Immune Stimulation

    Science.gov (United States)

    Tomlinson, Gillian S.; Booth, Helen; Petit, Sarah J.; Potton, Elspeth; Towers, Greg J.; Miller, Robert F.; Chain, Benjamin M.; Noursadeghi, Mahdad

    2012-01-01

    Alveolar macrophages (AM) are thought to have a key role in the immunopathogenesis of respiratory diseases. We sought to test the hypothesis that human AM exhibit an anti-inflammatory bias by making genome-wide comparisons with monocyte derived macrophages (MDM). Adherent AM obtained by bronchoalveolar lavage of patients under investigation for haemoptysis, but found to have no respiratory pathology, were compared to MDM from healthy volunteers by whole genome transcriptional profiling before and after innate immune stimulation. We found that freshly isolated AM exhibited a marked pro-inflammatory transcriptional signature. High levels of basal pro-inflammatory gene expression gave the impression of attenuated responses to lipopolysaccharide (LPS) and the RNA analogue, poly IC, but in rested cells pro-inflammatory gene expression declined and transcriptional responsiveness to these stimuli was restored. In comparison to MDM, both freshly isolated and rested AM showed upregulation of MHC class II molecules. In most experimental paradigms ex vivo adherent AM are used immediately after isolation. Therefore, the confounding effects of their pro-inflammatory profile at baseline need careful consideration. Moreover, despite the prevailing view that AM have an anti-inflammatory bias, our data clearly show that they can adopt a striking pro-inflammatory phenotype, and may have greater capacity for presentation of exogenous antigens than MDM. PMID:22768282

  5. Pro-inflammatory fatty acid profile and colorectal cancer risk: A Mendelian randomisation analysis.

    Science.gov (United States)

    May-Wilson, Sebastian; Sud, Amit; Law, Philip J; Palin, Kimmo; Tuupanen, Sari; Gylfe, Alexandra; Hänninen, Ulrika A; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Sarin, Antti-Pekka; Eriksson, Johan G; Rissanen, Harri; Knekt, Paul; Pukkala, Eero; Jousilahti, Pekka; Salomaa, Veikko; Ripatti, Samuli; Palotie, Aarno; Renkonen-Sinisalo, Laura; Lepistö, Anna; Böhm, Jan; Mecklin, Jukka-Pekka; Al-Tassan, Nada A; Palles, Claire; Farrington, Susan M; Timofeeva, Maria N; Meyer, Brian F; Wakil, Salma M; Campbell, Harry; Smith, Christopher G; Idziaszczyk, Shelley; Maughan, Timothy S; Fisher, David; Kerr, Rachel; Kerr, David; Passarelli, Michael N; Figueiredo, Jane C; Buchanan, Daniel D; Win, Aung K; Hopper, John L; Jenkins, Mark A; Lindor, Noralane M; Newcomb, Polly A; Gallinger, Steven; Conti, David; Schumacher, Fred; Casey, Graham; Aaltonen, Lauri A; Cheadle, Jeremy P; Tomlinson, Ian P; Dunlop, Malcolm G; Houlston, Richard S

    2017-10-01

    While dietary fat has been established as a risk factor for colorectal cancer (CRC), associations between fatty acids (FAs) and CRC have been inconsistent. Using Mendelian randomisation (MR), we sought to evaluate associations between polyunsaturated (PUFA), monounsaturated (MUFA) and saturated FAs (SFAs) and CRC risk. We analysed genotype data on 9254 CRC cases and 18,386 controls of European ancestry. Externally weighted polygenic risk scores were generated and used to evaluate associations with CRC per one standard deviation increase in genetically defined plasma FA levels. Risk reduction was observed for oleic and palmitoleic MUFAs (OR OA  = 0.77, 95% CI: 0.65-0.92, P = 3.9 × 10 -3 ; OR POA  = 0.36, 95% CI: 0.15-0.84, P = 0.018). PUFAs linoleic and arachidonic acid had negative and positive associations with CRC respectively (OR LA  = 0.95, 95% CI: 0.93-0.98, P = 3.7 × 10 -4 ; OR AA  = 1.05, 95% CI: 1.02-1.07, P = 1.7 × 10 -4 ). The SFA stearic acid was associated with increased CRC risk (OR SA  = 1.17, 95% CI: 1.01-1.35, P = 0.041). Results from our analysis are broadly consistent with a pro-inflammatory FA profile having a detrimental effect in terms of CRC risk. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  6. Systemic and intraperitoneal proinflammatory cytokines profiles in patients on chronic peritoneal dialysis.

    Science.gov (United States)

    Maksić, Doko; Colić, Miodrag; Stanković-Popović, Verica; Radojević, Milorad; Bokonjić, Dubravko

    2007-01-01

    Cytokines are essential mediators of immune response and inflammatory reactions. Patients with chronic renal failure and on Continuous Ambulatory Peritoneal Dialysis commonly present abnormalities of immune function related to impaired kidney function, accumulation of uremic toxins and bioincompatibility of peritoneal dialysis solutions. Aim of this study was to examine effects of the CAPD solutions (standard v.s. biocompatible), as well as dialysis duration upon the local and systemic profile of the pro-inflammatory cytokines (IL-1, TNF and IL-6) in patients on CAPD. The cross-sectional study included 44 CAPD patients (27 M and 17 F, average mean age 57.12+/-16.66), of whom 21 patients were on the standard solutions (A.N.D.Y.Disc) for peritoneal dialysis and 23 on the biocompatible solutions (Gambrosol bio trio, Stay Safe balance). The average dialysis treatment period was 3.59+/-2.67 years. In all CAPD patients dialysed longer than 6 months, levels of IL-1. TNF and IL-6 in the serum and dialysis effluent were analysed in the phase without acute infection-related complications (CAPD peritonitis, infection of the catheter exit-site, other acute infections). The control group included 20 patients with the CRF (stage IV and V) whose serum levels of the examined cytokines were also determined. Levels of the inflammatory cytokines were measured by commercial specific ELISA kits (BioSource, Camarillo, California, USA). Statistical analysis of the obtained results was performed by commercial statistics PC software (Stat for Windows, R.4.5. SAD). The serum IL-1 and IL-6 levels were not statistically significantly different in patients on CAPD, irrespective of the type of the used dialysis solutions and in the control group of patients with CRF. The serum TNF levels, unlike IL-1 and IL-6, were statistically significantly higher in patients on CAPD in comparison with the control group of patients (13.203.23 v.s. 5.594.54, prenal funcion and number of CAPD peritonitis did

  7. Pro-inflammatory cytokine profile in dairy cows: consequences for new lactation

    Directory of Open Access Journals (Sweden)

    Erminio Trevisi

    2015-07-01

    Full Text Available To verify the potential relevance of proinflammatory cytokine (PIC with periparturient health problems and performances, the changes of plasma interleukin-1beta (IL-1β and interleukin-6 (IL-6 have been investigated in 21 Holstein-Friesian cows from 35 d before to 28 d after parturition. The overall PIC concentration was higher during late pregnancy compared to the first month of lactation, but showed a high variability among the cows. Therefore, cows were retrospectively divided in 3 groups according to the values of area under the concentration curve of IL- 1β concentrations from -35 d before to the day of parturition and designated as up (UPIL1, intermediate (INIL1 and low (LOIL1 IL-1β group. The concentrations of IL-6 and to some extent the concentrations of albumin and reactive oxygen metabolites (ROMs were well related to the grouping based on IL-1β concentrations. After calving the UPIL1 cows showed a more severe acute phase reaction (APR, based on the marked increase of haptoglobin and the lower plasma albumin concentrations during the first week of lactation, and the highest oxidative stress, based on the higher concentrations of ROMs. Moreover, the UPIL1 group showed higher number of mastitis, lower feed intake and milk yield compared with INIL1 and LOIL1. Our results demonstrated that cows with the highest PIC concentrations in the last month of pregnancy showed the worse health status in early lactation (clinical and subclinical problems and a lower milk yield. Thus, these data support the utility of PIC measurement in late pregnancy as prognostic markers for a risky transition period.

  8. Lack of pro-inflammatory cytokine mobilization predicts poor prognosis in patients with acute heart failure.

    Science.gov (United States)

    Vistnes, M; Høiseth, A D; Røsjø, H; Nygård, S; Pettersen, E; Søyseth, V; Hurlen, P; Christensen, G; Omland, T

    2013-03-01

    The aim of this study was to gain insight in the inflammatory response in acute heart failure (AHF) by assessing (1) plasma cytokine profiles and (2) prognostic value of circulating cytokines in AHF patients. Plasma levels of 26 cytokines were quantified by multiplex protein arrays in 36 patients with congestive AHF, characterized by echocardiographic, radiologic, and clinical examinations on admission, during hospitalization and at discharge. Recurrent AHF leading to death or readmission constituted the combined end point, and all patients were followed for 120 days after discharge. Levels of 15 of the measured cytokines were higher in AHF than in healthy subjects (n=22) on admission. Low levels of MCP-1, IL-1β and a low IL-1β/IL-1ra ratio predicted fatal and non-fatal AHF within 120 days. Patients with low circulating levels of IL-1β had lower left ventricular ejection fraction and higher levels of N-terminal pro-B-type natriuretic peptide, while patients with low levels of MCP-1 had higher E/E' and inferior caval vein diameter, than patients with high levels. Immune activation, reflected in increased cytokine levels, is present in AHF patients. Interestingly, failure to increase secretion of IL-1β and MCP-1 during AHF is associated with poor outcome. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Pro-inflammatory genetic profile and familiarity of acute myocardial infarction

    Directory of Open Access Journals (Sweden)

    Ianni Manuela

    2012-06-01

    for cardiovascular diseases. This inflammatory genetic profile, along with classical cardiovascular risk factors, may be used for better defining individual risk of AMI in unaffected subjects.

  10. Procalcitonin and proinflammatory parameters in diabetic foot infection as new predictive factor

    Science.gov (United States)

    Raheem, Shler Gh.; Al-Barzinji, Ruqaya M.; Mansoor, Husham Y.; Al-Dabbagh, Ali A.

    2017-09-01

    Diabetic foot is a common complication of diabetes due to changes in blood vessels and nerves, often leads to ulceration and subsequent limb amputation if not treated early. A new diagnostic marker of bacterial infections is procalcitonin. C-reactive protein, Interleukin1β, Interleukin-6 and tumor necrosis factor-α as proinflammatory parameters increased in Diabetic foot infection. We evaluated above parameters in patients with diabetic foot infections in different grades. A total of 130 diabetic patients were enrolled in this case control study between June 2011 and March 2012 in Rizgary, Emergency and Hawler Teaching Hospitals, 90 of them with diabetic foot lesion as a patient group. 40 without foot lesion, as a patient control and 20 individuals as healthy control. Assessment of above parameters in sera of study groups and also bacteriological tests (bacterial isolation and identification) were done. Serum procalcitonin levels significantly increased in patients with diabetic foot with higher Wagner grades (III, IV and V) (0.28 ± 0.04, 0.30 ± 0.07 and 0.60 ± 0.11) respectively (Pfoot ulcer based on Wagner classification system was also associated with circulating levels of C-reactive protein, Interleukin1β, Interleukin-6 and tumor necrosis factor-α (G III, IV and V) (5.36 ± 0.70, 6.38 ± 0.65, and 9.13 ± 0.88), (1.21 ± 0.08, 1.56 ± 0.16 and 2.02 ± 0.07), (23.02 ± 2.98, 36.32 ± 5.75 and 43.36 ± 6.16), and (215.39 ± 16.8, 259.21 ± 40.7 and 398.45 ± 33.4) respectively (Pdiabetic foot patients may be a procalcitonin especially in those with higher Wagner grades and with polymicrobial infection.

  11. Genetic priming of a proinflammatory profile predicts low IQ in octogenarians

    DEFF Research Database (Denmark)

    Krabbe, K. S.; Mortensen, E. L.; Avlund, K.

    2009-01-01

    The purpose of the study was to test the hypothesis that single nucleotide polymorphisms (SNPs) within interleukin (IL)-18, TNF-alpha, IL-6 and IL-10 gene promoter regions are risk factors for cognitive decline in healthy octogenarians, and to isolate the strongest inflammatory biomarkers...... of cognitive function in the peripheral blood. The Wechsler Adult Intelligence Scale was administered to 112 individuals at ages 80 and 85. An IL-18 haplotype was an independent risk factor of poor Performance IQ. The TNF-308GA genotype was related to individual declines in Verbal IQ, and the IL-10-592 CC...

  12. Predictive profiling and its legal limits : Effectiveness gone forever

    NARCIS (Netherlands)

    Lammerant, Hans; de Hert, Paul; van der Sloot, B.; Broeders, D.; Schrijvers, E.

    2016-01-01

    We examine predictive group profiling in the Big Data context as an instrument of governmental control and regulation. We first define profiling by drawing some useful distinctions (section 6.1). We then discuss examples of predictive group profiling from policing (such as parole prediction methods

  13. Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota.

    Science.gov (United States)

    Larsen, Jeppe Madura; Steen-Jensen, Daniel Bisgaard; Laursen, Janne Marie; Søndergaard, Jonas Nørskov; Musavian, Hanieh Sadat; Butt, Tariq Mahmood; Brix, Susanne

    2012-01-01

    Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella spp.), healthy lungs (commensal Prevotella spp.) or both (commensal Veillonella spp. and Actinomyces spp.). All bacteria were found to induce activation of DCs as demonstrated by similar induction of CD83, CD40 and CD86 surface expression. However, asthma and COPD-associated pathogenic bacteria provoked a 3-5 fold higher production of IL-23, IL-12p70 and IL-10 cytokines compared to the commensal bacteria. Based on the differential cytokine production profiles, the studied airway bacteria could be segregated into three groups (Haemophilus spp. and Moraxella spp. vs. Prevotella spp. and Veillonella spp. vs. Actinomyces spp.) reflecting their pro-inflammatory effects on DCs. Co-culture experiments found that Prevotella spp. were able to reduce Haemophillus influenzae-induced IL-12p70 in DCs, whereas no effect was observed on IL-23 and IL-10 production. This study demonstrates intrinsic differences in DC stimulating properties of bacteria associated with the airway microbiota.

  14. Pro-Inflammatory Cytokines Predict Relapse-Free Survival after One Month of Interferon-α but Not Observation in Intermediate Risk Melanoma Patients.

    Directory of Open Access Journals (Sweden)

    Ahmad A Tarhini

    Full Text Available E1697 was a phase III trial of adjuvant interferon (IFN-α2b for one month (Arm B versus observation (Arm A in patients with resected melanoma at intermediate risk. We evaluated the levels of candidate serum cytokines, the HLA genotype, polymorphisms of CTLA4 and FOXP3 genes and the development of autoantibodies for their association with relapse free survival (RFS in Arm A and Arm B among 268 patients with banked biospecimens.ELISA was used to test 5 autoantibodies. Luminex/One Lambda LABTypeRSSO was used for HLA Genotyping. Selected CTLA4 and FOXP3 Single nucleotide polymorphisms (SNPs and microsatellites were tested for by polymerase chain reaction (PCR. Sixteen serum cytokines were tested at baseline and one month by Luminex xMAP multiplex technology. Cox Proportional Hazards model was applied and the Wald test was used to test the marginal association of each individual marker and RFS. We used the Lasso approach to select the markers to be included in a multi-marker Cox Proportional Hazards model. The ability of the resulting models to predict one year RFS was evaluated by the time-dependent ROC curve. The leave-one-out method of cross validation (LOOCV was used to avoid over-fitting of the data.In the multi-marker modeling analysis conducted in Arm B, one month serum IL2Rα, IL-12p40 and IFNα levels predicted one year RFS with LOOCV AUC = 82%. Among the three markers selected, IL2Rα and IFNα were the most stable (selected in all the cross validation cycles. The risk score (linear combination of the 3 markers separated the RFS curves of low and high risk groups well (p = 0.05. This model did not hold for Arm A, indicating a differential marker profile in Arm B linked to the intervention (adjuvant therapy.Early on-treatment proinflammatory serum markers (IL2Rα, IL-12p40, IFNα significantly predict RFS in our cohort of patients treated with adjuvant IFN-α2b and warrant further study.

  15. Slurry discharge management-beach profile prediction

    Energy Technology Data Exchange (ETDEWEB)

    Bravo, R.; Nawrot, J.R. [Southern Illinois University at Carbondale, Carbondale, IL (United States). Dept. of Civil Engineering

    1996-11-01

    Mine tailings dams are embankments used by the mining industry to retain the tailings products after the mineral preparation process. Based on the acid-waste stereotype that all coal slurry is acid producing, current reclamation requires a four foot soil cover for inactive slurry disposal areas. Compliance with this requirement is both difficult and costly and in some case unnecessary, as not all the slurry, or portions of slurry impoundments are acid producing. Reduced costs and recent popularity of wetland development has prompted many operators to request reclamation variances for slurry impoundments. Waiting to address slurry reclamation until after the impoundment is full, limits the flexibility of reclamation opportunities. This paper outlines a general methodology to predict the formation of the beach profile for mine tailings dams, by the discharge volume and location of the slurry into the impoundment. The review is presented under the perspective of geotechnical engineering and waste disposal management emphasizing the importance of pre-planning slurry disposal land reclamation. 4 refs., 5 figs.

  16. A predictable Java profile - rationale and implementations

    DEFF Research Database (Denmark)

    Søndergaard, Hans; Bøgholm, Thomas; Hansen, Rene Rydhof

    A Java profile suitable for development of high integrity embedded systems is presented. It is based on event handlers which are grouped in missions and equipped with respectively private handler memory and shared mission memory. This is a result of our previous work on developing a Java profile......, and is directly inspired by interactions with the Open Group on their on-going work on a safety critical Java profile (JSR-302). The main contribution is an arrangement of the class hierarchy such that the proposal is a generalization of Real-Time Specification for Java (RTSJ). A further contribution...

  17. Red wine intake but not other alcoholic beverages increases total antioxidant capacity and improves pro-inflammatory profile after an oral fat diet in healthy volunteers.

    Science.gov (United States)

    Torres, A; Cachofeiro, V; Millán, J; Lahera, V; Nieto, M L; Martín, R; Bello, E; Alvarez-Sala, L A

    2015-12-01

    Different alcoholic beverages exert different effects on inflammation and oxidative stress but these results are controversial and scanty in some aspects. We analyze the effect of different alcoholic beverages after a fat-enriched diet on lipid profile, inflammatory factors and oxidative stress in healthy people in a controlled environment. We have performed a cross-over design in five different weeks. Sixteen healthy volunteers have received the same oral fat-enriched diet (1486kcal/m(2)) and a daily total amount of 16g/m(2) of alcohol, of different beverages (red wine, vodka, brandy or rum) and equivalent caloric intakes as sugar with water in the control group. We have measured the levels of serum lipids, high sensitivity C-reactive protein (hsCRP), tumor necrosis factor α (TNFα), interleukin 6 (IL-6), soluble phospholipase A2 (sPLA2), lipid peroxidation (LPO) and total antioxidant capacity (TAC). Red wine intake was associated with decreased of mean concentrations of hsCRP, TNFα and IL-6 induced by fat-enriched diet (p<0.05); nevertheless, sPLA2 concentrations were not significantly modified. After a fat-enriched diet added with red wine, TAC increased as compared to the same diet supplemented with rum, brandy, vodka or the control (water with sugar) (p<0.05). Moderate red wine intake, but not other alcoholic beverages, decreased pro-inflammatory factors and increased total antioxidant capacity despite a fat-enriched diet intake in healthy young volunteers. Copyright © 2015 Elsevier España, S.L.U. y Sociedad Española de Medicina Interna (SEMI). All rights reserved.

  18. Androgen receptor profiling predicts prostate cancer outcome

    NARCIS (Netherlands)

    S. Stelloo (Suzan); E. Nevedomskaya (Ekaterina); H.G. van der Poel (Henk G.); J. de Jong (Jeroen); G.J.H.L. Leenders (Geert); G.W. Jenster (Guido); L. Wessels (Lodewyk); A.M. Bergman (Andries); W. Zwart (Wilbert)

    2015-01-01

    textabstractProstate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer

  19. Prediction of temperature profile in oil wells

    International Nuclear Information System (INIS)

    Laderion, A.

    2000-01-01

    A mathematical model has been developed to predict the temperature distribution in well bores either offshore or inshore. It is incorporate the different activities encountered during drilling operations. Furthermore, the effect of drill collar and casings and bit rotating in a well during completion has been considered. The two dimensional approach is presented in the form of a computer program which is adopted for solution of the finite difference equations describing the heat transmission in the well bore in the form of a direct solution technique. The power law model has been selected for drilling mud and its indices have been calculated. Comparing measured data, recorded for a period of 82 hours during different activities in a drilling operation for 15/20 A-4, an exploration well in the Central North Sea with calculated results, show there is a good agreement between the prediction and measured temperatures in the well bore

  20. Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota

    NARCIS (Netherlands)

    Larsen, J.M.; Steen-Jensen, D.B.; Laursen, J.M.; Sondergaard, J.N.; Musavian, H.S.; Butt, T.M.; Brix, S.

    2012-01-01

    Recent studies using culture-independent methods have characterized the human airway microbiota and report microbial communities distinct from other body sites. Changes in these airway bacterial communities appear to be associated with inflammatory lung disease, yet the pro-inflammatory properties

  1. The prediction of BRDFs from surface profile measurements

    International Nuclear Information System (INIS)

    Church, E.L.; Takacs, P.Z.; Leonard, T.A.

    1989-01-01

    This paper discusses methods of predicting the BRDF of smooth surfaces from profile measurements of their surface finish. The conversion of optical profile data to the BRDF at the same wavelength is essentially independent of scattering models, while the conversion of mechanical measurements, and wavelength scaling in general, are model dependent. Procedures are illustrated for several surfaces, including two from the recent HeNe BRDF round robin, and results are compared with measured data. Reasonable agreement is found except for surfaces which involve significant scattering from isolated surface defects which are poorly sampled in the profile data

  2. Profiled support vector machines for antisense oligonucleotide efficacy prediction

    Directory of Open Access Journals (Sweden)

    Martín-Guerrero José D

    2004-09-01

    Full Text Available Abstract Background This paper presents the use of Support Vector Machines (SVMs for prediction and analysis of antisense oligonucleotide (AO efficacy. The collected database comprises 315 AO molecules including 68 features each, inducing a problem well-suited to SVMs. The task of feature selection is crucial given the presence of noisy or redundant features, and the well-known problem of the curse of dimensionality. We propose a two-stage strategy to develop an optimal model: (1 feature selection using correlation analysis, mutual information, and SVM-based recursive feature elimination (SVM-RFE, and (2 AO prediction using standard and profiled SVM formulations. A profiled SVM gives different weights to different parts of the training data to focus the training on the most important regions. Results In the first stage, the SVM-RFE technique was most efficient and robust in the presence of low number of samples and high input space dimension. This method yielded an optimal subset of 14 representative features, which were all related to energy and sequence motifs. The second stage evaluated the performance of the predictors (overall correlation coefficient between observed and predicted efficacy, r; mean error, ME; and root-mean-square-error, RMSE using 8-fold and minus-one-RNA cross-validation methods. The profiled SVM produced the best results (r = 0.44, ME = 0.022, and RMSE= 0.278 and predicted high (>75% inhibition of gene expression and low efficacy (http://aosvm.cgb.ki.se/. Conclusions The SVM approach is well suited to the AO prediction problem, and yields a prediction accuracy superior to previous methods. The profiled SVM was found to perform better than the standard SVM, suggesting that it could lead to improvements in other prediction problems as well.

  3. A lifetime prediction method for LEDs considering mission profiles

    DEFF Research Database (Denmark)

    Qu, Xiaohui; Wang, Huai; Zhan, Xiaoqing

    2016-01-01

    and to benchmark the cost-competitiveness of different lighting technologies. The existing lifetime data released by LED manufacturers or standard organizations are usually applicable only for specific temperature and current levels. Significant lifetime discrepancies may be observed in field operations due...... to the varying operational and environmental conditions during the entire service time (i.e., mission profiles). To overcome the challenge, this paper proposes an advanced lifetime prediction method, which takes into account the field operation mission profiles and the statistical properties of the life data...

  4. Gaussian interaction profile kernels for predicting drug-target interaction.

    Science.gov (United States)

    van Laarhoven, Twan; Nabuurs, Sander B; Marchiori, Elena

    2011-11-01

    The in silico prediction of potential interactions between drugs and target proteins is of core importance for the identification of new drugs or novel targets for existing drugs. However, only a tiny portion of all drug-target pairs in current datasets are experimentally validated interactions. This motivates the need for developing computational methods that predict true interaction pairs with high accuracy. We show that a simple machine learning method that uses the drug-target network as the only source of information is capable of predicting true interaction pairs with high accuracy. Specifically, we introduce interaction profiles of drugs (and of targets) in a network, which are binary vectors specifying the presence or absence of interaction with every target (drug) in that network. We define a kernel on these profiles, called the Gaussian Interaction Profile (GIP) kernel, and use a simple classifier, (kernel) Regularized Least Squares (RLS), for prediction drug-target interactions. We test comparatively the effectiveness of RLS with the GIP kernel on four drug-target interaction networks used in previous studies. The proposed algorithm achieves area under the precision-recall curve (AUPR) up to 92.7, significantly improving over results of state-of-the-art methods. Moreover, we show that using also kernels based on chemical and genomic information further increases accuracy, with a neat improvement on small datasets. These results substantiate the relevance of the network topology (in the form of interaction profiles) as source of information for predicting drug-target interactions. Software and Supplementary Material are available at http://cs.ru.nl/~tvanlaarhoven/drugtarget2011/. tvanlaarhoven@cs.ru.nl; elenam@cs.ru.nl. Supplementary data are available at Bioinformatics online.

  5. A Lifetime Prediction Method for LEDs Considering Real Mission Profiles

    DEFF Research Database (Denmark)

    Qu, Xiaohui; Wang, Huai; Zhan, Xiaoqing

    2017-01-01

    operations due to the varying operational and environmental conditions during the entire service time (i.e., mission profiles). To overcome the challenge, this paper proposes an advanced lifetime prediction method, which takes into account the field operation mission profiles and also the statistical......The Light-Emitting Diode (LED) has become a very promising alternative lighting source with the advantages of longer lifetime and higher efficiency than traditional ones. The lifetime prediction of LEDs is important to guide the LED system designers to fulfill the design specifications...... properties of the life data available from accelerated degradation testing. The electrical and thermal characteristics of LEDs are measured by a T3Ster system, used for the electro-thermal modeling. It also identifies key variables (e.g., heat sink parameters) that can be designed to achieve a specified...

  6. Comparison of Cluster Lensing Profiles with Lambda CDM Predictions

    Energy Technology Data Exchange (ETDEWEB)

    Broadhurst, Tom; /Tel Aviv U.; Umetsu, Keiichi; /Taipei, Inst. Astron. Astrophys.; Medezinski, Elinor; /Tel Aviv U.; Oguri, Masamune; /KIPAC, Menlo Park; Rephaeli, Yoel; /Tel Aviv U. /San Diego, CASS

    2008-05-21

    We derive lens distortion and magnification profiles of four well known clusters observed with Subaru. Each cluster is very well fitted by the general form predicted for Cold Dark Matter (CDM) dominated halos, with good consistency found between the independent distortion and magnification measurements. The inferred level of mass concentration is surprisingly high, 8 < c{sub vir} < 15 ( = 10.39 {+-} 0.91), compared to the relatively shallow profiles predicted by the {Lambda}CDM model, c{sub vir} = 5.06 {+-} 1.10 (for = 1.25 x 10{sup 15} M{sub {circle_dot}}/h). This represents a 4{sigma} discrepancy, and includes the relatively modest effects of projection bias and profile evolution derived from N-body simulations, which oppose each other with little residual effect. In the context of CDM based cosmologies, this discrepancy implies some modification of the widely assumed spectrum of initial density perturbations, so clusters collapse earlier (z {ge} 1) than predicted (z < 0.5) when the Universe was correspondingly denser.

  7. Random Subspace Aggregation for Cancer Prediction with Gene Expression Profiles

    Directory of Open Access Journals (Sweden)

    Liying Yang

    2016-01-01

    Full Text Available Background. Precisely predicting cancer is crucial for cancer treatment. Gene expression profiles make it possible to analyze patterns between genes and cancers on the genome-wide scale. Gene expression data analysis, however, is confronted with enormous challenges for its characteristics, such as high dimensionality, small sample size, and low Signal-to-Noise Ratio. Results. This paper proposes a method, termed RS_SVM, to predict gene expression profiles via aggregating SVM trained on random subspaces. After choosing gene features through statistical analysis, RS_SVM randomly selects feature subsets to yield random subspaces and training SVM classifiers accordingly and then aggregates SVM classifiers to capture the advantage of ensemble learning. Experiments on eight real gene expression datasets are performed to validate the RS_SVM method. Experimental results show that RS_SVM achieved better classification accuracy and generalization performance in contrast with single SVM, K-nearest neighbor, decision tree, Bagging, AdaBoost, and the state-of-the-art methods. Experiments also explored the effect of subspace size on prediction performance. Conclusions. The proposed RS_SVM method yielded superior performance in analyzing gene expression profiles, which demonstrates that RS_SVM provides a good channel for such biological data.

  8. Proteome Profiling Outperforms Transcriptome Profiling for Coexpression Based Gene Function Prediction

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Jing; Ma, Zihao; Carr, Steven A.; Mertins, Philipp; Zhang, Hui; Zhang, Zhen; Chan, Daniel W.; Ellis, Matthew J. C.; Townsend, R. Reid; Smith, Richard D.; McDermott, Jason E.; Chen, Xian; Paulovich, Amanda G.; Boja, Emily S.; Mesri, Mehdi; Kinsinger, Christopher R.; Rodriguez, Henry; Rodland, Karin D.; Liebler, Daniel C.; Zhang, Bing

    2016-11-11

    Coexpression of mRNAs under multiple conditions is commonly used to infer cofunctionality of their gene products despite well-known limitations of this “guilt-by-association” (GBA) approach. Recent advancements in mass spectrometry-based proteomic technologies have enabled global expression profiling at the protein level; however, whether proteome profiling data can outperform transcriptome profiling data for coexpression based gene function prediction has not been systematically investigated. Here, we address this question by constructing and analyzing mRNA and protein coexpression networks for three cancer types with matched mRNA and protein profiling data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Our analyses revealed a marked difference in wiring between the mRNA and protein coexpression networks. Whereas protein coexpression was driven primarily by functional similarity between coexpressed genes, mRNA coexpression was driven by both cofunction and chromosomal colocalization of the genes. Functionally coherent mRNA modules were more likely to have their edges preserved in corresponding protein networks than functionally incoherent mRNA modules. Proteomic data strengthened the link between gene expression and function for at least 75% of Gene Ontology (GO) biological processes and 90% of KEGG pathways. A web application Gene2Net (http://cptac.gene2net.org) developed based on the three protein coexpression networks revealed novel gene-function relationships, such as linking ERBB2 (HER2) to lipid biosynthetic process in breast cancer, identifying PLG as a new gene involved in complement activation, and identifying AEBP1 as a new epithelial-mesenchymal transition (EMT) marker. Our results demonstrate that proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Proteomics should be integrated if not preferred in gene function and human disease studies

  9. Purinergic signalling links mechanical breath profile and alveolar mechanics with the pro-inflammatory innate immune response causing ventilation-induced lung injury.

    Science.gov (United States)

    Hasan, Djo; Blankman, Paul; Nieman, Gary F

    2017-09-01

    Severe pulmonary infection or vigorous cyclic deformation of the alveolar epithelial type I (AT I) cells by mechanical ventilation leads to massive extracellular ATP release. High levels of extracellular ATP saturate the ATP hydrolysis enzymes CD39 and CD73 resulting in persistent high ATP levels despite the conversion to adenosine. Above a certain level, extracellular ATP molecules act as danger-associated molecular patterns (DAMPs) and activate the pro-inflammatory response of the innate immunity through purinergic receptors on the surface of the immune cells. This results in lung tissue inflammation, capillary leakage, interstitial and alveolar oedema and lung injury reducing the production of surfactant by the damaged AT II cells and deactivating the surfactant function by the concomitant extravasated serum proteins through capillary leakage followed by a substantial increase in alveolar surface tension and alveolar collapse. The resulting inhomogeneous ventilation of the lungs is an important mechanism in the development of ventilation-induced lung injury. The high levels of extracellular ATP and the upregulation of ecto-enzymes and soluble enzymes that hydrolyse ATP to adenosine (CD39 and CD73) increase the extracellular adenosine levels that inhibit the innate and adaptive immune responses rendering the host susceptible to infection by invading microorganisms. Moreover, high levels of extracellular adenosine increase the expression, the production and the activation of pro-fibrotic proteins (such as TGF-β, α-SMA, etc.) followed by the establishment of lung fibrosis.

  10. Validation of predicted exponential concentration profiles of chemicals in soils

    International Nuclear Information System (INIS)

    Hollander, Anne; Baijens, Iris; Ragas, Ad; Huijbregts, Mark; Meent, Dik van de

    2007-01-01

    Multimedia mass balance models assume well-mixed homogeneous compartments. Particularly for soils, this does not correspond to reality, which results in potentially large uncertainties in estimates of transport fluxes from soils. A theoretically expected exponential decrease model of chemical concentrations with depth has been proposed, but hardly tested against empirical data. In this paper, we explored the correspondence between theoretically predicted soil concentration profiles and 84 field measured profiles. In most cases, chemical concentrations in soils appear to decline exponentially with depth, and values for the chemical specific soil penetration depth (d p ) are predicted within one order of magnitude. Over all, the reliability of multimedia models will improve when they account for depth-dependent soil concentrations, so we recommend to take into account the described theoretical exponential decrease model of chemical concentrations with depth in chemical fate studies. In this model the d p -values should estimated be either based on local conditions or on a fixed d p -value, which we recommend to be 10 cm for chemicals with a log K ow > 3. - Multimedia mass model predictions will improve when taking into account depth dependent soil concentrations

  11. Predicting Post-Editor Profiles from the Translation Process

    DEFF Research Database (Denmark)

    Singla, Karan; Orrego-Carmona, David; Gonzales, Ashleigh Rhea

    2014-01-01

    The purpose of the current investigation is to predict post-editor profiles based on user behaviour and demographics using machine learning techniques to gain a better understanding of post-editor styles. Our study extracts process unit features from the CasMaCat LS14 database from the CRITT...... of translation process features. The classification and clustering of participants resulting from our study suggest this type of exploration could be used as a tool to develop new translation tool features or customization possibilities....

  12. Acylcarnitines profile best predicts survival in horses with atypical myopathy.

    Directory of Open Access Journals (Sweden)

    François Boemer

    Full Text Available Equine atypical myopathy (AM is caused by hypoglycin A intoxication and is characterized by a high fatality rate. Predictive estimation of survival in AM horses is necessary to prevent unnecessary suffering of animals that are unlikely to survive and to focus supportive therapy on horses with a possible favourable prognosis of survival. We hypothesized that outcome may be predicted early in the course of disease based on the assumption that the acylcarnitine profile reflects the derangement of muscle energetics. We developed a statistical model to prognosticate the risk of death of diseased animals and found that estimation of outcome may be drawn from three acylcarnitines (C2, C10:2 and C18 -carnitines with a high sensitivity and specificity. The calculation of the prognosis of survival makes it possible to distinguish the horses that will survive from those that will die despite severe signs of acute rhabdomyolysis in both groups.

  13. Acylcarnitines profile best predicts survival in horses with atypical myopathy

    Science.gov (United States)

    Detilleux, Johann; Cello, Christophe; Amory, Hélène; Marcillaud-Pitel, Christel; Richard, Eric; van Galen, Gaby; van Loon, Gunther; Lefère, Laurence; Votion, Dominique-Marie

    2017-01-01

    Equine atypical myopathy (AM) is caused by hypoglycin A intoxication and is characterized by a high fatality rate. Predictive estimation of survival in AM horses is necessary to prevent unnecessary suffering of animals that are unlikely to survive and to focus supportive therapy on horses with a possible favourable prognosis of survival. We hypothesized that outcome may be predicted early in the course of disease based on the assumption that the acylcarnitine profile reflects the derangement of muscle energetics. We developed a statistical model to prognosticate the risk of death of diseased animals and found that estimation of outcome may be drawn from three acylcarnitines (C2, C10:2 and C18 -carnitines) with a high sensitivity and specificity. The calculation of the prognosis of survival makes it possible to distinguish the horses that will survive from those that will die despite severe signs of acute rhabdomyolysis in both groups. PMID:28846683

  14. Periodontal profile classes predict periodontal disease progression and tooth loss.

    Science.gov (United States)

    Morelli, Thiago; Moss, Kevin L; Preisser, John S; Beck, James D; Divaris, Kimon; Wu, Di; Offenbacher, Steven

    2018-02-01

    Current periodontal disease taxonomies have limited utility for predicting disease progression and tooth loss; in fact, tooth loss itself can undermine precise person-level periodontal disease classifications. To overcome this limitation, the current group recently introduced a novel patient stratification system using latent class analyses of clinical parameters, including patterns of missing teeth. This investigation sought to determine the clinical utility of the Periodontal Profile Classes and Tooth Profile Classes (PPC/TPC) taxonomy for risk assessment, specifically for predicting periodontal disease progression and incident tooth loss. The analytic sample comprised 4,682 adult participants of two prospective cohort studies (Dental Atherosclerosis Risk in Communities Study and Piedmont Dental Study) with information on periodontal disease progression and incident tooth loss. The PPC/TPC taxonomy includes seven distinct PPCs (person-level disease pattern and severity) and seven TPCs (tooth-level disease). Logistic regression modeling was used to estimate relative risks (RR) and 95% confidence intervals (CI) for the association of these latent classes with disease progression and incident tooth loss, adjusting for examination center, race, sex, age, diabetes, and smoking. To obtain personalized outcome propensities, risk estimates associated with each participant's PPC and TPC were combined into person-level composite risk scores (Index of Periodontal Risk [IPR]). Individuals in two PPCs (PPC-G: Severe Disease and PPC-D: Tooth Loss) had the highest tooth loss risk (RR = 3.6; 95% CI = 2.6 to 5.0 and RR = 3.8; 95% CI = 2.9 to 5.1, respectively). PPC-G also had the highest risk for periodontitis progression (RR = 5.7; 95% CI = 2.2 to 14.7). Personalized IPR scores were positively associated with both periodontitis progression and tooth loss. These findings, upon additional validation, suggest that the periodontal/tooth profile classes and the derived

  15. Prediction of fracture profile using digital image correlation

    Science.gov (United States)

    Chaitanya, G. M. S. K.; Sasi, B.; Kumar, Anish; Babu Rao, C.; Purnachandra Rao, B.; Jayakumar, T.

    2015-04-01

    Digital Image Correlation (DIC) based full field strain mapping methodology is used for mapping strain on an aluminum sample subjected to tensile deformation. The local strains on the surface of the specimen are calculated at different strain intervals. Early localization of strain is observed at a total strain of 0.050ɛ; itself, whereas a visually apparent localization of strain is observed at a total strain of 0.088ɛ;. Orientation of the line of fracture (12.0°) is very close to the orientation of locus of strain maxima (11.6°) computed from the strain mapping at 0.063ɛ itself. These results show the efficacy of the DIC based method to predict the location as well as the profile of the fracture, at an early stage.

  16. Behavioral Profile Predicts Dominance Status in Mountain Chickadees.

    Science.gov (United States)

    Fox, Rebecca A; Ladage, Lara D; Roth, Timothy C; Pravosudov, Vladimir V

    2009-06-01

    Individual variation in stable behavioral traits may explain variation in ecologically-relevant behaviors such as foraging, dispersal, anti-predator behavior, and dominance. We investigated behavioral variation in mountain chickadees (Poecile gambeli), a North American parid that lives in dominance-structured winter flocks, using two common measures of behavioral profile: exploration of a novel room and novel object exploration. We related those behavioral traits to dominance status in male chickadees following brief, pair-wise encounters. Low-exploring birds (birds that visited less than four locations in the novel room) were significantly more likely to become dominant in brief, pairwise encounters with high-exploring birds (i.e., birds that visited all perching locations within a novel room). On the other hand, there was no relationship between novel object exploration and dominance. Interestingly, novel room exploration was also not correlated with novel object exploration. These results suggest that behavioral profile may predict the social status of group-living individuals. Moreover, our results contradict the idea that novel object exploration and novel room exploration are always interchangeable measures of individuals' sensitivity to environmental novelty.

  17. Divergent pro-inflammatory profile of human dendritic cells in response to commensal and pathogenic bacteria associated with the airway microbiota

    DEFF Research Database (Denmark)

    Larsen, Jeppe Madura; Steen-Jensen, Daniel Bisgaard; Laursen, Janne Marie

    2012-01-01

    of individual bacterial species are unknown. In this study, we compared the immune stimulatory capacity on human monocyte-derived dendritic cells (DCs) of selected airway commensal and pathogenic bacteria predominantly associated with lungs of asthma or COPD patients (pathogenic Haemophillus spp. and Moraxella...... spp.), healthy lungs (commensal Prevotella spp.) or both (commensal Veillonella spp. and Actinomyces spp.). All bacteria were found to induce activation of DCs as demonstrated by similar induction of CD83, CD40 and CD86 surface expression. However, asthma and COPD-associated pathogenic bacteria...... provoked a 3-5 fold higher production of IL-23, IL-12p70 and IL-10 cytokines compared to the commensal bacteria. Based on the differential cytokine production profiles, the studied airway bacteria could be segregated into three groups (Haemophilus spp. and Moraxella spp. vs. Prevotella spp. and Veillonella...

  18. The Reliability and Predictive Validity of the Stalking Risk Profile.

    Science.gov (United States)

    McEwan, Troy E; Shea, Daniel E; Daffern, Michael; MacKenzie, Rachel D; Ogloff, James R P; Mullen, Paul E

    2018-03-01

    This study assessed the reliability and validity of the Stalking Risk Profile (SRP), a structured measure for assessing stalking risks. The SRP was administered at the point of assessment or retrospectively from file review for 241 adult stalkers (91% male) referred to a community-based forensic mental health service. Interrater reliability was high for stalker type, and moderate-to-substantial for risk judgments and domain scores. Evidence for predictive validity and discrimination between stalking recidivists and nonrecidivists for risk judgments depended on follow-up duration. Discrimination was moderate (area under the curve = 0.66-0.68) and positive and negative predictive values good over the full follow-up period ( Mdn = 170.43 weeks). At 6 months, discrimination was better than chance only for judgments related to stalking of new victims (area under the curve = 0.75); however, high-risk stalkers still reoffended against their original victim(s) 2 to 4 times as often as low-risk stalkers. Implications for the clinical utility and refinement of the SRP are discussed.

  19. Predicting fiber refractive index from a measured preform index profile

    Science.gov (United States)

    Kiiveri, P.; Koponen, J.; Harra, J.; Novotny, S.; Husu, H.; Ihalainen, H.; Kokki, T.; Aallos, V.; Kimmelma, O.; Paul, J.

    2018-02-01

    When producing fiber lasers and amplifiers, silica glass compositions consisting of three to six different materials are needed. Due to the varying needs of different applications, substantial number of different glass compositions are used in the active fiber structures. Often it is not possible to find material parameters for theoretical models to estimate thermal and mechanical properties of those glass compositions. This makes it challenging to predict accurately fiber core refractive index values, even if the preform index profile is measured. Usually the desired fiber refractive index value is achieved experimentally, which is expensive. To overcome this problem, we analyzed statistically the changes between the measured preform and fiber index values. We searched for correlations that would help to predict the Δn-value change from preform to fiber in a situation where we don't know the values of the glass material parameters that define the change. Our index change models were built using the data collected from preforms and fibers made by the Direct Nanoparticle Deposition (DND) technology.

  20. Assist feature printability prediction by 3-D resist profile reconstruction

    Science.gov (United States)

    Zheng, Xin; Huang, Jensheng; Chin, Fook; Kazarian, Aram; Kuo, Chun-Chieh

    2012-06-01

    properties may then be used to optimize the printability vs. efficacy of an SRAF either prior to or during an Optical Proximity Correction (OPC) run. The process models that are used during OPC have never been able to reliably predict which SRAFs will print. This appears to be due to the fact that OPC process models are generally created using data that does not include printed subresolution patterns. An enhancement to compact modeling capability to predict Assist Features (AF) printability is developed and discussed. A hypsometric map representing 3-D resist profile was built by applying a first principle approximation to estimate the "energy loss" from the resist top to bottom. Such a 3-D resist profile is an extrapolation of a well calibrated traditional OPC model without any additional information. Assist features are detected at either top of resist (dark field) or bottom of resist (bright field). Such detection can be done by just extracting top or bottom resist models from our 3-D resist model. There is no measurement of assist features needed when we build AF but it can be included if interested but focusing on resist calibration to account for both exposure dosage and focus change sensitivities. This approach significantly increases resist model's capability for predicting printed SRAF accuracy. And we don't need to calibrate an SRAF model in addition to the OPC model. Without increase in computation time, this compact model can draw assist feature contour with real placement and size at any vertical plane. The result is compared and validated with 3-D rigorous modeling as well as SEM images. Since this method does not change any form of compact modeling, it can be integrated into current MBAF solutions without any additional work.

  1. Insulin Resistance Predicts Atherogenic Lipoprotein Profile in Nondiabetic Subjects

    Directory of Open Access Journals (Sweden)

    Flávia De C. Cartolano

    2017-01-01

    Full Text Available Background. Atherogenic diabetes is associated with an increased cardiovascular risk and mortality in diabetic individuals; however, the impact of insulin resistance (IR in lipid metabolism in preclinical stages is generally underreported. For that, we evaluated the capacity of IR to predict an atherogenic lipid subfraction profile. Methods. Complete clinical evaluation and biochemical analysis (lipid, glucose profile, LDL, and HDL subfractions and LDL phenotype and size were performed in 181 patients. The impact of IR as a predictor of atherogenic lipoproteins was tested by logistic regression analysis in raw and adjusted models. Results. HDL-C and Apo AI were significantly lower in individuals with IR. Individuals with IR had a higher percentage of small HDL particles, lower percentage in the larger ones, and reduced frequency of phenotype A (IR = 62%; non-IR = 83%. IR individuals had reduced probability to have large HDL (OR = 0.213; CI = 0.999–0.457 and had twice more chances to show increased small HDL (OR = 2.486; CI = 1.341–7.051. IR was a significant predictor of small LDL (OR = 3.075; CI = 1.341–7.051 and atherogenic phenotype (OR = 3.176; CI = 1.469–6.867. Conclusion. IR, previously DM2 diagnosis, is a strong predictor of quantitative and qualitative features of lipoproteins directly associated with an increased atherogenic risk.

  2. A comparison on radar range profiles between in-flight measurements and RCS-predictions

    NARCIS (Netherlands)

    Heiden, R. van der; Ewijk, L.J. van; Groen, F.C.A.

    1998-01-01

    The validation of Radar Cross Section (RCS) prediction techniques against real measurements is crucial to acquire confidence in predictions when measurements are nut available. In this paper we present the results of a comparison on one-dimensional signatures, i.e. radar range profiles. The profiles

  3. A new algorithm predicts pressure and temperature profiles of gas/gas-condensate transmission pipelines

    Energy Technology Data Exchange (ETDEWEB)

    Mokhatab, Saied [OIEC - Oil Industries' Engineering and Construction Group, Tehran (Iran, Islamic Republic of); Vatani, Ali [University of Tehran (Iran, Islamic Republic of)

    2003-07-01

    The main objective of the present study has been the development of a relatively simple analytical algorithm for predicting flow temperature and pressure profiles along the two-phase, gas/gas-condensate transmission pipelines. Results demonstrate the ability of the method to predict reasonably accurate pressure gradient and temperature gradient profiles under operating conditions. (author)

  4. Psoriasis prediction from genome-wide SNP profiles

    Directory of Open Access Journals (Sweden)

    Fang Xiangzhong

    2011-01-01

    Full Text Available Abstract Background With the availability of large-scale genome-wide association study (GWAS data, choosing an optimal set of SNPs for disease susceptibility prediction is a challenging task. This study aimed to use single nucleotide polymorphisms (SNPs to predict psoriasis from searching GWAS data. Methods Totally we had 2,798 samples and 451,724 SNPs. Process for searching a set of SNPs to predict susceptibility for psoriasis consisted of two steps. The first one was to search top 1,000 SNPs with high accuracy for prediction of psoriasis from GWAS dataset. The second one was to search for an optimal SNP subset for predicting psoriasis. The sequential information bottleneck (sIB method was compared with classical linear discriminant analysis(LDA for classification performance. Results The best test harmonic mean of sensitivity and specificity for predicting psoriasis by sIB was 0.674(95% CI: 0.650-0.698, while only 0.520(95% CI: 0.472-0.524 was reported for predicting disease by LDA. Our results indicate that the new classifier sIB performs better than LDA in the study. Conclusions The fact that a small set of SNPs can predict disease status with average accuracy of 68% makes it possible to use SNP data for psoriasis prediction.

  5. Gene Expression Profiling of Human Vaginal Cells In Vitro Discriminates Compounds with Pro-Inflammatory and Mucosa-Altering Properties: Novel Biomarkers for Preclinical Testing of HIV Microbicide Candidates.

    Directory of Open Access Journals (Sweden)

    Irina A Zalenskaya

    Full Text Available Inflammation and immune activation of the cervicovaginal mucosa are considered factors that increase susceptibility to HIV infection. Therefore, it is essential to screen candidate anti-HIV microbicides for potential mucosal immunomodulatory/inflammatory effects prior to further clinical development. The goal of this study was to develop an in vitro method for preclinical evaluation of the inflammatory potential of new candidate microbicides using a microarray gene expression profiling strategy.To this end, we compared transcriptomes of human vaginal cells (Vk2/E6E7 treated with well-characterized pro-inflammatory (PIC and non-inflammatory (NIC compounds. PICs included compounds with different mechanisms of action. Gene expression was analyzed using Affymetrix U133 Plus 2 arrays. Data processing was performed using GeneSpring 11.5 (Agilent Technologies, Santa Clara, CA.Microarraray comparative analysis allowed us to generate a panel of 20 genes that were consistently deregulated by PICs compared to NICs, thus distinguishing between these two groups. Functional analysis mapped 14 of these genes to immune and inflammatory responses. This was confirmed by the fact that PICs induced NFkB pathway activation in Vk2 cells. By testing microbicide candidates previously characterized in clinical trials we demonstrated that the selected PIC-associated genes properly identified compounds with mucosa-altering effects. The discriminatory power of these genes was further demonstrated after culturing vaginal cells with vaginal bacteria. Prevotella bivia, prevalent bacteria in the disturbed microbiota of bacterial vaginosis, induced strong upregulation of seven selected PIC-associated genes, while a commensal Lactobacillus gasseri associated to vaginal health did not cause any changes.In vitro evaluation of the immunoinflammatory potential of microbicides using the PIC-associated genes defined in this study could help in the initial screening of candidates prior

  6. Automatic selection of reference taxa for protein-protein interaction prediction with phylogenetic profiling

    DEFF Research Database (Denmark)

    Simonsen, Martin; Maetschke, S.R.; Ragan, M.A.

    2012-01-01

    Motivation: Phylogenetic profiling methods can achieve good accuracy in predicting protein–protein interactions, especially in prokaryotes. Recent studies have shown that the choice of reference taxa (RT) is critical for accurate prediction, but with more than 2500 fully sequenced taxa publicly......: We present three novel methods for automating the selection of RT, using machine learning based on known protein–protein interaction networks. One of these methods in particular, Tree-Based Search, yields greatly improved prediction accuracies. We further show that different methods for constituting...... phylogenetic profiles often require very different RT sets to support high prediction accuracy....

  7. Compact Web browsing profiles for click-through rate prediction

    DEFF Research Database (Denmark)

    Fruergaard, Bjarne Ørum; Hansen, Lars Kai

    2014-01-01

    In real time advertising we are interested in finding features that improve click-through rate prediction. One source of available information is the bipartite graph of websites previously engaged by identifiable users. In this work, we investigate three different decompositions of such a graph...

  8. Predicting fragmentation sizing profiles for different blasting patterns

    International Nuclear Information System (INIS)

    Sheikh, A.M.; Chung, S.H.

    1987-01-01

    This paper evaluates the efficiency of blasting in a large scale underground heap leaching operation. The prediction model is based on the dynamic tensile breaking strength of rock formation, the detonation characteristics of the explosives and the drill hole pattern. The modelling includes crack pattern development and fragmentation computation fitted by the Rosin-Rammler distribution equation

  9. Geometrical theory to predict eccentric photorefraction intensity profiles in the human eye

    Science.gov (United States)

    Roorda, Austin; Campbell, Melanie C. W.; Bobier, W. R.

    1995-08-01

    In eccentric photorefraction, light returning from the retina of the eye is photographed by a camera focused on the eye's pupil. We use a geometrical model of eccentric photorefraction to generate intensity profiles across the pupil image. The intensity profiles for three different monochromatic aberration functions induced in a single eye are predicted and show good agreement with the measured eccentric photorefraction intensity profiles. A directional reflection from the retina is incorporated into the calculation. Intensity profiles for symmetric and asymmetric aberrations are generated and measured. The latter profile shows a dependency on the source position and the meridian. The magnitude of the effect of thresholding on measured pattern extents is predicted. Monochromatic aberrations in human eyes will cause deviations in the eccentric photorefraction measurements from traditional crescents caused by defocus and may cause misdiagnoses of ametropia or anisometropia. Our results suggest that measuring refraction along the vertical meridian is preferred for screening studies with the eccentric photorefractor.

  10. Comparisons of Crosswind Velocity Profile Estimates Used in Fast-Time Wake Vortex Prediction Models

    Science.gov (United States)

    Pruis, Mathew J.; Delisi, Donald P.; Ahmad, Nashat N.

    2011-01-01

    Five methods for estimating crosswind profiles used in fast-time wake vortex prediction models are compared in this study. Previous investigations have shown that temporal and spatial variations in the crosswind vertical profile have a large impact on the transport and time evolution of the trailing vortex pair. The most important crosswind parameters are the magnitude of the crosswind and the gradient in the crosswind shear. It is known that pulsed and continuous wave lidar measurements can provide good estimates of the wind profile in the vicinity of airports. In this study comparisons are made between estimates of the crosswind profiles from a priori information on the trajectory of the vortex pair as well as crosswind profiles derived from different sensors and a regional numerical weather prediction model.

  11. Cell-specific prediction and application of drug-induced gene expression profiles.

    Science.gov (United States)

    Hodos, Rachel; Zhang, Ping; Lee, Hao-Chih; Duan, Qiaonan; Wang, Zichen; Clark, Neil R; Ma'ayan, Avi; Wang, Fei; Kidd, Brian; Hu, Jianying; Sontag, David; Dudley, Joel

    2018-01-01

    Gene expression profiling of in vitro drug perturbations is useful for many biomedical discovery applications including drug repurposing and elucidation of drug mechanisms. However, limited data availability across cell types has hindered our capacity to leverage or explore the cell-specificity of these perturbations. While recent efforts have generated a large number of drug perturbation profiles across a variety of human cell types, many gaps remain in this combinatorial drug-cell space. Hence, we asked whether it is possible to fill these gaps by predicting cell-specific drug perturbation profiles using available expression data from related conditions--i.e. from other drugs and cell types. We developed a computational framework that first arranges existing profiles into a three-dimensional array (or tensor) indexed by drugs, genes, and cell types, and then uses either local (nearest-neighbors) or global (tensor completion) information to predict unmeasured profiles. We evaluate prediction accuracy using a variety of metrics, and find that the two methods have complementary performance, each superior in different regions in the drug-cell space. Predictions achieve correlations of 0.68 with true values, and maintain accurate differentially expressed genes (AUC 0.81). Finally, we demonstrate that the predicted profiles add value for making downstream associations with drug targets and therapeutic classes.

  12. Early pharmaceutical profiling to predict oral drug absorption

    DEFF Research Database (Denmark)

    Bergström, Christel A S; Holm, René; Jørgensen, Søren Astrup

    2014-01-01

    Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmac......Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary...... and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties...

  13. Effects of DTM resolution on slope steepness and soil loss prediction on hillslope profiles

    Science.gov (United States)

    Eder Paulo Moreira; William J. Elliot; Andrew T. Hudak

    2011-01-01

    Topographic attributes play a critical role in predicting erosion in models such as the Water Erosion Prediction Project (WEPP). The effects of four different high resolution hillslope profiles were studied using four different DTM resolutions: 1-m, 3-m, 5-m and 10-m. The WEPP model used a common scenario encountered in the forest environment and the selected hillslope...

  14. Comparison of predicted and measured pulsed-column profiles and inventories

    International Nuclear Information System (INIS)

    Ostenak, C.A.; Cermak, A.F.

    1983-01-01

    Nuclear materials accounting and process control in fuels reprocessing plants can be improved by near-real-time estimation of the in-process inventory in solvent-extraction contactors. Experimental studies were conducted on pilot- and plant-scale pulsed columns by Allied-General Nuclear Service (AGNS), and the extensive uranium concentration-profile and inventory data were analyzed by Los Alamos and AGNS to develop and evaluate different predictive inventory techniques. Preliminary comparisons of predicted and measured pulsed-column profiles and inventories show promise for using these predictive techniques to improve nuclear materials accounting and process control in fuels reprocessing plants

  15. Validity of a manual soft tissue profile prediction method following mandibular setback osteotomy.

    Science.gov (United States)

    Kolokitha, Olga-Elpis

    2007-10-01

    The aim of this study was to determine the validity of a manual cephalometric method used for predicting the post-operative soft tissue profiles of patients who underwent mandibular setback surgery and compare it to a computerized cephalometric prediction method (Dentofacial Planner). Lateral cephalograms of 18 adults with mandibular prognathism taken at the end of pre-surgical orthodontics and approximately one year after surgery were used. To test the validity of the manual method the prediction tracings were compared to the actual post-operative tracings. The Dentofacial Planner software was used to develop the computerized post-surgical prediction tracings. Both manual and computerized prediction printouts were analyzed by using the cephalometric system PORDIOS. Statistical analysis was performed by means of t-test. Comparison between manual prediction tracings and the actual post-operative profile showed that the manual method results in more convex soft tissue profiles; the upper lip was found in a more prominent position, upper lip thickness was increased and, the mandible and lower lip were found in a less posterior position than that of the actual profiles. Comparison between computerized and manual prediction methods showed that in the manual method upper lip thickness was increased, the upper lip was found in a more anterior position and the lower anterior facial height was increased as compared to the computerized prediction method. Cephalometric simulation of post-operative soft tissue profile following orthodontic-surgical management of mandibular prognathism imposes certain limitations related to the methods implied. However, both manual and computerized prediction methods remain a useful tool for patient communication.

  16. A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP Inhibitors

    Science.gov (United States)

    2017-02-01

    affecting the function of Fanconi Anemia (FA) genes ( FANCA /B/C/D2/E/F/G/I/J/L/M, PALB2) or DNA damage response genes involved in HR 5 (ATM, ATR...Award Number: W81XWH-10-1-0585 TITLE: A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP Inhibitors...To) 15 July 2010 – 2 Nov.2016 4. TITLE AND SUBTITLE A Gene Expression Profile of BRCAness That Predicts for Responsiveness to Platinum and PARP

  17. NESmapper: accurate prediction of leucine-rich nuclear export signals using activity-based profiles.

    Directory of Open Access Journals (Sweden)

    Shunichi Kosugi

    2014-09-01

    Full Text Available The nuclear export of proteins is regulated largely through the exportin/CRM1 pathway, which involves the specific recognition of leucine-rich nuclear export signals (NESs in the cargo proteins, and modulates nuclear-cytoplasmic protein shuttling by antagonizing the nuclear import activity mediated by importins and the nuclear import signal (NLS. Although the prediction of NESs can help to define proteins that undergo regulated nuclear export, current methods of predicting NESs, including computational tools and consensus-sequence-based searches, have limited accuracy, especially in terms of their specificity. We found that each residue within an NES largely contributes independently and additively to the entire nuclear export activity. We created activity-based profiles of all classes of NESs with a comprehensive mutational analysis in mammalian cells. The profiles highlight a number of specific activity-affecting residues not only at the conserved hydrophobic positions but also in the linker and flanking regions. We then developed a computational tool, NESmapper, to predict NESs by using profiles that had been further optimized by training and combining the amino acid properties of the NES-flanking regions. This tool successfully reduced the considerable number of false positives, and the overall prediction accuracy was higher than that of other methods, including NESsential and Wregex. This profile-based prediction strategy is a reliable way to identify functional protein motifs. NESmapper is available at http://sourceforge.net/projects/nesmapper.

  18. Predicting lower third molar eruption on panoramic radiographs after cephalometric comparison of profile and panoramic radiographs

    DEFF Research Database (Denmark)

    Begtrup, Anders; Grønastøð, Halldis Á; Christensen, Ib Jarle

    2012-01-01

    and to find a simple and reliable method for predicting the eruption of the mandibular third molar by measurements on panoramic radiographs. The material consisted of profile and panoramic radiographs, taken before orthodontic treatment, of 30 males and 23 females (median age 22, range 18-48 years......Previous studies have suggested methods for predicting third molar tooth eruption radiographically. Still, this prediction is associated with uncertainty. The aim of the present study was to elucidate the association between cephalometric measurements on profile and panoramic radiographs...... the length from the ramus to the incisors (olr-id) showed a statistically significant correlation. By combining this length with the mesiodistal width of the lower second molar, the prediction of eruption of the lower third molar was strengthened. A new formula for calculating the probability of eruption...

  19. Technical player profiles related to the physical fitness of young female volleyball players predict team performance.

    Science.gov (United States)

    Dávila-Romero, C; Hernández-Mocholí, M A; García-Hermoso, A

    2015-03-01

    This study is divided into three sequential stages: identification of fitness and game performance profiles (individual player performance), an assessment of the relationship between these profiles, and an assessment of the relationship between individual player profiles and team performance during play (in championship performance). The overall study sample comprised 525 (19 teams) female volleyball players aged 12-16 years and a subsample (N.=43) used to examine study aims one and two was selected from overall sample. Anthropometric, fitness and individual player performance (actual game) data were collected in the subsample. These data were analyzed through clustering methods, ANOVA and independence chi-square test. Then, we investigated whether the proportion of players with the highest individual player performance profile might predict a team's results in the championship. Cluster analysis identified three volleyball fitness profiles (high, medium, and low) and two individual player performance profiles (high and low). The results showed a relationship between both types of profile (fitness and individual player performance). Then, linear regression revealed a moderate relationship between the number of players with a high volleyball fitness profile and a team's results in the championship (R2=0.23). The current study findings may enable coaches and trainers to manage training programs more efficiently in order to obtain tailor-made training, identify volleyball-specific physical fitness training requirements and reach better results during competitions.

  20. Validity of a Manual Soft Tissue Profile Prediction Method Following Mandibular Setback Osteotomy

    OpenAIRE

    Kolokitha, Olga-Elpis

    2007-01-01

    Objectives The aim of this study was to determine the validity of a manual cephalometric method used for predicting the post-operative soft tissue profiles of patients who underwent mandibular setback surgery and compare it to a computerized cephalometric prediction method (Dentofacial Planner). Lateral cephalograms of 18 adults with mandibular prognathism taken at the end of pre-surgical orthodontics and approximately one year after surgery were used. Methods To test the validity of the manu...

  1. Predicting Low Energy Dopant Implant Profiles in Semiconductors using Molecular Dynamics

    Energy Technology Data Exchange (ETDEWEB)

    Beardmore, K.M.; Gronbech-Jensen, N.

    1999-05-02

    The authors present a highly efficient molecular dynamics scheme for calculating dopant density profiles in group-IV alloy, and III-V zinc blende structure materials. Their scheme incorporates several necessary methods for reducing computational overhead, plus a rare event algorithm to give statistical accuracy over several orders of magnitude change in the dopant concentration. The code uses a molecular dynamics (MD) model to describe ion-target interactions. Atomic interactions are described by a combination of 'many-body' and pair specific screened Coulomb potentials. Accumulative damage is accounted for using a Kinchin-Pease type model, inelastic energy loss is represented by a Firsov expression, and electronic stopping is described by a modified Brandt-Kitagawa model which contains a single adjustable ion-target dependent parameter. Thus, the program is easily extensible beyond a given validation range, and is therefore truly predictive over a wide range of implant energies and angles. The scheme is especially suited for calculating profiles due to low energy and to situations where a predictive capability is required with the minimum of experimental validation. They give examples of using the code to calculate concentration profiles and 2D 'point response' profiles of dopants in crystalline silicon and gallium-arsenide. Here they can predict the experimental profile over five orders of magnitude for <100> and <110> channeling and for non-channeling implants at energies up to hundreds of keV.

  2. Prediction of Human Pharmacokinetic Profile After Transdermal Drug Application Using Excised Human Skin.

    Science.gov (United States)

    Yamamoto, Syunsuke; Karashima, Masatoshi; Arai, Yuta; Tohyama, Kimio; Amano, Nobuyuki

    2017-09-01

    Although several mathematical models have been reported for the estimation of human plasma concentration profiles of drug substances after dermal application, the successful cases that can predict human pharmacokinetic profiles are limited. Therefore, the aim of this study is to investigate the prediction of human plasma concentrations after dermal application using in vitro permeation parameters obtained from excised human skin. The in vitro skin permeability of 7 marketed drug products was evaluated. The plasma concentration-time profiles of the drug substances in humans after their dermal application were simulated using compartment models and the clinical pharmacokinetic parameters. The transdermal process was simulated using the in vitro skin permeation rate and lag time assuming a zero-order absorption. These simulated plasma concentration profiles were compared with the clinical data. The result revealed that the steady-state plasma concentration of diclofenac and the maximum concentrations of nicotine, bisoprolol, rivastigmine, and lidocaine after topical application were within 2-fold of the clinical data. Furthermore, the simulated concentration profiles of bisoprolol, nicotine, and rivastigmine reproduced the decrease in absorption due to drug depletion from the formulation. In conclusion, this simple compartment model using in vitro human skin permeation parameters as zero-order absorption predicted the human plasma concentrations accurately. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  3. Leading-Edge Noise Prediction of General Airfoil Profiles with Spanwise-Varying Inflow Conditions

    NARCIS (Netherlands)

    Miotto, Renato Fuzaro; Wolf, William Roberto; De Santana, Leandro Dantas

    2018-01-01

    This paper presents a study of the leading-edge noise radiated by an airfoil undergoing a turbulent inflow. The noise prediction of generic airfoil profiles subjected to spanwise-varying inflow conditions is performed with the support of Amiet’s theory and the inverse strip technique. In the

  4. Predicting multi-class customer profiles based on transactions : a case study in food sales

    NARCIS (Netherlands)

    Apeh, E.; Zliobaite, I.; Pechenizkiy, M.; Gabrys, B.; Bramer, M.; Petridis, M.

    2012-01-01

    Predicting the class of customer profiles is a key task in marketing, which enables businesses to approach the customers in a right way to satisfy the customer’s evolving needs. However, due to costs, privacy and/or data protection, only the business’ owned transactional data is typically available

  5. Leading-Edge Noise Prediction of General Airfoil Profiles with Spanwise-Varying Inflow Conditions

    NARCIS (Netherlands)

    Miotto, Renato Fuzaro; Wolf, William Roberto; De Santana, Leandro Dantas

    This paper presents a study of the leading-edge noise radiated by an airfoil undergoing a turbulent inflow. The noise prediction of generic airfoil profiles subjected to spanwise-varying inflow conditions is performed with the support of Amiet’s theory and the inverse strip technique. In the

  6. Modeling and prediction of extraction profile for microwave-assisted extraction based on absorbed microwave energy.

    Science.gov (United States)

    Chan, Chung-Hung; Yusoff, Rozita; Ngoh, Gek-Cheng

    2013-09-01

    A modeling technique based on absorbed microwave energy was proposed to model microwave-assisted extraction (MAE) of antioxidant compounds from cocoa (Theobroma cacao L.) leaves. By adapting suitable extraction model at the basis of microwave energy absorbed during extraction, the model can be developed to predict extraction profile of MAE at various microwave irradiation power (100-600 W) and solvent loading (100-300 ml). Verification with experimental data confirmed that the prediction was accurate in capturing the extraction profile of MAE (R-square value greater than 0.87). Besides, the predicted yields from the model showed good agreement with the experimental results with less than 10% deviation observed. Furthermore, suitable extraction times to ensure high extraction yield at various MAE conditions can be estimated based on absorbed microwave energy. The estimation is feasible as more than 85% of active compounds can be extracted when compared with the conventional extraction technique. Copyright © 2013 Elsevier Ltd. All rights reserved.

  7. Prediction of metastasis from low-malignant breast cancer by gene expression profiling

    DEFF Research Database (Denmark)

    Thomassen, Mads; Tan, Qihua; Eiriksdottir, Freyja

    2007-01-01

    examined in these studies is the low-risk patients for whom outcome is very difficult to predict with currently used methods. These patients do not receive adjuvant treatment according to the guidelines of the Danish Breast Cancer Cooperative Group (DBCG). In this study, 26 tumors from low-risk patients...... with different characteristics and risk, expression-based classification specifically developed in low-risk patients have higher predictive power in this group.......Promising results for prediction of outcome in breast cancer have been obtained by genome wide gene expression profiling. Some studies have suggested that an extensive overtreatment of breast cancer patients might be reduced by risk assessment with gene expression profiling. A patient group hardly...

  8. Predicting adverse drug reaction profiles by integrating protein interaction networks with drug structures.

    Science.gov (United States)

    Huang, Liang-Chin; Wu, Xiaogang; Chen, Jake Y

    2013-01-01

    The prediction of adverse drug reactions (ADRs) has become increasingly important, due to the rising concern on serious ADRs that can cause drugs to fail to reach or stay in the market. We proposed a framework for predicting ADR profiles by integrating protein-protein interaction (PPI) networks with drug structures. We compared ADR prediction performances over 18 ADR categories through four feature groups-only drug targets, drug targets with PPI networks, drug structures, and drug targets with PPI networks plus drug structures. The results showed that the integration of PPI networks and drug structures can significantly improve the ADR prediction performance. The median AUC values for the four groups were 0.59, 0.61, 0.65, and 0.70. We used the protein features in the best two models, "Cardiac disorders" (median-AUC: 0.82) and "Psychiatric disorders" (median-AUC: 0.76), to build ADR-specific PPI networks with literature supports. For validation, we examined 30 drugs withdrawn from the U.S. market to see if our approach can predict their ADR profiles and explain why they were withdrawn. Except for three drugs having ADRs in the categories we did not predict, 25 out of 27 withdrawn drugs (92.6%) having severe ADRs were successfully predicted by our approach. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  9. Understanding and Predicting Profile Structure and Parametric Scaling of Intrinsic Rotation

    Science.gov (United States)

    Wang, Weixing

    2016-10-01

    It is shown for the first time that turbulence-driven residual Reynolds stress can account for both the shape and magnitude of the observed intrinsic toroidal rotation profile. Nonlinear, global gyrokinetic simulations using GTS of DIII-D ECH plasmas indicate a substantial ITG fluctuation-induced non-diffusive momentum flux generated around a mid-radius-peaked intrinsic toroidal rotation profile. The non-diffusive momentum flux is dominated by the residual stress with a negligible contribution from the momentum pinch. The residual stress profile shows a robust anti-gradient, dipole structure in a set of ECH discharges with varying ECH power. Such interesting features of non-diffusive momentum fluxes, in connection with edge momentum sources and sinks, are found to be critical to drive the non-monotonic core rotation profiles in the experiments. Both turbulence intensity gradient and zonal flow ExB shear are identified as major contributors to the generation of the k∥-asymmetry needed for the residual stress generation. By balancing the residual stress and the momentum diffusion, a self-organized, steady-state rotation profile is calculated. The predicted core rotation profiles agree well with the experimentally measured main-ion toroidal rotation. The validated model is further used to investigate the characteristic dependence of global rotation profile structure in the multi-dimensional parametric space covering turbulence type, q-profile structure and collisionality with the goal of developing physics understanding needed for rotation profile control and optimization. Interesting results obtained include intrinsic rotation reversal induced by ITG-TEM transition in flat-q profile regime and by change in q-profile from weak to normal shear.. Fluctuation-generated poloidal Reynolds stress is also shown to significantly modify the neoclassical poloidal rotation in a way consistent with experimental observations. Finally, the first-principles-based model is applied

  10. Longitudinal prediction and concurrent functioning of adolescent girls demonstrating various profiles of dating violence and victimization.

    Science.gov (United States)

    Chiodo, Debbie; Crooks, Claire V; Wolfe, David A; McIsaac, Caroline; Hughes, Ray; Jaffe, Peter G

    2012-08-01

    Adolescent girls are involved in physical dating violence as both perpetrators and victims, and there are negative consequences associated with each of these behaviors. This article used a prospective design with 519 girls dating in grade 9 to predict profiles of dating violence in grade 11 based on relationships with families of origin (child maltreatment experiences, harsh parenting), and peers (harassment, delinquency, relational aggression). In addition, dating violence profiles were compared on numerous indices of adjustment (school connectedness, grades, self-efficacy and community connectedness) and maladjustment (suicide attempts, distress, delinquency, sexual behavior) for descriptive purposes. The most common profile was no dating violence (n = 367) followed by mutual violence (n = 81). Smaller numbers of girls reported victimization or perpetration only (ns = 39 and 32, respectively). Predicting grade 11 dating violence profile membership from grade 9 relationships was limited, although delinquency, parental rejection, and sexual harassment perpetration predicted membership to the mutually violent group, and delinquency predicted the perpetrator-only group. Compared to the non-violent group, the mutually violent girls in grade 11 had lower grades, poorer self-efficacy, and lower school connectedness and community involvement. Furthermore, they had higher rates of peer aggression and delinquency, were less likely to use condoms and were much more likely to have considered suicide. There were fewer differences among the profiles for girls involved with dating violence. In addition, the victims-only group reported higher rates of sexual intercourse, comparable to the mutually violent group and those involved in nonviolent relationships. Implications for prevention and intervention are highlighted.

  11. A statistical approach for predicting thermal diffusivity profiles in fusion plasmas as a transport model

    International Nuclear Information System (INIS)

    Yokoyama, Masayuki

    2014-01-01

    A statistical approach is proposed to predict thermal diffusivity profiles as a transport “model” in fusion plasmas. It can provide regression expressions for the ion and electron heat diffusivities (χ i and χ e ), separately, to construct their radial profiles. An approach that this letter is proposing outstrips the conventional scaling laws for the global confinement time (τ E ) since it also deals with profiles (temperature, density, heating depositions etc.). This approach has become possible with the analysis database accumulated by the extensive application of the integrated transport analysis suite to experiment data. In this letter, TASK3D-a analysis database for high-ion-temperature (high-T i ) plasmas in the LHD (Large Helical Device) is used as an example to describe an approach. (author)

  12. HMMBinder: DNA-Binding Protein Prediction Using HMM Profile Based Features.

    Science.gov (United States)

    Zaman, Rianon; Chowdhury, Shahana Yasmin; Rashid, Mahmood A; Sharma, Alok; Dehzangi, Abdollah; Shatabda, Swakkhar

    2017-01-01

    DNA-binding proteins often play important role in various processes within the cell. Over the last decade, a wide range of classification algorithms and feature extraction techniques have been used to solve this problem. In this paper, we propose a novel DNA-binding protein prediction method called HMMBinder. HMMBinder uses monogram and bigram features extracted from the HMM profiles of the protein sequences. To the best of our knowledge, this is the first application of HMM profile based features for the DNA-binding protein prediction problem. We applied Support Vector Machines (SVM) as a classification technique in HMMBinder. Our method was tested on standard benchmark datasets. We experimentally show that our method outperforms the state-of-the-art methods found in the literature.

  13. HMMBinder: DNA-Binding Protein Prediction Using HMM Profile Based Features

    Directory of Open Access Journals (Sweden)

    Rianon Zaman

    2017-01-01

    Full Text Available DNA-binding proteins often play important role in various processes within the cell. Over the last decade, a wide range of classification algorithms and feature extraction techniques have been used to solve this problem. In this paper, we propose a novel DNA-binding protein prediction method called HMMBinder. HMMBinder uses monogram and bigram features extracted from the HMM profiles of the protein sequences. To the best of our knowledge, this is the first application of HMM profile based features for the DNA-binding protein prediction problem. We applied Support Vector Machines (SVM as a classification technique in HMMBinder. Our method was tested on standard benchmark datasets. We experimentally show that our method outperforms the state-of-the-art methods found in the literature.

  14. The prediction of concentration profiles for a NIMCIX column absorbing uranium from aqueous solution

    International Nuclear Information System (INIS)

    Wright, R.S.

    1979-01-01

    A procedure is proposed for the prediction of concentration profiles for a countercurrent ion-exchange absorption column, use being made of equilibrium and kinetic data derived from small-scale batch tests. A comparison is presented between the predictions and the measured performance of a column (2,5 m in diameter) absorbing uranium from solution. The method is shown to be adequate for design purposes provided that the data used are from tests in which the solution and resin conditions approximate those for which the plant is being designed [af

  15. Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

    Directory of Open Access Journals (Sweden)

    W. B. Mattes

    2013-01-01

    Full Text Available Addressing safety concerns such as drug-induced kidney injury (DIKI early in the drug pharmaceutical development process ensures both patient safety and efficient clinical development. We describe a unique adjunct to standard safety assessment wherein the metabolite profile of treated animals is compared with the MetaMap Tox metabolomics database in order to predict the potential for a wide variety of adverse events, including DIKI. To examine this approach, a study of five compounds (phenytoin, cyclosporin A, doxorubicin, captopril, and lisinopril was initiated by the Technology Evaluation Consortium under the auspices of the Drug Safety Executive Council (DSEC. The metabolite profiles for rats treated with these compounds matched established reference patterns in the MetaMap Tox metabolomics database indicative of each compound’s well-described clinical toxicities. For example, the DIKI associated with cyclosporine A and doxorubicin was correctly predicted by metabolite profiling, while no evidence for DIKI was found for phenytoin, consistent with its clinical picture. In some cases the clinical toxicity (hepatotoxicity, not generally seen in animal studies, was detected with MetaMap Tox. Thus metabolite profiling coupled with the MetaMap Tox metabolomics database offers a unique and powerful approach for augmenting safety assessment and avoiding clinical adverse events such as DIKI.

  16. Vacuum-assisted breast biopsy of suspected mammographic breast diagnoses: predictive value of serum proteomic profile

    International Nuclear Information System (INIS)

    Schittulli, F.; Ventrella, V.

    2009-01-01

    The project planned a series of actions oriented to different scientific questions: to complete the prospective collection of serum samples for serum proteomic analysis according to SOPs needed for the Italy-USA program; the identification of different mammographic signs for prediction of histological diagnosis of breast lesions through mammotone; the analysis of relationship between serum proteomic profile and micro histology characteristics of breast lesions

  17. Body composition indices and predicted cardiovascular disease risk profile among urban dwellers in Malaysia.

    Science.gov (United States)

    Su, Tin Tin; Amiri, Mohammadreza; Mohd Hairi, Farizah; Thangiah, Nithiah; Dahlui, Maznah; Majid, Hazreen Abdul

    2015-01-01

    This study aims to compare various body composition indices and their association with a predicted cardiovascular disease (CVD) risk profile in an urban population in Kuala Lumpur, Malaysia. A cross-sectional survey was conducted in metropolitan Kuala Lumpur, Malaysia, in 2012. Households were selected using a simple random-sampling method, and adult members were invited for medical screening. The Framingham Risk Scoring algorithm was used to predict CVD risk, which was then analyzed in association with body composition measurements, including waist circumference, waist-hip ratio, waist-height ratio, body fat percentage, and body mass index. Altogether, 882 individuals were included in our analyses. Indices that included waist-related measurements had the strongest association with CVD risk in both genders. After adjusting for demographic and socioeconomic variables, waist-related measurements retained the strongest correlations with predicted CVD risk in males. However, body mass index, waist-height ratio, and waist circumference had the strongest correlation with CVD risk in females. The waist-related indicators of abdominal obesity are important components of CVD risk profiles. As waist-related parameters can quickly and easily be measured, they should be routinely obtained in primary care settings and population health screens in order to assess future CVD risk profiles and design appropriate interventions.

  18. Body Composition Indices and Predicted Cardiovascular Disease Risk Profile among Urban Dwellers in Malaysia

    Directory of Open Access Journals (Sweden)

    Tin Tin Su

    2015-01-01

    Full Text Available Objectives. This study aims to compare various body composition indices and their association with a predicted cardiovascular disease (CVD risk profile in an urban population in Kuala Lumpur, Malaysia. Methods. A cross-sectional survey was conducted in metropolitan Kuala Lumpur, Malaysia, in 2012. Households were selected using a simple random-sampling method, and adult members were invited for medical screening. The Framingham Risk Scoring algorithm was used to predict CVD risk, which was then analyzed in association with body composition measurements, including waist circumference, waist-hip ratio, waist-height ratio, body fat percentage, and body mass index. Results. Altogether, 882 individuals were included in our analyses. Indices that included waist-related measurements had the strongest association with CVD risk in both genders. After adjusting for demographic and socioeconomic variables, waist-related measurements retained the strongest correlations with predicted CVD risk in males. However, body mass index, waist-height ratio, and waist circumference had the strongest correlation with CVD risk in females. Conclusions. The waist-related indicators of abdominal obesity are important components of CVD risk profiles. As waist-related parameters can quickly and easily be measured, they should be routinely obtained in primary care settings and population health screens in order to assess future CVD risk profiles and design appropriate interventions.

  19. Latent profiles of nonresidential father engagement six years after divorce predict long-term offspring outcomes.

    Science.gov (United States)

    Modecki, Kathryn Lynn; Hagan, Melissa J; Sandler, Irwin; Wolchik, Sharlene A

    2015-01-01

    This study examined profiles of nonresidential father engagement (i.e., support to the adolescent, contact frequency, remarriage, relocation, and interparental conflict) with their adolescent children (N = 156) 6 to 8 years following divorce and the prospective relation between these profiles and the psychosocial functioning of their offspring, 9 years later. Parental divorce occurred during late childhood to early adolescence; indicators of nonresidential father engagement were assessed during adolescence, and mental health problems and academic achievement of offspring were assessed 9 years later in young adulthood. Three profiles of father engagement were identified in our sample of mainly White, non-Hispanic divorced fathers: Moderate Involvement/Low Conflict, Low Involvement/Moderate Conflict, and High Involvement/High Conflict. Profiles differentially predicted offspring outcomes 9 years later when they were young adults, controlling for quality of the mother-adolescent relationship, mother's remarriage, mother's income, and gender, age, and offspring mental health problems in adolescence. Offspring of fathers characterized as Moderate Involvement/Low Conflict had the highest academic achievement and the lowest number of externalizing problems 9 years later compared to offspring whose fathers had profiles indicating either the highest or lowest levels of involvement but higher levels of conflict. Results indicate that greater paternal psychosocial support and more frequent father-adolescent contact do not outweigh the negative impact of interparental conflict on youth outcomes in the long term. Implications of findings for policy and intervention are discussed.

  20. Enhanced sensitivity to low dose irradiation of ApoE-/- mice mediated by early pro-inflammatory profile and delayed activation of the TGFβ1 cascade involved in fibrogenesis.

    Directory of Open Access Journals (Sweden)

    Virginie Monceau

    Full Text Available AIM: Investigating long-term cardiac effects of low doses of ionizing radiation is highly relevant in the context of interventional cardiology and radiotherapy. Epidemiological data report that low doses of irradiation to the heart can result in significant increase in the cardiovascular mortality by yet unknown mechanisms. In addition co-morbidity factor such as hypertension or/and atherosclerosis can enhance cardiac complications. Therefore, we explored the mechanisms that lead to long-term cardiac remodelling and investigated the interaction of radiation-induced damage to heart and cardiovascular systems with atherosclerosis, using wild-type and ApoE-deficient mice. METHODS AND RESULTS: ApoE-/- and wild-type mice were locally irradiated to the heart at 0, 0.2 and 2 Gy (RX. Twenty, 40 and 60 weeks post-irradiation, echocardiography were performed and hearts were collected for cardiomyocyte isolation, histopathological analysis, study of inflammatory infiltration and fibrosis deposition. Common and strain-specific pathogenic pathways were found. Significant alteration of left ventricular function (eccentric hypertrophy occurred in both strains of mice. Low dose irradiation (0.2 Gy induced premature death in ApoE-/- mice (47% died at 20 weeks. Acute inflammatory infiltrate was observed in scarring areas with accumulation of M1-macrophages and secretion of IL-6. Increased expression of the fibrogenic factors (TGF-β1 and PAI-1 was measured earlier in cardiomyocytes isolated from ApoE-/- than in wt animals. CONCLUSION: The present study shows that cardiac exposure to low dose of ionizing radiation induce significant physiological, histopathological, cellular and molecular alterations in irradiated heart with mild functional impairment. Atherosclerotic predisposition precipitated cardiac damage induced by low doses with an early pro-inflammatory polarization of macrophages.

  1. Mindfulness-Based Stress Reduction training reduces loneliness and pro-inflammatory gene expression in older adults: a small randomized controlled trial.

    Science.gov (United States)

    Creswell, J David; Irwin, Michael R; Burklund, Lisa J; Lieberman, Matthew D; Arevalo, Jesusa M G; Ma, Jeffrey; Breen, Elizabeth Crabb; Cole, Steven W

    2012-10-01

    Lonely older adults have increased expression of pro-inflammatory genes as well as increased risk for morbidity and mortality. Previous behavioral treatments have attempted to reduce loneliness and its concomitant health risks, but have had limited success. The present study tested whether the 8-week Mindfulness-Based Stress Reduction (MBSR) program (compared to a Wait-List control group) reduces loneliness and downregulates loneliness-related pro-inflammatory gene expression in older adults (N = 40). Consistent with study predictions, mixed effect linear models indicated that the MBSR program reduced loneliness, compared to small increases in loneliness in the control group (treatment condition × time interaction: F(1,35) = 7.86, p = .008). Moreover, at baseline, there was an association between reported loneliness and upregulated pro-inflammatory NF-κB-related gene expression in circulating leukocytes, and MBSR downregulated this NF-κB-associated gene expression profile at post-treatment. Finally, there was a trend for MBSR to reduce C Reactive Protein (treatment condition × time interaction: (F(1,33) = 3.39, p = .075). This work provides an initial indication that MBSR may be a novel treatment approach for reducing loneliness and related pro-inflammatory gene expression in older adults. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    Directory of Open Access Journals (Sweden)

    Stéphanie Pérot

    Full Text Available Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely

  3. Insights into an original pocket-ligand pair classification: a promising tool for ligand profile prediction.

    Science.gov (United States)

    Pérot, Stéphanie; Regad, Leslie; Reynès, Christelle; Spérandio, Olivier; Miteva, Maria A; Villoutreix, Bruno O; Camproux, Anne-Claude

    2013-01-01

    Pockets are today at the cornerstones of modern drug discovery projects and at the crossroad of several research fields, from structural biology to mathematical modeling. Being able to predict if a small molecule could bind to one or more protein targets or if a protein could bind to some given ligands is very useful for drug discovery endeavors, anticipation of binding to off- and anti-targets. To date, several studies explore such questions from chemogenomic approach to reverse docking methods. Most of these studies have been performed either from the viewpoint of ligands or targets. However it seems valuable to use information from both ligands and target binding pockets. Hence, we present a multivariate approach relating ligand properties with protein pocket properties from the analysis of known ligand-protein interactions. We explored and optimized the pocket-ligand pair space by combining pocket and ligand descriptors using Principal Component Analysis and developed a classification engine on this paired space, revealing five main clusters of pocket-ligand pairs sharing specific and similar structural or physico-chemical properties. These pocket-ligand pair clusters highlight correspondences between pocket and ligand topological and physico-chemical properties and capture relevant information with respect to protein-ligand interactions. Based on these pocket-ligand correspondences, a protocol of prediction of clusters sharing similarity in terms of recognition characteristics is developed for a given pocket-ligand complex and gives high performances. It is then extended to cluster prediction for a given pocket in order to acquire knowledge about its expected ligand profile or to cluster prediction for a given ligand in order to acquire knowledge about its expected pocket profile. This prediction approach shows promising results and could contribute to predict some ligand properties critical for binding to a given pocket, and conversely, some key pocket

  4. Predictive properties of plasma amino acid profile for cardiovascular disease in patients with type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Shinji Kume

    Full Text Available Prevention of cardiovascular disease (CVD is an important therapeutic object of diabetes care. This study assessed whether an index based on plasma free amino acid (PFAA profiles could predict the onset of CVD in diabetic patients. The baseline concentrations of 31 PFAAs were measured with high-performance liquid chromatography-electrospray ionization-mass spectrometry in 385 Japanese patients with type 2 diabetes registered in 2001 for our prospective observational follow-up study. During 10 years of follow-up, 63 patients developed cardiovascular composite endpoints (myocardial infarction, angina pectoris, worsening of heart failure and stroke. Using the PFAA profiles and clinical information, an index (CVD-AI consisting of six amino acids to predict the onset of any endpoints was retrospectively constructed. CVD-AI levels were significantly higher in patients who did than did not develop CVD. The area under the receiver-operator characteristic curve of CVD-AI (0.72 [95% confidence interval (CI: 0.64-0.79] showed equal or slightly better discriminatory capacity than urinary albumin excretion rate (0.69 [95% CI: 0.62-0.77] on predicting endpoints. A multivariate Cox proportional hazards regression analysis showed that the high level of CVD-AI was identified as an independent risk factor for CVD (adjusted hazard ratio: 2.86 [95% CI: 1.57-5.19]. This predictive effect of CVD-AI was observed even in patients with normoalbuminuria, as well as those with albuminuria. In conclusion, these results suggest that CVD-AI based on PFAA profiles is useful for identifying diabetic patients at risk for CVD regardless of the degree of albuminuria, or for improving the discriminative capability by combining it with albuminuria.

  5. Predictive Properties of Plasma Amino Acid Profile for Cardiovascular Disease in Patients with Type 2 Diabetes

    Science.gov (United States)

    Kume, Shinji; Araki, Shin-ichi; Ono, Nobukazu; Shinhara, Atsuko; Muramatsu, Takahiko; Araki, Hisazumi; Isshiki, Keiji; Nakamura, Kazuki; Miyano, Hiroshi; Koya, Daisuke; Haneda, Masakazu; Ugi, Satoshi; Kawai, Hiromichi; Kashiwagi, Atsunori; Uzu, Takashi; Maegawa, Hiroshi

    2014-01-01

    Prevention of cardiovascular disease (CVD) is an important therapeutic object of diabetes care. This study assessed whether an index based on plasma free amino acid (PFAA) profiles could predict the onset of CVD in diabetic patients. The baseline concentrations of 31 PFAAs were measured with high-performance liquid chromatography-electrospray ionization-mass spectrometry in 385 Japanese patients with type 2 diabetes registered in 2001 for our prospective observational follow-up study. During 10 years of follow-up, 63 patients developed cardiovascular composite endpoints (myocardial infarction, angina pectoris, worsening of heart failure and stroke). Using the PFAA profiles and clinical information, an index (CVD-AI) consisting of six amino acids to predict the onset of any endpoints was retrospectively constructed. CVD-AI levels were significantly higher in patients who did than did not develop CVD. The area under the receiver-operator characteristic curve of CVD-AI (0.72 [95% confidence interval (CI): 0.64–0.79]) showed equal or slightly better discriminatory capacity than urinary albumin excretion rate (0.69 [95% CI: 0.62–0.77]) on predicting endpoints. A multivariate Cox proportional hazards regression analysis showed that the high level of CVD-AI was identified as an independent risk factor for CVD (adjusted hazard ratio: 2.86 [95% CI: 1.57–5.19]). This predictive effect of CVD-AI was observed even in patients with normoalbuminuria, as well as those with albuminuria. In conclusion, these results suggest that CVD-AI based on PFAA profiles is useful for identifying diabetic patients at risk for CVD regardless of the degree of albuminuria, or for improving the discriminative capability by combining it with albuminuria. PMID:24971671

  6. SVM-PB-Pred: SVM based protein block prediction method using sequence profiles and secondary structures.

    Science.gov (United States)

    Suresh, V; Parthasarathy, S

    2014-01-01

    We developed a support vector machine based web server called SVM-PB-Pred, to predict the Protein Block for any given amino acid sequence. The input features of SVM-PB-Pred include i) sequence profiles (PSSM) and ii) actual secondary structures (SS) from DSSP method or predicted secondary structures from NPS@ and GOR4 methods. There were three combined input features PSSM+SS(DSSP), PSSM+SS(NPS@) and PSSM+SS(GOR4) used to test and train the SVM models. Similarly, four datasets RS90, DB433, LI1264 and SP1577 were used to develop the SVM models. These four SVM models developed were tested using three different benchmarking tests namely; (i) self consistency, (ii) seven fold cross validation test and (iii) independent case test. The maximum possible prediction accuracy of ~70% was observed in self consistency test for the SVM models of both LI1264 and SP1577 datasets, where PSSM+SS(DSSP) input features was used to test. The prediction accuracies were reduced to ~53% for PSSM+SS(NPS@) and ~43% for PSSM+SS(GOR4) in independent case test, for the SVM models of above two same datasets. Using our method, it is possible to predict the protein block letters for any query protein sequence with ~53% accuracy, when the SP1577 dataset and predicted secondary structure from NPS@ server were used. The SVM-PB-Pred server can be freely accessed through http://bioinfo.bdu.ac.in/~svmpbpred.

  7. Elderly fall risk prediction based on a physiological profile approach using artificial neural networks.

    Science.gov (United States)

    Razmara, Jafar; Zaboli, Mohammad Hassan; Hassankhani, Hadi

    2016-11-01

    Falls play a critical role in older people's life as it is an important source of morbidity and mortality in elders. In this article, elders fall risk is predicted based on a physiological profile approach using a multilayer neural network with back-propagation learning algorithm. The personal physiological profile of 200 elders was collected through a questionnaire and used as the experimental data for learning and testing the neural network. The profile contains a series of simple factors putting elders at risk for falls such as vision abilities, muscle forces, and some other daily activities and grouped into two sets: psychological factors and public factors. The experimental data were investigated to select factors with high impact using principal component analysis. The experimental results show an accuracy of ≈90 percent and ≈87.5 percent for fall prediction among the psychological and public factors, respectively. Furthermore, combining these two datasets yield an accuracy of ≈91 percent that is better than the accuracy of single datasets. The proposed method suggests a set of valid and reliable measurements that can be employed in a range of health care systems and physical therapy to distinguish people who are at risk for falls.

  8. ORION: a web server for protein fold recognition and structure prediction using evolutionary hybrid profiles.

    Science.gov (United States)

    Ghouzam, Yassine; Postic, Guillaume; Guerin, Pierre-Edouard; de Brevern, Alexandre G; Gelly, Jean-Christophe

    2016-06-20

    Protein structure prediction based on comparative modeling is the most efficient way to produce structural models when it can be performed. ORION is a dedicated webserver based on a new strategy that performs this task. The identification by ORION of suitable templates is performed using an original profile-profile approach that combines sequence and structure evolution information. Structure evolution information is encoded into profiles using structural features, such as solvent accessibility and local conformation -with Protein Blocks-, which give an accurate description of the local protein structure. ORION has recently been improved, increasing by 5% the quality of its results. The ORION web server accepts a single protein sequence as input and searches homologous protein structures within minutes. Various databases such as PDB, SCOP and HOMSTRAD can be mined to find an appropriate structural template. For the modeling step, a protein 3D structure can be directly obtained from the selected template by MODELLER and displayed with global and local quality model estimation measures. The sequence and the predicted structure of 4 examples from the CAMEO server and a recent CASP11 target from the 'Hard' category (T0818-D1) are shown as pertinent examples. Our web server is accessible at http://www.dsimb.inserm.fr/ORION/.

  9. Profile control simulations and experiments on TCV: a controller test environment and results using a model-based predictive controller

    Science.gov (United States)

    Maljaars, E.; Felici, F.; Blanken, T. C.; Galperti, C.; Sauter, O.; de Baar, M. R.; Carpanese, F.; Goodman, T. P.; Kim, D.; Kim, S. H.; Kong, M.; Mavkov, B.; Merle, A.; Moret, J. M.; Nouailletas, R.; Scheffer, M.; Teplukhina, A. A.; Vu, N. M. T.; The EUROfusion MST1-team; The TCV-team

    2017-12-01

    The successful performance of a model predictive profile controller is demonstrated in simulations and experiments on the TCV tokamak, employing a profile controller test environment. Stable high-performance tokamak operation in hybrid and advanced plasma scenarios requires control over the safety factor profile (q-profile) and kinetic plasma parameters such as the plasma beta. This demands to establish reliable profile control routines in presently operational tokamaks. We present a model predictive profile controller that controls the q-profile and plasma beta using power requests to two clusters of gyrotrons and the plasma current request. The performance of the controller is analyzed in both simulation and TCV L-mode discharges where successful tracking of the estimated inverse q-profile as well as plasma beta is demonstrated under uncertain plasma conditions and the presence of disturbances. The controller exploits the knowledge of the time-varying actuator limits in the actuator input calculation itself such that fast transitions between targets are achieved without overshoot. A software environment is employed to prepare and test this and three other profile controllers in parallel in simulations and experiments on TCV. This set of tools includes the rapid plasma transport simulator RAPTOR and various algorithms to reconstruct the plasma equilibrium and plasma profiles by merging the available measurements with model-based predictions. In this work the estimated q-profile is merely based on RAPTOR model predictions due to the absence of internal current density measurements in TCV. These results encourage to further exploit model predictive profile control in experiments on TCV and other (future) tokamaks.

  10. Alcoholism: a systemic proinflammatory condition.

    Science.gov (United States)

    González-Reimers, Emilio; Santolaria-Fernández, Francisco; Martín-González, María Candelaria; Fernández-Rodríguez, Camino María; Quintero-Platt, Geraldine

    2014-10-28

    Excessive ethanol consumption affects virtually any organ, both by indirect and direct mechanisms. Considerable research in the last two decades has widened the knowledge about the paramount importance of proinflammatory cytokines and oxidative damage in the pathogenesis of many of the systemic manifestations of alcoholism. These cytokines derive primarily from activated Kupffer cells exposed to Gram-negative intestinal bacteria, which reach the liver in supra-physiological amounts due to ethanol-mediated increased gut permeability. Reactive oxygen species (ROS) that enhance the inflammatory response are generated both by activation of Kupffer cells and by the direct metabolic effects of ethanol. The effects of this increased cytokine secretion and ROS generation lie far beyond liver damage. In addition to the classic consequences of endotoxemia associated with liver cirrhosis that were described several decades ago, important research in the last ten years has shown that cytokines may also induce damage in remote organs such as brain, bone, muscle, heart, lung, gonads, peripheral nerve, and pancreas. These effects are even seen in alcoholics without significant liver disease. Therefore, alcoholism can be viewed as an inflammatory condition, a concept which opens the possibility of using new therapeutic weapons to treat some of the complications of this devastating and frequent disease. In this review we examine some of the most outstanding consequences of the altered cytokine regulation that occurs in alcoholics in organs other than the liver.

  11. Non-invasively predicting differentiation of pancreatic cancer through comparative serum metabonomic profiling.

    Science.gov (United States)

    Wen, Shi; Zhan, Bohan; Feng, Jianghua; Hu, Weize; Lin, Xianchao; Bai, Jianxi; Huang, Heguang

    2017-11-02

    The differentiation of pancreatic ductal adenocarcinoma (PDAC) could be associated with prognosis and may influence the choices of clinical management. No applicable methods could reliably predict the tumor differentiation preoperatively. Thus, the aim of this study was to compare the metabonomic profiling of pancreatic ductal adenocarcinoma with different differentiations and assess the feasibility of predicting tumor differentiations through metabonomic strategy based on nuclear magnetic resonance spectroscopy. By implanting pancreatic cancer cell strains Panc-1, Bxpc-3 and SW1990 in nude mice in situ, we successfully established the orthotopic xenograft models of PDAC with different differentiations. The metabonomic profiling of serum from different PDAC was achieved and analyzed by using 1 H nuclear magnetic resonance (NMR) spectroscopy combined with the multivariate statistical analysis. Then, the differential metabolites acquired were used for enrichment analysis of metabolic pathways to get a deep insight. An obvious metabonomic difference was demonstrated between all groups and the pattern recognition models were established successfully. The higher concentrations of amino acids, glycolytic and glutaminolytic participators in SW1990 and choline-contain metabolites in Panc-1 relative to other PDAC cells were demonstrated, which may be served as potential indicators for tumor differentiation. The metabolic pathways and differential metabolites identified in current study may be associated with specific pathways such as serine-glycine-one-carbon and glutaminolytic pathways, which can regulate tumorous proliferation and epigenetic regulation. The NMR-based metabonomic strategy may be served as a non-invasive detection method for predicting tumor differentiation preoperatively.

  12. Response-predictive gene expression profiling of glioma progenitor cells in vitro.

    Directory of Open Access Journals (Sweden)

    Sylvia Moeckel

    Full Text Available High-grade gliomas are amongst the most deadly human tumors. Treatment results are disappointing. Still, in several trials around 20% of patients respond to therapy. To date, diagnostic strategies to identify patients that will profit from a specific therapy do not exist.In this study, we used serum-free short-term treated in vitro cell cultures to predict treatment response in vitro. This approach allowed us (a to enrich specimens for brain tumor initiating cells and (b to confront cells with a therapeutic agent before expression profiling.As a proof of principle we analyzed gene expression in 18 short-term serum-free cultures of high-grade gliomas enhanced for brain tumor initiating cells (BTIC before and after in vitro treatment with the tyrosine kinase inhibitor Sunitinib. Profiles from treated progenitor cells allowed to predict therapy-induced impairment of proliferation in vitro.For the tyrosine kinase inhibitor Sunitinib used in this dataset, the approach revealed additional predictive information in comparison to the evaluation of classical signaling analysis.

  13. Prediction of Phenotypic Antimicrobial Resistance Profiles From Whole Genome Sequences of Non-typhoidal Salmonella enterica.

    Science.gov (United States)

    Neuert, Saskia; Nair, Satheesh; Day, Martin R; Doumith, Michel; Ashton, Philip M; Mellor, Kate C; Jenkins, Claire; Hopkins, Katie L; Woodford, Neil; de Pinna, Elizabeth; Godbole, Gauri; Dallman, Timothy J

    2018-01-01

    Surveillance of antimicrobial resistance (AMR) in non-typhoidal Salmonella enterica (NTS), is essential for monitoring transmission of resistance from the food chain to humans, and for establishing effective treatment protocols. We evaluated the prediction of phenotypic resistance in NTS from genotypic profiles derived from whole genome sequencing (WGS). Genes and chromosomal mutations responsible for phenotypic resistance were sought in WGS data from 3,491 NTS isolates received by Public Health England's Gastrointestinal Bacteria Reference Unit between April 2014 and March 2015. Inferred genotypic AMR profiles were compared with phenotypic susceptibilities determined for fifteen antimicrobials using EUCAST guidelines. Discrepancies between phenotypic and genotypic profiles for one or more antimicrobials were detected for 76 isolates (2.18%) although only 88/52,365 (0.17%) isolate/antimicrobial combinations were discordant. Of the discrepant results, the largest number were associated with streptomycin (67.05%, n = 59). Pan-susceptibility was observed in 2,190 isolates (62.73%). Overall, resistance to tetracyclines was most common (26.27% of isolates, n = 917) followed by sulphonamides (23.72%, n = 828) and ampicillin (21.43%, n = 748). Multidrug resistance (MDR), i.e., resistance to three or more antimicrobial classes, was detected in 848 isolates (24.29%) with resistance to ampicillin, streptomycin, sulphonamides and tetracyclines being the most common MDR profile ( n = 231; 27.24%). For isolates with this profile, all but one were S . Typhimurium and 94.81% ( n = 219) had the resistance determinants bla TEM-1, strA-strB, sul2 and tet (A). Extended-spectrum β-lactamase genes were identified in 41 isolates (1.17%) and multiple mutations in chromosomal genes associated with ciprofloxacin resistance in 82 isolates (2.35%). This study showed that WGS is suitable as a rapid means of determining AMR patterns of NTS for public health surveillance.

  14. Profile control simulations and experiments on TCV : A controller test environment and results using a model-based predictive controller

    NARCIS (Netherlands)

    Maljaars, E.; Felici, F.; Blanken, T.C.; Galperti, C.; Sauter, O.; de Baar, M.R.; Carpanese, F.; Goodman, T.P.; Kim, D.; Kim, S.H.; Kong, M.G.; Mavkov, B.; Merle, A.; Moret, J.M.; Nouailletas, R.; Scheffer, M.; Teplukhina, A.A.; Vu, N.M.T.

    2017-01-01

    The successful performance of a model predictive profile controller is demonstrated in simulations and experiments on the TCV tokamak, employing a profile controller test environment. Stable high-performance tokamak operation in hybrid and advanced plasma scenarios requires control over the safety

  15. Profile control simulations and experiments on TCV: a controller test environment and results using a model-based predictive controller

    NARCIS (Netherlands)

    Maljaars, B.; Felici, F.; Blanken, T. C.; Galperti, C.; Sauter, O.; de Baar, M. R.; Carpanese, F.; Goodman, T. P.; Kim, D.; Kim, S. H.; Kong, M.; Mavkov, B.; Merle, A.; Moret, J.; Nouailletas, R.; Scheffer, M.; Teplukhina, A.; Vu, T.

    2017-01-01

    The successful performance of a model predictive profile controller is demonstrated in simulations and experiments on the TCV tokamak, employing a profile controller test environment. Stable high-performance tokamak operation in hybrid and advanced plasma scenarios requires control over the safety

  16. Profiles

    International Nuclear Information System (INIS)

    2004-01-01

    Profiles is a synthetic overview of more than 100 national energy markets in the world, providing insightful facts and key energy statistics. A Profile is structured around 6 main items and completed by key statistics: Ministries, public agencies, energy policy are concerned; main companies in the oil, gas, electricity and coal sectors, status, shareholders; reserve, production, imports and exports, electricity and refining capacities; deregulation of prices, subsidies, taxes; consumption trends by sector, energy market shares; main energy projects, production and consumption prospects. Statistical Profiles are present in about 3 pages the main data and indicators on oil, gas, coal and electricity. (A.L.B.)

  17. Development of Castration Resistant Prostate Cancer can be Predicted by a DNA Hypermethylation Profile.

    Science.gov (United States)

    Angulo, Javier C; Andrés, Guillermo; Ashour, Nadia; Sánchez-Chapado, Manuel; López, Jose I; Ropero, Santiago

    2016-03-01

    Detection of DNA hypermethylation has emerged as a novel molecular biomarker for prostate cancer diagnosis and evaluation of prognosis. We sought to define whether a hypermethylation profile of patients with prostate cancer on androgen deprivation would predict castrate resistant prostate cancer. Genome-wide methylation analysis was performed using a methylation cancer panel in 10 normal prostates and 45 tumor samples from patients placed on androgen deprivation who were followed until castrate resistant disease developed. Castrate resistant disease was defined according to EAU (European Association of Urology) guideline criteria. Two pathologists reviewed the Gleason score, Ki-67 index and neuroendocrine differentiation. Hierarchical clustering analysis was performed and relationships with outcome were investigated by Cox regression and log rank analysis. We found 61 genes that were significantly hypermethylated in greater than 20% of tumors analyzed. Three clusters of patients were characterized by a DNA methylation profile, including 1 at risk for earlier castrate resistant disease (log rank p = 0.019) and specific mortality (log rank p = 0.002). Hypermethylation of ETV1 (HR 3.75) and ZNF215 (HR 2.89) predicted disease progression despite androgen deprivation. Hypermethylation of IRAK3 (HR 13.72), ZNF215 (HR 4.81) and SEPT9 (HR 7.64) were independent markers of prognosis. Prostate specific antigen greater than 25 ng/ml, Gleason pattern 5, Ki-67 index greater than 12% and metastasis at diagnosis also predicted a negative response to androgen deprivation. Study limitations included the retrospective design and limited number of cases. Epigenetic silencing of the mentioned genes could be novel molecular markers for the prognosis of advanced prostate cancer. It might predict castrate resistance during hormone deprivation and, thus, disease specific mortality. Gene hypermethylation is associated with disease progression in patients who receive hormone therapy. It

  18. Hierarchical Status Predicts Behavioral Vulnerability and Nucleus Accumbens Metabolic Profile Following Chronic Social Defeat Stress.

    Science.gov (United States)

    Larrieu, Thomas; Cherix, Antoine; Duque, Aranzazu; Rodrigues, João; Lei, Hongxia; Gruetter, Rolf; Sandi, Carmen

    2017-07-24

    Extensive data highlight the existence of major differences in individuals' susceptibility to stress [1-4]. While genetic factors [5, 6] and exposure to early life stress [7, 8] are key components for such neurobehavioral diversity, intriguing observations revealed individual differences in response to stress in inbred mice [9-12]. This raised the possibility that other factors might be critical in stress vulnerability. A key challenge in the field is to identify non-invasively risk factors for vulnerability to stress. Here, we investigated whether behavioral factors, emerging from preexisting dominance hierarchies, could predict vulnerability to chronic stress [9, 13-16]. We applied a chronic social defeat stress (CSDS) model of depression in C57BL/6J mice to investigate the predictive power of hierarchical status to pinpoint which individuals will exhibit susceptibility to CSDS. Given that the high social status of dominant mice would be the one particularly challenged by CSDS, we predicted and found that dominant individuals were the ones showing a strong susceptibility profile as indicated by strong social avoidance following CSDS, while subordinate mice were not affected. Data from 1 H-NMR spectroscopy revealed that the metabolic profile in the nucleus accumbens (NAc) relates to social status and vulnerability to stress. Under basal conditions, subordinates show lower levels of energy-related metabolites compared to dominants. In subordinates, but not dominants, levels of these metabolites were increased after exposure to CSDS. To the best of our knowledge, this is the first study that identifies non-invasively the origin of behavioral risk factors predictive of stress-induced depression-like behaviors associated with metabolic changes. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Profiling persistent tubercule bacilli from patient sputa during therapy predicts early drug efficacy.

    Science.gov (United States)

    Honeyborne, Isobella; McHugh, Timothy D; Kuittinen, Iitu; Cichonska, Anna; Evangelopoulos, Dimitrios; Ronacher, Katharina; van Helden, Paul D; Gillespie, Stephen H; Fernandez-Reyes, Delmiro; Walzl, Gerhard; Rousu, Juho; Butcher, Philip D; Waddell, Simon J

    2016-04-07

    New treatment options are needed to maintain and improve therapy for tuberculosis, which caused the death of 1.5 million people in 2013 despite potential for an 86 % treatment success rate. A greater understanding of Mycobacterium tuberculosis (M.tb) bacilli that persist through drug therapy will aid drug development programs. Predictive biomarkers for treatment efficacy are also a research priority. Genome-wide transcriptional profiling was used to map the mRNA signatures of M.tb from the sputa of 15 patients before and 3, 7 and 14 days after the start of standard regimen drug treatment. The mRNA profiles of bacilli through the first 2 weeks of therapy reflected drug activity at 3 days with transcriptional signatures at days 7 and 14 consistent with reduced M.tb metabolic activity similar to the profile of pre-chemotherapy bacilli. These results suggest that a pre-existing drug-tolerant M.tb population dominates sputum before and after early drug treatment, and that the mRNA signature at day 3 marks the killing of a drug-sensitive sub-population of bacilli. Modelling patient indices of disease severity with bacterial gene expression patterns demonstrated that both microbiological and clinical parameters were reflected in the divergent M.tb responses and provided evidence that factors such as bacterial load and disease pathology influence the host-pathogen interplay and the phenotypic state of bacilli. Transcriptional signatures were also defined that predicted measures of early treatment success (rate of decline in bacterial load over 3 days, TB test positivity at 2 months, and bacterial load at 2 months). This study defines the transcriptional signature of M.tb bacilli that have been expectorated in sputum after two weeks of drug therapy, characterizing the phenotypic state of bacilli that persist through treatment. We demonstrate that variability in clinical manifestations of disease are detectable in bacterial sputa signatures, and that the changing M.tb m

  20. Prediction of the Inlet Nozzle Velocity Profiles for the CANDU-6 Moderator Analysis

    International Nuclear Information System (INIS)

    Yoon, Churl; Park, Joo Hwan

    2006-01-01

    For the moderator analysis of the CANDU reactors in Korea, predicting local moderator subcooling in the Calandria vessels is one of the main concerns for the estimation of heat sink capability of moderator under LOCA transients. The moderator circulation pattern is determined by the combined forces of the inlet jet momentum and the buoyancy flow. Even though the inlet boundary condition plays an important role in determining the moderator circulations, no measured data of detailed inlet velocity profiles is available. The purpose of this study is to produce the velocity profiles at the inlet nozzles by a CFD simulation. To produce the velocity vector fields at the inlet nozzle surfaces, the internal flows in the nozzle assembly were simulated by using a commercial CFD code, CFX-5.7. In the reference, the analytical capability of CFX-5.7 had been estimated by a validation of the CFD code against available experimental data for separate flow phenomena. Various turbulence models and grid spacing had been also tested. In the following section, the interface treatment between the computational domains would be explained. In section 3, the inlet nozzle flow through the CANDU moderator nozzle assembly was predicted by using the obtained technology of the CFD simulation

  1. How good are publicly available web services that predict bioactivity profiles for drug repurposing?

    Science.gov (United States)

    Murtazalieva, K A; Druzhilovskiy, D S; Goel, R K; Sastry, G N; Poroikov, V V

    2017-10-01

    Drug repurposing provides a non-laborious and less expensive way for finding new human medicines. Computational assessment of bioactivity profiles shed light on the hidden pharmacological potential of the launched drugs. Currently, several freely available computational tools are available via the Internet, which predict multitarget profiles of drug-like compounds. They are based on chemical similarity assessment (ChemProt, SuperPred, SEA, SwissTargetPrediction and TargetHunter) or machine learning methods (ChemProt and PASS). To compare their performance, this study has created two evaluation sets, consisting of (1) 50 well-known repositioned drugs and (2) 12 drugs recently patented for new indications. In the first set, sensitivity values varied from 0.64 (TarPred) to 1.00 (PASS Online) for the initial indications and from 0.64 (TarPred) to 0.98 (PASS Online) for the repurposed indications. In the second set, sensitivity values varied from 0.08 (SuperPred) to 1.00 (PASS Online) for the initial indications and from 0.00 (SuperPred) to 1.00 (PASS Online) for the repurposed indications. Thus, this analysis demonstrated that the performance of machine learning methods surpassed those of chemical similarity assessments, particularly in the case of novel repurposed indications.

  2. Profiles of verbal working memory growth predict speech and language development in children with cochlear implants.

    Science.gov (United States)

    Kronenberger, William G; Pisoni, David B; Harris, Michael S; Hoen, Helena M; Xu, Huiping; Miyamoto, Richard T

    2013-06-01

    Verbal short-term memory (STM) and working memory (WM) skills predict speech and language outcomes in children with cochlear implants (CIs) even after conventional demographic, device, and medical factors are taken into account. However, prior research has focused on single end point outcomes as opposed to the longitudinal process of development of verbal STM/WM and speech-language skills. In this study, the authors investigated relations between profiles of verbal STM/WM development and speech-language development over time. Profiles of verbal STM/WM development were identified through the use of group-based trajectory analysis of repeated digit span measures over at least a 2-year time period in a sample of 66 children (ages 6-16 years) with CIs. Subjects also completed repeated assessments of speech and language skills during the same time period. Clusters representing different patterns of development of verbal STM (digit span forward scores) were related to the growth rate of vocabulary and language comprehension skills over time. Clusters representing different patterns of development of verbal WM (digit span backward scores) were related to the growth rate of vocabulary and spoken word recognition skills over time. Different patterns of development of verbal STM/WM capacity predict the dynamic process of development of speech and language skills in this clinical population.

  3. Predicting Mental Imagery-Based BCI Performance from Personality, Cognitive Profile and Neurophysiological Patterns.

    Directory of Open Access Journals (Sweden)

    Camille Jeunet

    Full Text Available Mental-Imagery based Brain-Computer Interfaces (MI-BCIs allow their users to send commands to a computer using their brain-activity alone (typically measured by ElectroEncephaloGraphy-EEG, which is processed while they perform specific mental tasks. While very promising, MI-BCIs remain barely used outside laboratories because of the difficulty encountered by users to control them. Indeed, although some users obtain good control performances after training, a substantial proportion remains unable to reliably control an MI-BCI. This huge variability in user-performance led the community to look for predictors of MI-BCI control ability. However, these predictors were only explored for motor-imagery based BCIs, and mostly for a single training session per subject. In this study, 18 participants were instructed to learn to control an EEG-based MI-BCI by performing 3 MI-tasks, 2 of which were non-motor tasks, across 6 training sessions, on 6 different days. Relationships between the participants' BCI control performances and their personality, cognitive profile and neurophysiological markers were explored. While no relevant relationships with neurophysiological markers were found, strong correlations between MI-BCI performances and mental-rotation scores (reflecting spatial abilities were revealed. Also, a predictive model of MI-BCI performance based on psychometric questionnaire scores was proposed. A leave-one-subject-out cross validation process revealed the stability and reliability of this model: it enabled to predict participants' performance with a mean error of less than 3 points. This study determined how users' profiles impact their MI-BCI control ability and thus clears the way for designing novel MI-BCI training protocols, adapted to the profile of each user.

  4. Gas chromatography/mass spectrometry based component profiling and quality prediction for Japanese sake.

    Science.gov (United States)

    Mimura, Natsuki; Isogai, Atsuko; Iwashita, Kazuhiro; Bamba, Takeshi; Fukusaki, Eiichiro

    2014-10-01

    Sake is a Japanese traditional alcoholic beverage, which is produced by simultaneous saccharification and alcohol fermentation of polished and steamed rice by Aspergillus oryzae and Saccharomyces cerevisiae. About 300 compounds have been identified in sake, and the contribution of individual components to the sake flavor has been examined at the same time. However, only a few compounds could explain the characteristics alone and most of the attributes still remain unclear. The purpose of this study was to examine the relationship between the component profile and the attributes of sake. Gas chromatography coupled with mass spectrometry (GC/MS)-based non-targeted analysis was employed to obtain the low molecular weight component profile of Japanese sake including both nonvolatile and volatile compounds. Sake attributes and overall quality were assessed by analytical descriptive sensory test and the prediction model of the sensory score from the component profile was constructed by means of orthogonal projections to latent structures (OPLS) regression analysis. Our results showed that 12 sake attributes [ginjo-ka (aroma of premium ginjo sake), grassy/aldehydic odor, sweet aroma/caramel/burnt odor, sulfury odor, sour taste, umami, bitter taste, body, amakara (dryness), aftertaste, pungent/smoothness and appearance] and overall quality were accurately explained by component profiles. In addition, we were able to select statistically significant components according to variable importance on projection (VIP). Our methodology clarified the correlation between sake attribute and 200 low molecular components and presented the importance of each component thus, providing new insights to the flavor study of sake. Copyright © 2014 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  5. Electromyographic Patterns during Golf Swing: Activation Sequence Profiling and Prediction of Shot Effectiveness.

    Science.gov (United States)

    Verikas, Antanas; Vaiciukynas, Evaldas; Gelzinis, Adas; Parker, James; Olsson, M Charlotte

    2016-04-23

    This study analyzes muscle activity, recorded in an eight-channel electromyographic (EMG) signal stream, during the golf swing using a 7-iron club and exploits information extracted from EMG dynamics to predict the success of the resulting shot. Muscles of the arm and shoulder on both the left and right sides, namely flexor carpi radialis, extensor digitorum communis, rhomboideus and trapezius, are considered for 15 golf players (∼5 shots each). The method using Gaussian filtering is outlined for EMG onset time estimation in each channel and activation sequence profiling. Shots of each player revealed a persistent pattern of muscle activation. Profiles were plotted and insights with respect to player effectiveness were provided. Inspection of EMG dynamics revealed a pair of highest peaks in each channel as the hallmark of golf swing, and a custom application of peak detection for automatic extraction of swing segment was introduced. Various EMG features, encompassing 22 feature sets, were constructed. Feature sets were used individually and also in decision-level fusion for the prediction of shot effectiveness. The prediction of the target attribute, such as club head speed or ball carry distance, was investigated using random forest as the learner in detection and regression tasks. Detection evaluates the personal effectiveness of a shot with respect to the player-specific average, whereas regression estimates the value of target attribute, using EMG features as predictors. Fusion after decision optimization provided the best results: the equal error rate in detection was 24.3% for the speed and 31.7% for the distance; the mean absolute percentage error in regression was 3.2% for the speed and 6.4% for the distance. Proposed EMG feature sets were found to be useful, especially when used in combination. Rankings of feature sets indicated statistics for muscle activity in both the left and right body sides, correlation-based analysis of EMG dynamics and features

  6. Electromyographic Patterns during Golf Swing: Activation Sequence Profiling and Prediction of Shot Effectiveness

    Directory of Open Access Journals (Sweden)

    Antanas Verikas

    2016-04-01

    Full Text Available This study analyzes muscle activity, recorded in an eight-channel electromyographic (EMG signal stream, during the golf swing using a 7-iron club and exploits information extracted from EMG dynamics to predict the success of the resulting shot. Muscles of the arm and shoulder on both the left and right sides, namely flexor carpi radialis, extensor digitorum communis, rhomboideus and trapezius, are considered for 15 golf players (∼5 shots each. The method using Gaussian filtering is outlined for EMG onset time estimation in each channel and activation sequence profiling. Shots of each player revealed a persistent pattern of muscle activation. Profiles were plotted and insights with respect to player effectiveness were provided. Inspection of EMG dynamics revealed a pair of highest peaks in each channel as the hallmark of golf swing, and a custom application of peak detection for automatic extraction of swing segment was introduced. Various EMG features, encompassing 22 feature sets, were constructed. Feature sets were used individually and also in decision-level fusion for the prediction of shot effectiveness. The prediction of the target attribute, such as club head speed or ball carry distance, was investigated using random forest as the learner in detection and regression tasks. Detection evaluates the personal effectiveness of a shot with respect to the player-specific average, whereas regression estimates the value of target attribute, using EMG features as predictors. Fusion after decision optimization provided the best results: the equal error rate in detection was 24.3% for the speed and 31.7% for the distance; the mean absolute percentage error in regression was 3.2% for the speed and 6.4% for the distance. Proposed EMG feature sets were found to be useful, especially when used in combination. Rankings of feature sets indicated statistics for muscle activity in both the left and right body sides, correlation-based analysis of EMG

  7. Immune Profiles to Predict Response to Desensitization Therapy in Highly HLA-Sensitized Kidney Transplant Candidates.

    Science.gov (United States)

    Yabu, Julie M; Siebert, Janet C; Maecker, Holden T

    2016-01-01

    Kidney transplantation is the most effective treatment for end-stage kidney disease. Sensitization, the formation of human leukocyte antigen (HLA) antibodies, remains a major barrier to successful kidney transplantation. Despite the implementation of desensitization strategies, many candidates fail to respond. Current progress is hindered by the lack of biomarkers to predict response and to guide therapy. Our objective was to determine whether differences in immune and gene profiles may help identify which candidates will respond to desensitization therapy. Single-cell mass cytometry by time-of-flight (CyTOF) phenotyping, gene arrays, and phosphoepitope flow cytometry were performed in a study of 20 highly sensitized kidney transplant candidates undergoing desensitization therapy. Responders to desensitization therapy were defined as 5% or greater decrease in cumulative calculated panel reactive antibody (cPRA) levels, and non-responders had 0% decrease in cPRA. Using a decision tree analysis, we found that a combination of transitional B cell and regulatory T cell (Treg) frequencies at baseline before initiation of desensitization therapy could distinguish responders from non-responders. Using a support vector machine (SVM) and longitudinal data, TRAF3IP3 transcripts and HLA-DR-CD38+CD4+ T cells could also distinguish responders from non-responders. Combining all assays in a multivariate analysis and elastic net regression model with 72 analytes, we identified seven that were highly interrelated and eleven that predicted response to desensitization therapy. Measuring baseline and longitudinal immune and gene profiles could provide a useful strategy to distinguish responders from non-responders to desensitization therapy. This study presents the integration of novel translational studies including CyTOF immunophenotyping in a multivariate analysis model that has potential applications to predict response to desensitization, select candidates, and personalize

  8. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models.

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com .

  9. TargetNet: a web service for predicting potential drug-target interaction profiling via multi-target SAR models

    Science.gov (United States)

    Yao, Zhi-Jiang; Dong, Jie; Che, Yu-Jing; Zhu, Min-Feng; Wen, Ming; Wang, Ning-Ning; Wang, Shan; Lu, Ai-Ping; Cao, Dong-Sheng

    2016-05-01

    Drug-target interactions (DTIs) are central to current drug discovery processes and public health fields. Analyzing the DTI profiling of the drugs helps to infer drug indications, adverse drug reactions, drug-drug interactions, and drug mode of actions. Therefore, it is of high importance to reliably and fast predict DTI profiling of the drugs on a genome-scale level. Here, we develop the TargetNet server, which can make real-time DTI predictions based only on molecular structures, following the spirit of multi-target SAR methodology. Naïve Bayes models together with various molecular fingerprints were employed to construct prediction models. Ensemble learning from these fingerprints was also provided to improve the prediction ability. When the user submits a molecule, the server will predict the activity of the user's molecule across 623 human proteins by the established high quality SAR model, thus generating a DTI profiling that can be used as a feature vector of chemicals for wide applications. The 623 SAR models related to 623 human proteins were strictly evaluated and validated by several model validation strategies, resulting in the AUC scores of 75-100 %. We applied the generated DTI profiling to successfully predict potential targets, toxicity classification, drug-drug interactions, and drug mode of action, which sufficiently demonstrated the wide application value of the potential DTI profiling. The TargetNet webserver is designed based on the Django framework in Python, and is freely accessible at http://targetnet.scbdd.com.

  10. Cannabis use in children with individualized risk profiles: Predicting the effect of universal prevention intervention.

    Science.gov (United States)

    Miovský, Michal; Vonkova, Hana; Čablová, Lenka; Gabrhelík, Roman

    2015-11-01

    To study the effect of a universal prevention intervention targeting cannabis use in individual children with different risk profiles. A school-based randomized controlled prevention trial was conducted over a period of 33 months (n=1874 sixth-graders, baseline mean age 11.82). We used a two-level random intercept logistic model for panel data to predict the probabilities of cannabis use for each child. Specifically, we used eight risk/protective factors to characterize each child and then predicted two probabilities of cannabis use for each child if the child had the intervention or not. Using the two probabilities, we calculated the absolute and relative effect of the intervention for each child. According to the two probabilities, we also divided the sample into a low-risk group (the quarter of the children with the lowest probabilities), a moderate-risk group, and a high-risk group (the quarter of the children with the highest probabilities) and showed the average effect of the intervention on these groups. The differences between the intervention group and the control group were statistically significant in each risk group. The average predicted probabilities of cannabis use for a child from the low-risk group were 4.3% if the child had the intervention and 6.53% if no intervention was provided. The corresponding probabilities for a child from the moderate-risk group were 10.91% and 15.34% and for a child from the high-risk group 25.51% and 32.61%. School grades, thoughts of hurting oneself, and breaking the rules were the three most important factors distinguishing high-risk and low-risk children. We predicted the effect of the intervention on individual children, characterized by their risk/protective factors. The predicted absolute effect and relative effect of any intervention for any selected risk/protective profile of a given child may be utilized in both prevention practice and research. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. TEMA and Dot Enumeration Profiles Predict Mental Addition Problem Solving Speed Longitudinally.

    Science.gov (United States)

    Major, Clare S; Paul, Jacob M; Reeve, Robert A

    2017-01-01

    Different math indices can be used to assess math potential at school entry. We evaluated whether standardized math achievement (TEMA-2 performance), core number abilities (dot enumeration, symbolic magnitude comparison), non-verbal intelligence (NVIQ) and visuo-spatial working memory (VSWM), in combination or separately, predicted mental addition problem solving speed over time. We assessed 267 children's TEMA-2, magnitude comparison, dot enumeration, and VSWM abilities at school entry (5 years) and NVIQ at 8 years. Mental addition problem solving speed was assessed at 6, 8, and 10 years. Longitudinal path analysis supported a model in which dot enumeration performance ability profiles and previous mental addition speed predicted future mental addition speed on all occasions, supporting a componential account of math ability. Standardized math achievement and NVIQ predicted mental addition speed at specific time points, while VSWM and symbolic magnitude comparison did not contribute unique variance to the model. The implications of using standardized math achievement and dot enumeration ability to index math learning potential at school entry are discussed.

  12. Quantitative prediction of shrimp disease incidence via the profiles of gut eukaryotic microbiota.

    Science.gov (United States)

    Xiong, Jinbo; Yu, Weina; Dai, Wenfang; Zhang, Jinjie; Qiu, Qiongfen; Ou, Changrong

    2018-04-01

    One common notion is emerging that gut eukaryotes are commensal or beneficial, rather than detrimental. To date, however, surprisingly few studies have been taken to discern the factors that govern the assembly of gut eukaryotes, despite growing interest in the dysbiosis of gut microbiota-disease relationship. Herein, we firstly explored how the gut eukaryotic microbiotas were assembled over shrimp postlarval to adult stages and a disease progression. The gut eukaryotic communities changed markedly as healthy shrimp aged, and converged toward an adult-microbiota configuration. However, the adult-like stability was distorted by disease exacerbation. A null model untangled that the deterministic processes that governed the gut eukaryotic assembly tended to be more important over healthy shrimp development, whereas this trend was inverted as the disease progressed. After ruling out the baseline of gut eukaryotes over shrimp ages, we identified disease-discriminatory taxa (species level afforded the highest accuracy of prediction) that characteristic of shrimp health status. The profiles of these taxa contributed an overall 92.4% accuracy in predicting shrimp health status. Notably, this model can accurately diagnose the onset of shrimp disease. Interspecies interaction analysis depicted how the disease-discriminatory taxa interacted with one another in sustaining shrimp health. Taken together, our findings offer novel insights into the underlying ecological processes that govern the assembly of gut eukaryotes over shrimp postlarval to adult stages and a disease progression. Intriguingly, the established model can quantitatively and accurately predict the incidences of shrimp disease.

  13. Professional choice self-efficacy: predicting traits and personality profiles in high school students

    Directory of Open Access Journals (Sweden)

    Rodolfo Augusto Matteo Ambiel

    2016-01-01

    Full Text Available Abstract This study aimed to verify the predictive capacity of the Big Five personality factors related to professional choice self-efficacy, as well as to draw a personality profile of people with diverse self-efficacy levels. There were 308 high school students participating, from three different grades (57.5 % women, from public and private schools, average 26.64 years of age. Students completed two instruments, Escala de Autoeficácia para Escolha Profissional (Professional Choice Self-efficacy Scale and Bateria Fatorial de Personalidade (Factorial Personality Battery. Results were obtained using multiple regression analysis, analysis of variance with repeated measures profile and Cohen’s d to estimate the effect size of differences. Results showed that Extraversion, Agreeableness and Conscientiousness were the main predictors of self-efficacy. Differences from medium to large were observed between extreme groups, and Extraversion and Conscientiousness were the personality factors that better distinguish people with low and high levels of self-efficacy. Theses results partially corroborate with the hypothesis. Results were discussed based on literature and on the practical implications of the results. New studies are proposed.

  14. Theoretical prediction of pullout strengths for dental and orthopaedic screws with conical profile and buttress threads.

    Science.gov (United States)

    Shih, Kao-Shang; Hou, Sheng-Mou; Lin, Shang-Chih

    2017-12-01

    The pullout strength of a screw is an indicator of how secure bone fragments are being held in place. Such bone-purchasing ability is sensitive to bone quality, thread design, and the pilot hole, and is often evaluated by experimental and numerical methods. Historically, there are some mathematical formulae to simulate the screw withdrawal from the synthetic bone. There are great variations in screw specifications. However, extensive investigation of the correlation between experimental and analytical results has not been reported in literature. Referring to the literature formulae, this study aims to evaluate the differences in the calculated pullout strengths. The pullout tests of the surgical screws are measured and the sawbone is used as the testing block. The absolute errors and correlation coefficients of the experimental and analytical results are calculated as the comparison baselines of the formulae. The absolute error of the dental, traumatic, and spinal groups are 21.7%, 95.5%, and 37.0%, respectively. For the screws with a conical profile and/or tiny threads, the calculated and measured results are not well correlated. The formulae are not accurate indicators of the pullout strengths of the screws where the design parameters are slightly varied. However, the experimental and numerical results are highly correlated for the cylindrical screws. The pullout strength of a conical screw is higher than that of its counterpart, but all formulae consistently predict the opposite results. In general, the bony purchase of the buttress threads is securer than that of the symmetric thread. An absolute error of up to 51.4% indicates the theoretical results cannot predict the actual value of the pullout strength. Only thread diameter, pitch, and depth are considered in the investigated formulae. The thread profile and shape should be formulated to modify the slippage mechanism at the bone-screw interfaces and simulate the strength change in the squeezed bones

  15. Higher schizotypy predicts better metabolic profile in unaffected siblings of patients with schizophrenia.

    Science.gov (United States)

    Atbasoglu, E Cem; Gumus-Akay, Guvem; Guloksuz, Sinan; Saka, Meram Can; Ucok, Alp; Alptekin, Koksal; Gullu, Sevim; van Os, Jim

    2018-04-01

    Type 2 diabetes (T2D) is more frequent in schizophrenia (Sz) than in the general population. This association is partly accounted for by shared susceptibility genetic variants. We tested the hypotheses that a genetic predisposition to Sz would be associated with higher likelihood of insulin resistance (IR), and that IR would be predicted by subthreshold psychosis phenotypes. Unaffected siblings of Sz patients (n = 101) were compared with a nonclinical sample (n = 305) in terms of IR, schizotypy (SzTy), and a behavioural experiment of "jumping to conclusions". The measures, respectively, were the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Structured Interview for Schizotypy-Revised (SIS-R), and the Beads Task (BT). The likelihood of IR was examined in multiple regression models that included sociodemographic, metabolic, and cognitive parameters alongside group status, SIS-R scores, and BT performance. Insulin resistance was less frequent in siblings (31.7%) compared to controls (43.3%) (p model that examined all relevant parameters included the tSzTy tertiles, TG and HDL-C levels, and BMI, as significant predictors of IR. Lack of IR was predicted by the highest as compared to the lowest SzTy tertile [OR (95%CI): 0.43 (0.21-0.85), p = 0.015]. Higher dopaminergic activity may contribute to both schizotypal features and a favourable metabolic profile in the same individual. This is compatible with dopamine's regulatory role in glucose metabolism via indirect central actions and a direct action on pancreatic insulin secretion. The relationship between dopaminergic activity and metabolic profile in Sz must be examined in longitudinal studies with younger unaffected siblings.

  16. The Impact of Mission Profile Models on the Predicted Lifetime of IGBT Modules in the Modular Multilevel Converter

    DEFF Research Database (Denmark)

    Zhang, Yi; Wang, Huai; Wang, Zhongxu

    2017-01-01

    and electrical power modeling methods on the estimated lifetime of IGBT modules in an MMC for offshore wind power application. In a 30 MW MMC case study, an annual wind speed profile with a resolution of 1 s/data, 10 minute/data, and 1 hour/data are considered, respectively. A method to re-generate higher......The reliability aspect study of Modular Multilevel Converter (MMC) is of great interest in industry applications, such as offshore wind. Lifetime prediction of key components is an important tool to design MMC with fulfilled reliability specifications. While many efforts have been made...... to the lifetime prediction of IGBT modules in renewable energy applications by considering long-term varying operation conditions (i.e., mission profile), the justifications of using the associated mission profiles are still missed. This paper investigates the impact of mission profile data resolutions...

  17. Identifying and Predicting Profiles of Medical Noncompliance: Pediatric Caregivers' Antibiotic Stewardship.

    Science.gov (United States)

    Smith, Rachel A; Kim, Youllee; M'Ikanatha, Nkuchia M

    2018-05-14

    Sometimes compliance with medical recommendations is problematic. We investigated pediatric caregivers' (N = 606) patterns of noncompliance with antibiotic stewardship based on the obstacle hypothesis. We tested predictors of noncompliance framed by the obstacle hypothesis, dissonance theory, and psychological reactance. The results revealed four profiles of caregivers' stewardship: one marked by compliance (Stewards) and three marked by types of noncompliance (Stockers, Persuaders, and Dissenters). The covariate analysis showed that, although psychological reactance predicted being noncompliant, it was types of obstacles and discrepant experiences that predicted caregivers' patterns of noncompliance with antibiotic stewardship. Campaign planning often focuses on identifying the belief most associated with the targeted outcome, such as compliance. Noncompliance research, however, points out that persuaders may be successful to the extent to which they anticipate obstacles to compliance and address them in their influence attempts. A shift from medical noncompliance to patient engagement also affords an opportunity to consider how some recommendations create obstacles for others and to find positive ways to embrace conflicting needs, tensions, and reasons for refusal in order to promote collective goals.

  18. Global proteomics profiling improves drug sensitivity prediction: results from a multi-omics, pan-cancer modeling approach.

    Science.gov (United States)

    Ali, Mehreen; Khan, Suleiman A; Wennerberg, Krister; Aittokallio, Tero

    2018-04-15

    Proteomics profiling is increasingly being used for molecular stratification of cancer patients and cell-line panels. However, systematic assessment of the predictive power of large-scale proteomic technologies across various drug classes and cancer types is currently lacking. To that end, we carried out the first pan-cancer, multi-omics comparative analysis of the relative performance of two proteomic technologies, targeted reverse phase protein array (RPPA) and global mass spectrometry (MS), in terms of their accuracy for predicting the sensitivity of cancer cells to both cytotoxic chemotherapeutics and molecularly targeted anticancer compounds. Our results in two cell-line panels demonstrate how MS profiling improves drug response predictions beyond that of the RPPA or the other omics profiles when used alone. However, frequent missing MS data values complicate its use in predictive modeling and required additional filtering, such as focusing on completely measured or known oncoproteins, to obtain maximal predictive performance. Rather strikingly, the two proteomics profiles provided complementary predictive signal both for the cytotoxic and targeted compounds. Further, information about the cellular-abundance of primary target proteins was found critical for predicting the response of targeted compounds, although the non-target features also contributed significantly to the predictive power. The clinical relevance of the selected protein markers was confirmed in cancer patient data. These results provide novel insights into the relative performance and optimal use of the widely applied proteomic technologies, MS and RPPA, which should prove useful in translational applications, such as defining the best combination of omics technologies and marker panels for understanding and predicting drug sensitivities in cancer patients. Processed datasets, R as well as Matlab implementations of the methods are available at https://github.com/mehr-een/bemkl-rbps. mehreen

  19. In Silico Analysis of Microarray-Based Gene Expression Profiles Predicts Tumor Cell Response to Withanolides

    Directory of Open Access Journals (Sweden)

    Thomas Efferth

    2012-05-01

    Full Text Available Withania somnifera (L. Dunal (Indian ginseng, winter cherry, Solanaceae is widely used in traditional medicine. Roots are either chewed or used to prepare beverages (aqueous decocts. The major secondary metabolites of Withania somnifera are the withanolides, which are C-28-steroidal lactone triterpenoids. Withania somnifera extracts exert chemopreventive and anticancer activities in vitro and in vivo. The aims of the present in silico study were, firstly, to investigate whether tumor cells develop cross-resistance between standard anticancer drugs and withanolides and, secondly, to elucidate the molecular determinants of sensitivity and resistance of tumor cells towards withanolides. Using IC50 concentrations of eight different withanolides (withaferin A, withaferin A diacetate, 3-azerininylwithaferin A, withafastuosin D diacetate, 4-B-hydroxy-withanolide E, isowithanololide E, withafastuosin E, and withaperuvin and 19 established anticancer drugs, we analyzed the cross-resistance profile of 60 tumor cell lines. The cell lines revealed cross-resistance between the eight withanolides. Consistent cross-resistance between withanolides and nitrosoureas (carmustin, lomustin, and semimustin was also observed. Then, we performed transcriptomic microarray-based COMPARE and hierarchical cluster analyses of mRNA expression to identify mRNA expression profiles predicting sensitivity or resistance towards withanolides. Genes from diverse functional groups were significantly associated with response of tumor cells to withaferin A diacetate, e.g. genes functioning in DNA damage and repair, stress response, cell growth regulation, extracellular matrix components, cell adhesion and cell migration, constituents of the ribosome, cytoskeletal organization and regulation, signal transduction, transcription factors, and others.

  20. Exploring the Inflammatory Metabolomic Profile to Predict Response to TNF-α Inhibitors in Rheumatoid Arthritis.

    Directory of Open Access Journals (Sweden)

    Bart V J Cuppen

    Full Text Available In clinical practice, approximately one-third of patients with rheumatoid arthritis (RA respond insufficiently to TNF-α inhibitors (TNFis. The aim of the study was to explore the use of a metabolomics to identify predictors for the outcome of TNFi therapy, and study the metabolomic fingerprint in active RA irrespective of patients' response. In the metabolomic profiling, lipids, oxylipins, and amines were measured in serum samples of RA patients from the observational BiOCURA cohort, before start of biological treatment. Multivariable logistic regression models were established to identify predictors for good- and non-response in patients receiving TNFi (n = 124. The added value of metabolites over prediction using clinical parameters only was determined by comparing the area under receiver operating characteristic curve (AUC-ROC, sensitivity, specificity, positive- and negative predictive value and by the net reclassification index (NRI. The models were further validated by 10-fold cross validation and tested on the complete TNFi treatment cohort including moderate responders. Additionally, metabolites were identified that cross-sectionally associated with the RA disease activity score based on a 28-joint count (DAS28, erythrocyte sedimentation rate (ESR or C-reactive protein (CRP. Out of 139 metabolites, the best-performing predictors were sn1-LPC(18:3-ω3/ω6, sn1-LPC(15:0, ethanolamine, and lysine. The model that combined the selected metabolites with clinical parameters showed a significant larger AUC-ROC than that of the model containing only clinical parameters (p = 0.01. The combined model was able to discriminate good- and non-responders with good accuracy and to reclassify non-responders with an improvement of 30% (total NRI = 0.23 and showed a prediction error of 0.27. For the complete TNFi cohort, the NRI was 0.22. In addition, 88 metabolites were associated with DAS28, ESR or CRP (p<0.05. Our study established an accurate

  1. Molecular and pro-inflammatory genetic profile in gastric carcinomas

    NARCIS (Netherlands)

    Sitarz, R.

    2009-01-01

    Gastric cancer is a result from the combination of environmental factors and an accumulation of specific genetic alterations, and affects mainly the older population. It is known that genetic factors play a more important role in early onset gastric cancers than in conventional gastric cancer

  2. Does Enjoying Friendship Help or Impede Academic Achievement? Academic and Social Intrinsic Value Profiles Predict Academic Achievement

    Science.gov (United States)

    Seo, Eunjin; Lee, You-kyung

    2018-01-01

    We examine the intrinsic value students placed on schoolwork (i.e. academic intrinsic value) and social relationships (i.e. social intrinsic value). We then look at how these values predict middle and high school achievement. To do this, we came up with four profiles based on cluster analyses of 6,562 South Korean middle school students. The four…

  3. pH-dependent solubility and permeability profiles: A useful tool for prediction of oral bioavailability.

    Science.gov (United States)

    Sieger, P; Cui, Y; Scheuerer, S

    2017-07-15

    pH-dependent solubility - permeability profiles offer a simple way to predict bioavailability after oral application, if bioavailability is only solubility and permeability driven. Combining both pH-dependent solubility and pH-dependent permeability in one diagram provides a pH-window (=ΔpH sol-perm ) from which the conditions for optimal oral bioavailability can be taken. The size of this window is directly proportional to the observed oral bioavailability. A set of 21 compounds, with known absolute human oral bioavailability, was used to establish this correlation. Compounds with ΔpH sol-perm bioavailability (bioavailability typically by approximately 25%. For compounds where ΔpH sol-perm ≥3 but still showing poor bioavailability, most probably other pharmacokinetic aspects (e.g. high clearance), are limiting exposure. Interestingly, the location of this pH-window seems to have a negligible influence on the observed oral bioavailability. In scenarios, where the bioavailability is impaired by certain factors, like for example proton pump inhibitor co-medication or food intake, the exact position of this pH-window might be beneficial for understanding the root cause. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Prediction of wall shear stresses in transitional boundary layers using near-wall mean velocity profiles

    International Nuclear Information System (INIS)

    Jeon, Woo Pyung; Shin, Sung Ho; Kang, Shin Hyoung

    2000-01-01

    The local wall shear stress in transitional boundary layer was estimated from the near-wall mean velocity data using the principle of Computational Preston tube Method(CPM). The previous DNS and experimental databases of transitional boundary layers were used to demonstrate the accuracy of the method and to provide the applicable range of wall unit y + . The skin friction coefficients predicted by the CPM agreed well with those from previous studies. To reexamine the applicability of the CPM, near-wall hot-wire measurements were conducted in developing transitional boundary layers on a flat plate with different freestream turbulence intensities. The intermittency profiles across the transitional boundary layers were reasonably obtained from the conditional sampling technique. An empirical correlation between the representative intermittency near the wall and the free parameter K 1 of the extended wall function of CPM has been newly proposed using the present and other experimental data. The CPM has been verified as a useful tool to measure the wall shear stress in transitional boundary layer with reasonable accuracy

  5. EvoCor: a platform for predicting functionally related genes using phylogenetic and expression profiles.

    Science.gov (United States)

    Dittmar, W James; McIver, Lauren; Michalak, Pawel; Garner, Harold R; Valdez, Gregorio

    2014-07-01

    The wealth of publicly available gene expression and genomic data provides unique opportunities for computational inference to discover groups of genes that function to control specific cellular processes. Such genes are likely to have co-evolved and be expressed in the same tissues and cells. Unfortunately, the expertise and computational resources required to compare tens of genomes and gene expression data sets make this type of analysis difficult for the average end-user. Here, we describe the implementation of a web server that predicts genes involved in affecting specific cellular processes together with a gene of interest. We termed the server 'EvoCor', to denote that it detects functional relationships among genes through evolutionary analysis and gene expression correlation. This web server integrates profiles of sequence divergence derived by a Hidden Markov Model (HMM) and tissue-wide gene expression patterns to determine putative functional linkages between pairs of genes. This server is easy to use and freely available at http://pilot-hmm.vbi.vt.edu/. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  6. The child behavior checklist dysregulation profile predicts adolescent DSM-5 pathological personality traits 4 years later.

    Science.gov (United States)

    De Caluwé, Elien; Decuyper, Mieke; De Clercq, Barbara

    2013-07-01

    Emotional dysregulation in childhood has been associated with various forms of later psychopathology, although no studies have investigated the personality related adolescent outcomes associated with early emotional dysregulation. The present study uses a typological approach to examine how the child behavior checklist-dysregulation profile (CBCL-DP) predicts DSM-5 pathological personality traits (as measured with the personality inventory for the diagnostic and statistical manual of mental disorders 5 or PID-5 by Krueger et al. (Psychol Med 2012)) across a time span of 4 years in a sample of 243 children aged 8-14 years (57.2 % girls). The results showed that children assigned to the CBCL-DP class are at risk for elevated scores on a wide range of DSM-5 personality pathology features, including higher scores on hostility, risk taking, deceitfulness, callousness, grandiosity, irresponsibility, impulsivity and manipulativeness. These results are discussed in the context of identifying early manifestations of persistent regulation problems, because of their enduring impact on a child's personality development.

  7. Prediction of incidence and stability of alcohol use disorders by latent internalizing psychopathology risk profiles in adolescence and young adulthood.

    Science.gov (United States)

    Behrendt, Silke; Bühringer, Gerhard; Höfler, Michael; Lieb, Roselind; Beesdo-Baum, Katja

    2017-10-01

    Comorbid internalizing mental disorders in alcohol use disorders (AUD) can be understood as putative independent risk factors for AUD or as expressions of underlying shared psychopathology vulnerabilities. However, it remains unclear whether: 1) specific latent internalizing psychopathology risk-profiles predict AUD-incidence and 2) specific latent internalizing comorbidity-profiles in AUD predict AUD-stability. To investigate baseline latent internalizing psychopathology risk profiles as predictors of subsequent AUD-incidence and -stability in adolescents and young adults. Data from the prospective-longitudinal EDSP study (baseline age 14-24 years) were used. The study-design included up to three follow-up assessments in up to ten years. DSM-IV mental disorders were assessed with the DIA-X/M-CIDI. To investigate risk-profiles and their associations with AUD-outcomes, latent class analysis with auxiliary outcome variables was applied. AUD-incidence: a 4-class model (N=1683) was identified (classes: normative-male [45.9%], normative-female [44.2%], internalizing [5.3%], nicotine dependence [4.5%]). Compared to the normative-female class, all other classes were associated with a higher risk of subsequent incident alcohol dependence (p<0.05). AUD-stability: a 3-class model (N=1940) was identified with only one class (11.6%) with high probabilities for baseline AUD. This class was further characterized by elevated substance use disorder (SUD) probabilities and predicted any subsequent AUD (OR 8.5, 95% CI 5.4-13.3). An internalizing vulnerability may constitute a pathway to AUD incidence in adolescence and young adulthood. In contrast, no indication for a role of internalizing comorbidity profiles in AUD-stability was found, which may indicate a limited importance of such profiles - in contrast to SUD-related profiles - in AUD stability. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Quantifying and Predicting Three-Dimensional Heterogeneity in Transient Storage Using Roving Profiling

    Science.gov (United States)

    Kaplan, D. A.; Reaver, N.; Hensley, R. T.; Cohen, M. J.

    2017-12-01

    Hydraulic transport is an important component of nutrient spiraling in streams. Quantifying conservative solute transport is a prerequisite for understanding the cycling and fate of reactive solutes, such as nutrients. Numerous studies have modeled solute transport within streams using the one-dimensional advection, dispersion and storage (ADS) equation calibrated to experimental data from tracer experiments. However, there are limitations to the information about in-stream transient storage that can be derived from calibrated ADS model parameters. Transient storage (TS) in the ADS model is most often modeled as a single process, and calibrated model parameters are "lumped" values that are the best-fit representation of multiple real-world TS processes. In this study, we developed a roving profiling method to assess and predict spatial heterogeneity of in-stream TS. We performed five tracer experiments on three spring-fed rivers in Florida (USA) using Rhodamine WT. During each tracer release, stationary fluorometers were deployed to measure breakthrough curves for multiple reaches within the river. Teams of roving samplers moved along the rivers measuring tracer concentrations at various locations and depths within the reaches. A Bayesian statistical method was used to calibrate the ADS model to the stationary breakthrough curves, resulting in probability distributions for both the advective and TS zone as a function of river distance and time. Rover samples were then assigned a probability of being from either the advective or TS zone by comparing measured concentrations to the probability distributions of concentrations in the ADS advective and TS zones. A regression model was used to predict the probability of any in-stream position being located within the advective versus TS zone based on spatiotemporal predictors (time, river position, depth, and distance from bank) and eco-geomorphological feature (eddies, woody debris, benthic depressions, and aquatic

  9. Neuro-Fuzzy Prediction of Cooperation Interaction Profile of Flexible Road Train Based on Hybrid Automaton Modeling

    Directory of Open Access Journals (Sweden)

    Banjanovic-Mehmedovic Lejla

    2016-01-01

    Full Text Available Accurate prediction of traffic information is important in many applications in relation to Intelligent Transport systems (ITS, since it reduces the uncertainty of future traffic states and improves traffic mobility. There is a lot of research done in the field of traffic information predictions such as speed, flow and travel time. The most important research was done in the domain of cooperative intelligent transport system (C-ITS. The goal of this paper is to introduce the novel cooperation behaviour profile prediction through the example of flexible Road Trains useful road cooperation parameter, which contributes to the improvement of traffic mobility in Intelligent Transportation Systems. This paper presents an approach towards the control and cooperation behaviour modelling of vehicles in the flexible Road Train based on hybrid automaton and neuro-fuzzy (ANFIS prediction of cooperation profile of the flexible Road Train. Hybrid automaton takes into account complex dynamics of each vehicle as well as discrete cooperation approach. The ANFIS is a particular class of the ANN family with attractive estimation and learning potentials. In order to provide statistical analysis, RMSE (root mean square error, coefficient of determination (R2 and Pearson coefficient (r, were utilized. The study results suggest that ANFIS would be an efficient soft computing methodology, which could offer precise predictions of cooperative interactions between vehicles in Road Train, which is useful for prediction mobility in Intelligent Transport systems.

  10. Prediction of Process-Induced Distortions in L-Shaped Composite Profiles Using Path-Dependent Constitutive Law

    Science.gov (United States)

    Ding, Anxin; Li, Shuxin; Wang, Jihui; Ni, Aiqing; Sun, Liangliang; Chang, Lei

    2016-10-01

    In this paper, the corner spring-in angles of AS4/8552 L-shaped composite profiles with different thicknesses are predicted using path-dependent constitutive law with the consideration of material properties variation due to phase change during curing. The prediction accuracy mainly depends on the properties in the rubbery and glassy states obtained by homogenization method rather than experimental measurements. Both analytical and finite element (FE) homogenization methods are applied to predict the overall properties of AS4/8552 composite. The effect of fiber volume fraction on the properties is investigated for both rubbery and glassy states using both methods. And the predicted results are compared with experimental measurements for the glassy state. Good agreement is achieved between the predicted results and available experimental data, showing the reliability of the homogenization method. Furthermore, the corner spring-in angles of L-shaped composite profiles are measured experimentally and the reliability of path-dependent constitutive law is validated as well as the properties prediction by FE homogenization method.

  11. Prediction of lymphatic metastasis based on gene expression profile analysis after brachytherapy for early-stage oral tongue carcinoma

    International Nuclear Information System (INIS)

    Watanabe, Hiroshi; Mogushi, Kaoru; Miura, Masahiko; Yoshimura, Ryo-ichi; Kurabayashi, Tohru; Shibuya, Hitoshi; Tanaka, Hiroshi; Noda, Shuhei; Iwakawa, Mayumi; Imai, Takashi

    2008-01-01

    Background and purpose: The management of lymphatic metastasis of early-stage oral tongue carcinoma patients is crucial for its prognosis. The purpose of this study was to evaluate the predictive ability of lymphatic metastasis after brachytherapy (BRT) for early-stage tongue carcinoma based on gene expression profiling. Patients and methods: Pre-therapeutic biopsies from 39 patients with T1 or T2 tongue cancer were analyzed for gene expression signatures using Codelink Uniset Human 20K Bioarray. All patients were treated with low dose-rate BRT for their primary lesions and underwent strict follow-up under a wait-and-see policy for cervical lymphatic metastasis. Candidate genes were selected for predicting lymph-node status in the reference group by the permutation test. Predictive accuracy was further evaluated by the prediction strength (PS) scoring system using an independent validation group. Results: We selected a set of 19 genes whose expression differed significantly between classes with or without lymphatic metastasis in the reference group. The lymph-node status in the validation group was predicted by the PS scoring system with an accuracy of 76%. Conclusions: Gene expression profiling using 19 genes in primary tumor tissues may allow prediction of lymphatic metastasis after BRT for early-stage oral tongue carcinoma

  12. Kozeny-Carman permeability relationship with disintegration process predicted from early dissolution profiles of immediate release tablets.

    Science.gov (United States)

    Kumari, Parveen; Rathi, Pooja; Kumar, Virender; Lal, Jatin; Kaur, Harmeet; Singh, Jasbir

    2017-07-01

    This study was oriented toward the disintegration profiling of the diclofenac sodium (DS) immediate-release (IR) tablets and development of its relationship with medium permeability k perm based on Kozeny-Carman equation. Batches (L1-L9) of DS IR tablets with different porosities and specific surface area were prepared at different compression forces and evaluated for porosity, in vitro dissolution and particle-size analysis of the disintegrated mass. The k perm was calculated from porosities and specific surface area, and disintegration profiles were predicted from the dissolution profiles of IR tablets by stripping/residual method. The disintegration profiles were subjected to exponential regression to find out the respective disintegration equations and rate constants k d . Batches L1 and L2 showed the fastest disintegration rates as evident from their bi-exponential equations while the rest of the batches L3-L9 exhibited the first order or mono-exponential disintegration kinetics. The 95% confidence interval (CI 95% ) revealed significant differences between k d values of different batches except L4 and L6. Similar results were also spotted for dissolution profiles of IR tablets by similarity (f 2 ) test. The final relationship between k d and k perm was found to be hyperbolic, signifying the initial effect of k perm on the disintegration rate. The results showed that disintegration profiling is possible because a relationship exists between k d and k perm . The later being relatable with porosity and specific surface area can be determined by nondestructive tests.

  13. Multigene expression profile for predicting efficacy of cisplatin and vinorelbine in non-small cell lung cancer

    DEFF Research Database (Denmark)

    Buhl, I. K.; Christensen, I. J.; Santoni-Rugiu, E.

    2016-01-01

    Background: There is a need for biomarkers to predict efficacy of adjuvant chemotherapy in resected non-small cell lung cancer (NSCLC). Presented is a combined cisplatin and vinorelbine marker from a previously validated model system [1] tested in two cohorts. Methods: The profiles consist...... and vinorelbine (ACT) and 62 patients who had no adjuvant treatment (OBS) [2] and 2) 95 stage Ib-IIIb completely resected NSCLC patients who all received adjuvant cisplatin and vinorelbine [3]. Endpoint is cancer specific survival. Results: The combined cisplatin and vinorelbine profiles scored as a continuous...... of correlated in vitro cytotoxicity of cisplatin and vinorelbine and mRNA expressions. Then each profile is correlated to mRNA expression of 3500 tumors. The cohorts are 1) a publically available dataset with 133 completely resected stage Ib-II NSCLC patients, 71 of whom received adjuvant cisplatin...

  14. Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles

    DEFF Research Database (Denmark)

    Birkhahn, M.; Mitra, A.P.; Williams, Johan

    2010-01-01

    % specificity. Since this is a small retrospective study using medium-throughput profiling, larger confirmatory studies are needed. Conclusions: Gene expression profiling across relevant cancer pathways appears to be a promising approach for Ta bladder tumor outcome prediction at initial diagnosis......Background: Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based...... on specific tumor biology, are yet to be identified. Objective: To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach. Design, setting, and participants: Retrospective study of patients with Ta G2/3 bladder tumors...

  15. Magnetic resonance metabolic profiling of breast cancer tissue obtained with core needle biopsy for predicting pathologic response to neoadjuvant chemotherapy.

    Directory of Open Access Journals (Sweden)

    Ji Soo Choi

    Full Text Available The purpose of this study was to determine whether metabolic profiling of core needle biopsy (CNB samples using high-resolution magic angle spinning (HR-MAS magnetic resonance spectroscopy (MRS could be used for predicting pathologic response to neoadjuvant chemotherapy (NAC in patients with locally advanced breast cancer. After institutional review board approval and informed consent were obtained, CNB tissue samples were collected from 37 malignant lesions in 37 patients before NAC treatment. The metabolic profiling of CNB samples were performed by HR-MAS MRS. Metabolic profiles were compared according to pathologic response to NAC using the Mann-Whitney test. Multivariate analysis was performed with orthogonal projections to latent structure-discriminant analysis (OPLS-DA. Various metabolites including choline-containing compounds were identified and quantified by HR-MAS MRS in all 37 breast cancer tissue samples obtained by CNB. In univariate analysis, the metabolite concentrations and metabolic ratios of CNB samples obtained with HR-MAS MRS were not significantly different between different pathologic response groups. However, there was a trend of lower levels of phosphocholine/creatine ratio and choline-containing metabolite concentrations in the pathologic complete response group compared to the non-pathologic complete response group. In multivariate analysis, the OPLS-DA models built with HR-MAS MR metabolic profiles showed visible discrimination between the pathologic response groups. This study showed OPLS-DA multivariate analysis using metabolic profiles of pretreatment CNB samples assessed by HR- MAS MRS may be used to predict pathologic response before NAC, although we did not identify the metabolite showing statistical significance in univariate analysis. Therefore, our preliminary results raise the necessity of further study on HR-MAS MR metabolic profiling of CNB samples for a large number of cancers.

  16. Prediction of spur overlap time, radical yield profiles, and decomposition of trichloroethylene induced by various pulse types of electron beam

    International Nuclear Information System (INIS)

    Kim, D.-W.; Han, K.-C.; Lee, W.-K.; Ihm, S.-K.

    1996-01-01

    A kinetic model was suggested to compute the yield profiles of primary radicals generated from water radiolysis. For various cases including pulse radiolysis and steady irradiation time of spur overlap was computed in order to ensure homogeneity over the entire system. As a result, consistency to roughly first order kinetics was resulted for decomposition of 1 ppm trichloroethylene (TCE) and slight deviation from the linear model was predicted for 10 ppm TCE. (author)

  17. Injury Profile SIMulator, a qualitative aggregative modelling framework to predict crop injury profile as a function of cropping practices, and the abiotic and biotic environment. I. Conceptual bases.

    Directory of Open Access Journals (Sweden)

    Jean-Noël Aubertot

    Full Text Available The limitation of damage caused by pests (plant pathogens, weeds, and animal pests in any agricultural crop requires integrated management strategies. Although significant efforts have been made to i develop, and to a lesser extent ii combine genetic, biological, cultural, physical and chemical control methods in Integrated Pest Management (IPM strategies (vertical integration, there is a need for tools to help manage Injury Profiles (horizontal integration. Farmers design cropping systems according to their goals, knowledge, cognition and perception of socio-economic and technological drivers as well as their physical, biological, and chemical environment. In return, a given cropping system, in a given production situation will exhibit a unique injury profile, defined as a dynamic vector of the main injuries affecting the crop. This simple description of agroecosystems has been used to develop IPSIM (Injury Profile SIMulator, a modelling framework to predict injury profiles as a function of cropping practices, abiotic and biotic environment. Due to the tremendous complexity of agroecosystems, a simple holistic aggregative approach was chosen instead of attempting to couple detailed models. This paper describes the conceptual bases of IPSIM, an aggregative hierarchical framework and a method to help specify IPSIM for a given crop. A companion paper presents a proof of concept of the proposed approach for a single disease of a major crop (eyespot on wheat. In the future, IPSIM could be used as a tool to help design ex-ante IPM strategies at the field scale if coupled with a damage sub-model, and a multicriteria sub-model that assesses the social, environmental, and economic performances of simulated agroecosystems. In addition, IPSIM could also be used to help make diagnoses on commercial fields. It is important to point out that the presented concepts are not crop- or pest-specific and that IPSIM can be used on any crop.

  18. Injury Profile SIMulator, a qualitative aggregative modelling framework to predict crop injury profile as a function of cropping practices, and the abiotic and biotic environment. I. Conceptual bases.

    Science.gov (United States)

    Aubertot, Jean-Noël; Robin, Marie-Hélène

    2013-01-01

    The limitation of damage caused by pests (plant pathogens, weeds, and animal pests) in any agricultural crop requires integrated management strategies. Although significant efforts have been made to i) develop, and to a lesser extent ii) combine genetic, biological, cultural, physical and chemical control methods in Integrated Pest Management (IPM) strategies (vertical integration), there is a need for tools to help manage Injury Profiles (horizontal integration). Farmers design cropping systems according to their goals, knowledge, cognition and perception of socio-economic and technological drivers as well as their physical, biological, and chemical environment. In return, a given cropping system, in a given production situation will exhibit a unique injury profile, defined as a dynamic vector of the main injuries affecting the crop. This simple description of agroecosystems has been used to develop IPSIM (Injury Profile SIMulator), a modelling framework to predict injury profiles as a function of cropping practices, abiotic and biotic environment. Due to the tremendous complexity of agroecosystems, a simple holistic aggregative approach was chosen instead of attempting to couple detailed models. This paper describes the conceptual bases of IPSIM, an aggregative hierarchical framework and a method to help specify IPSIM for a given crop. A companion paper presents a proof of concept of the proposed approach for a single disease of a major crop (eyespot on wheat). In the future, IPSIM could be used as a tool to help design ex-ante IPM strategies at the field scale if coupled with a damage sub-model, and a multicriteria sub-model that assesses the social, environmental, and economic performances of simulated agroecosystems. In addition, IPSIM could also be used to help make diagnoses on commercial fields. It is important to point out that the presented concepts are not crop- or pest-specific and that IPSIM can be used on any crop.

  19. Through-Thickness Residual Stress Profiles in Austenitic Stainless Steel Welds: A Combined Experimental and Prediction Study

    Science.gov (United States)

    Mathew, J.; Moat, R. J.; Paddea, S.; Francis, J. A.; Fitzpatrick, M. E.; Bouchard, P. J.

    2017-12-01

    Economic and safe management of nuclear plant components relies on accurate prediction of welding-induced residual stresses. In this study, the distribution of residual stress through the thickness of austenitic stainless steel welds has been measured using neutron diffraction and the contour method. The measured data are used to validate residual stress profiles predicted by an artificial neural network approach (ANN) as a function of welding heat input and geometry. Maximum tensile stresses with magnitude close to the yield strength of the material were observed near the weld cap in both axial and hoop direction of the welds. Significant scatter of more than 200 MPa was found within the residual stress measurements at the weld center line and are associated with the geometry and welding conditions of individual weld passes. The ANN prediction is developed in an attempt to effectively quantify this phenomenon of `innate scatter' and to learn the non-linear patterns in the weld residual stress profiles. Furthermore, the efficacy of the ANN method for defining through-thickness residual stress profiles in welds for application in structural integrity assessments is evaluated.

  20. A model for predicting the radial power profile in a fuel pin

    International Nuclear Information System (INIS)

    Palmer, I.D.; Hesketh, K.W.; Jackson, P.A.

    1983-01-01

    A simple, fast running computer program for calculating radial power profiles, throughout life, in both standard and duplex fuel pellets for all types of thermal reactor has been developed. The code sub-divides the pellet into a number of annuli for each of which it solves for the concentrations of uranium and plutonium and hence calculates a mean inverse diffusion length. The diffusion equation is solved in terms of Bessel functions and the resulting flux profile multiplied by the concentration profiles to give a radial rating profile which is normalised to unity. The model shows good agreement with the results of detailed physics calculations for different thermal reactors over a wide burn-up range. Its incorporation into the HOTROD-4C and SLEUTH-SEER-77 fuel performance codes has led to a negligible increase in running times. (author)

  1. Latent profiles of non-residential father engagement six years after divorce predict long term offspring outcomes

    Science.gov (United States)

    Modecki, Kathryn Lynn; Hagan, Melissa; Sandler, Irwin; Wolchik, Sharlene

    2014-01-01

    This study examined profiles of non-residential father engagement (i.e., support to the adolescent, contact frequency, remarriage, relocation, and interparental conflict) with their adolescent children (N = 156) six to eight years following divorce and the prospective relation between these profiles and the psychosocial functioning of their offspring, nine years later. Parental divorce occurred during late childhood to early adolescence; indicators of non-residential father engagement were assessed during adolescence, and mental health problems and academic achievement of offspring were assessed nine years later in young adulthood. Three profiles of father engagement were identified in our sample of mainly White, non-Hispanic divorced fathers: Moderate Involvement/Low Conflict, Low Involvement/Moderate Conflict, and High Involvement/High Conflict. Profiles differentially predicted offspring outcomes nine years later when they were young adults, controlling for quality of the mother-adolescent relationship, mother’s remarriage, mother’s income, and gender, age and offspring mental health problems in adolescence. Offspring of fathers characterized as Moderate Involvement/Low Conflict had the highest academic achievement and the lowest number of externalizing problems nine years later compared to offspring whose fathers had profiles indicating either the highest or lowest levels of involvement but higher levels of conflict. Results indicate that greater paternal psychosocial support and more frequent father-adolescent contact do not outweigh the negative impact of interparental conflict on youth outcomes in the long-term. Implications of findings for policy and intervention are discussed. PMID:24484456

  2. Integrating milk metabolite profile information for the prediction of traditional milk traits based on SNP information for Holstein cows.

    Directory of Open Access Journals (Sweden)

    Nina Melzer

    Full Text Available In this study the benefit of metabolome level analysis for the prediction of genetic value of three traditional milk traits was investigated. Our proposed approach consists of three steps: First, milk metabolite profiles are used to predict three traditional milk traits of 1,305 Holstein cows. Two regression methods, both enabling variable selection, are applied to identify important milk metabolites in this step. Second, the prediction of these important milk metabolite from single nucleotide polymorphisms (SNPs enables the detection of SNPs with significant genetic effects. Finally, these SNPs are used to predict milk traits. The observed precision of predicted genetic values was compared to the results observed for the classical genotype-phenotype prediction using all SNPs or a reduced SNP subset (reduced classical approach. To enable a comparison between SNP subsets, a special invariable evaluation design was implemented. SNPs close to or within known quantitative trait loci (QTL were determined. This enabled us to determine if detected important SNP subsets were enriched in these regions. The results show that our approach can lead to genetic value prediction, but requires less than 1% of the total amount of (40,317 SNPs., significantly more important SNPs in known QTL regions were detected using our approach compared to the reduced classical approach. Concluding, our approach allows a deeper insight into the associations between the different levels of the genotype-phenotype map (genotype-metabolome, metabolome-phenotype, genotype-phenotype.

  3. Applying geographic profiling used in the field of criminology for predicting the nest locations of bumble bees.

    Science.gov (United States)

    Suzuki-Ohno, Yukari; Inoue, Maki N; Ohno, Kazunori

    2010-07-21

    We tested whether geographic profiling (GP) can predict multiple nest locations of bumble bees. GP was originally developed in the field of criminology for predicting the area where an offender most likely resides on the basis of the actual crime sites and the predefined probability of crime interaction. The predefined probability of crime interaction in the GP model depends on the distance of a site from an offender's residence. We applied GP for predicting nest locations, assuming that foraging and nest sites were the crime sites and the offenders' residences, respectively. We identified the foraging and nest sites of the invasive species Bombus terrestris in 2004, 2005, and 2006. We fitted GP model coefficients to the field data of the foraging and nest sites, and used GP with the fitting coefficients. GP succeeded in predicting about 10-30% of actual nests. Sensitivity analysis showed that the predictability of the GP model mainly depended on the coefficient value of buffer zone, the distance at the mode of the foraging probability. GP will be able to predict the nest locations of bumble bees in other area by using the fitting coefficient values measured in this study. It will be possible to further improve the predictability of the GP model by considering food site preference and nest density. (c) 2010 Elsevier Ltd. All rights reserved.

  4. Proinflammatory Cytokines as Regulators of Vaginal Microbiota.

    Science.gov (United States)

    Kremleva, E A; Sgibnev, A V

    2016-11-01

    It was shown that IL-1β, IL-8, and IL-6 in concentrations similar to those in the vagina of healthy women stimulated the growth of normal microflora (Lactobacillus spp.) and suppressed the growth and biofilm production by S. aureus and E. coli. On the contrary, these cytokines in higher concentrations typical of vaginal dysbiosis suppressed normal microflora and stimulated the growth of opportunistic microorganisms. TGF-β1 in both doses produced a stimulating effects on study vaginal microsymbionts. It is hypothesized that pro-inflammatory cytokines serve as the molecules of interspecies communication coordinating the interactions of all components of the vaginal symbiotic system.

  5. Predicting the profile of nutrients available for absorption: from nutrient requirement to animal response and environmental impact.

    Science.gov (United States)

    Dijkstra, J; Kebreab, E; Mills, J A N; Pellikaan, W F; López, S; Bannink, A; France, J

    2007-02-01

    Current feed evaluation systems for dairy cattle aim to match nutrient requirements with nutrient intake at pre-defined production levels. These systems were not developed to address, and are not suitable to predict, the responses to dietary changes in terms of production level and product composition, excretion of nutrients to the environment, and nutrition related disorders. The change from a requirement to a response system to meet the needs of various stakeholders requires prediction of the profile of absorbed nutrients and its subsequent utilisation for various purposes. This contribution examines the challenges to predicting the profile of nutrients available for absorption in dairy cattle and provides guidelines for further improved prediction with regard to animal production responses and environmental pollution.The profile of nutrients available for absorption comprises volatile fatty acids, long-chain fatty acids, amino acids and glucose. Thus the importance of processes in the reticulo-rumen is obvious. Much research into rumen fermentation is aimed at determination of substrate degradation rates. Quantitative knowledge on rates of passage of nutrients out of the rumen is rather limited compared with that on degradation rates, and thus should be an important theme in future research. Current systems largely ignore microbial metabolic variation, and extant mechanistic models of rumen fermentation give only limited attention to explicit representation of microbial metabolic activity. Recent molecular techniques indicate that knowledge on the presence and activity of various microbial species is far from complete. Such techniques may give a wealth of information, but to include such findings in systems predicting the nutrient profile requires close collaboration between molecular scientists and mathematical modellers on interpreting and evaluating quantitative data. Protozoal metabolism is of particular interest here given the paucity of quantitative data

  6. Draft forces prediction model for standard single tines by using principles of soil mechanics and soil profile evaluation

    Directory of Open Access Journals (Sweden)

    Amer Khalid Ahmed Al-Neama

    2017-06-01

    Full Text Available This paper explains a model to predict the draft force acting on varying standard single tines by using principles of soil mechanics and soil profile evaluation. Draft force (Fd measurements were made with four standard single tines comprising Heavy Duty, Double Heart, Double Heart with Wings and Duck Foot. Tine widths were 6.5, 13.5, 45 and 40 cm, respectively. The test was conducted in a soil bin with sandy loam soil. The effects of forward speeds and working depths on draft forces were investigated under controlled lab conditions. Results were evaluated based on a prediction model. A good correlation between measured and predicted Fd values for all tines with an average absolute variation less than 15 % was found.

  7. Bradsim-prediction of solute concentration. Temperature and physical property profiles along pulsed plate columns

    International Nuclear Information System (INIS)

    Logsdail, D.H.; Evans, S.F.; Jenkins, J.A.; Smith, I.J.

    1988-01-01

    Dynamic model of the operation of the BRADSIM pulsed plate column is developed. Examples of simulation of the pures process extraction system are given. Profiles of dissolved substances concentrations and profiles of physical properties of liquid along the column are provided. Calculated values are compared with the experimental data, obtained in case of the column 50 mm in diameter, Harwell extractional facility and Sellafield pulsed column 300 mm in diameter for extraction systems uranyl nitrate-nitric acid-20% and 30% TBP in kerosene. 2 refs.; 6 figs

  8. Computational Analysis of Epidermal Growth Factor Receptor Mutations Predicts Differential Drug Sensitivity Profiles toward Kinase Inhibitors.

    Science.gov (United States)

    Akula, Sravani; Kamasani, Swapna; Sivan, Sree Kanth; Manga, Vijjulatha; Vudem, Dashavantha Reddy; Kancha, Rama Krishna

    2018-05-01

    A significant proportion of patients with lung cancer carry mutations in the EGFR kinase domain. The presence of a deletion mutation in exon 19 or L858R point mutation in the EGFR kinase domain has been shown to cause enhanced efficacy of inhibitor treatment in patients with NSCLC. Several less frequent (uncommon) mutations in the EGFR kinase domain with potential implications in treatment response have also been reported. The role of a limited number of uncommon mutations in drug sensitivity was experimentally verified. However, a huge number of these mutations remain uncharacterized for inhibitor sensitivity or resistance. A large-scale computational analysis of clinically reported 298 point mutants of EGFR kinase domain has been performed, and drug sensitivity profiles for each mutant toward seven kinase inhibitors has been determined by molecular docking. In addition, the relative inhibitor binding affinity toward each drug as compared with that of adenosine triphosphate was calculated for each mutant. The inhibitor sensitivity profiles predicted in this study for a set of previously characterized mutants correlated well with the published clinical, experimental, and computational data. Both the single and compound mutations displayed differential inhibitor sensitivity toward first- and next-generation kinase inhibitors. The present study provides predicted drug sensitivity profiles for a large panel of uncommon EGFR mutations toward multiple inhibitors, which may help clinicians in deciding mutant-specific treatment strategies. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

  9. A supply-demand model of fetal energy sufficiency predicts lipid profiles in male but not female Filipino adolescents.

    Science.gov (United States)

    Kuzawa, C W; Adair, L S

    2004-03-01

    To test the hypothesis that the balance between fetal nutritional demand and maternal nutritional supply during pregnancy will predict lipid profiles in offspring measured in adolescence. A total of 296 male and 307 female Filipino offspring (aged 14-16 y) and mothers enrolled in a longitudinal birth cohort study (begun in 1983-84) had lipid profiles measured. Data on maternal height (as a proxy for offspring growth potential and thus fetal nutritional demand) and third trimester maternal arm fat area (as a proxy for maternal supply) were used to create four groups hypothesized to reflect a gradient of fetal energy sufficiency. As fetal energy sufficiency increased among males, there was a decrease in total cholesterol (TC) (Psupply-demand model did not predict any lipid outcome or clinical risk criteria. Our findings in males support the hypothesis that the balance between fetal nutritional demand and maternal nutritional supply has implications for future lipid profiles. The lack of significant associations in females adds to mounting evidence for sex differences in lipid metabolism programming, and may reflect sex differences in fetal nutritional demand. The National Science Foundation, the Mellon Foundation, the Nestle Foundation, and the Emory University Internationalization Program.

  10. Proinflammatory cytokines in open versus laparoscopic cholecystectomy

    International Nuclear Information System (INIS)

    Abu-Eshy, Saeed A.; Al-Rofaidi, Abdallah A.; Al-Faki, Ahmed S.; Ghalib, Hashim W.; Moosa, Riyadh A.; Sadik, Ali A.; Salati, Mohammad I.

    2002-01-01

    Laparoscopic cholecystectomy, a minimal access surgery, is fast replacing open cholecystectomy and is being associated with less trauma. The objective of this study was to compare the proinflammatory cytokine levels in both laparoscopic cholecystectomy and open cholecystectomy. This study was carried out at Aseer Central Hospital, Aseer region, Abha Private Hospital and the College of Medicine and Medical Sciences, King Khalid University, Abha, Kingdom of Saudi Arabia, during the time period October 1998 through to November 2000. Sixty-one patients were included in the study, 27 of them had laparoscopic cholecystectomy and 34 had open cholecystectomy. Cytokines [Interleukin-6 Interleukin-1b, Tumor necrosis factor -a and Interleukin- 8] were measured in blood samples collected from the patients before, at and 24 hours post surgery, using commercially available kits. Interleukin-6 levels were significantly increased at 24 hours post surgery in the open cholecystectomy group of patients compared to the laparoscopic cholecystectomy group (P<0.04). No differences were found in the other cytokines levels (Interleukin-1b, tumor necrosis factor -a and Interleukin-8) between the open cholecystectomy and laparoscopic cholecystectomy groups. Laparoscopic cholecystectomy, a minimal access surgery, is associated with lower levels of the proinflammatory interleukin-6 cytokine compared to open cholecystectomy. (author)

  11. Cardiac and proinflammatory markers predict prognosis in cirrhosis

    DEFF Research Database (Denmark)

    Wiese, Signe; Mortensen, Christian; Gøtze, Jens P

    2014-01-01

    changes, and long-term survival. METHODS: One hundred and ninety-three stable cirrhotic patients (Child class: A = 46; B = 97; C = 50) had a full haemodynamic investigation performed with measurement of splanchnic and systemic haemodynamics and measurement of circulating levels of proBNP, proANP, copeptin...

  12. Prediction of crank torque and pedal angle profiles during pedaling movements by biomechanical optimization

    DEFF Research Database (Denmark)

    Farahani, Saeed Davoudabadi; Bertucci, William; Andersen, Michael Skipper

    2015-01-01

    This paper introduces the inverse-inverse dynamics method for prediction of human movement and applies it to prediction of cycling motions. Inverse-inverse dynamics optimizes a performance criterion by variation of a parameterized movement. First, a musculoskeletal model of cycling is built in th...

  13. The clinical utility of lipid profile and positive troponin in predicting future cardiac events

    Directory of Open Access Journals (Sweden)

    Arun Kumar

    2012-02-01

    Full Text Available Objective: To study the usefulness of traditional lipid profile levels in screening subjects who had developed chest pain due to cardiac event as indicated by a positive troponin I (TnI test. Methods: In this retrospective study data of the 740 patients presented to the emergency department with symptoms of cardiac ischemia that underwent both troponin and lipid profiles tests were compared with the lipid profiles of 411 normal healthy subjects (controls. The troponin was detected qualitatively when a specimen contains TnI above the 99th percentile (TnI >0.5 ng/ mL. The total cholesterol (TC, high density lipoproteins (HDL, very low density lipoproteins (VLDL, and triacyl glycerol (TG levels were also analyzed and low density lipoprotein level (LDL was calculated using Friedewald ’s formula. Results: Patients with chest pain and positive troponin test (with confirmed cardiac event were found to have significantly elevated levels of TC, TG, LDL and significantly reduced HDL levels when compared to the patients who experienced only chest pain (negative troponin and healthy controls. Conclusions: Traditional lipid profile levels still can be used in screening populations to identify the subjects with high risk of developing cardiac event which is identified by highly sensitive and specific positive troponin test.

  14. Early Childhood Profiles of Sleep Problems and Self-Regulation Predict Later School Adjustment

    Science.gov (United States)

    Williams, Kate E.; Nicholson, Jan M.; Walker, Sue; Berthelsen, Donna

    2016-01-01

    Background: Children's sleep problems and self-regulation problems have been independently associated with poorer adjustment to school, but there has been limited exploration of longitudinal early childhood profiles that include both indicators. Aims: This study explores the normative developmental pathway for sleep problems and self-regulation…

  15. Prediction of graft-versus-host disease in humans by donor gene-expression profiling.

    Directory of Open Access Journals (Sweden)

    Chantal Baron

    2007-01-01

    Full Text Available BACKGROUND: Graft-versus-host disease (GVHD results from recognition of host antigens by donor T cells following allogeneic hematopoietic cell transplantation (AHCT. Notably, histoincompatibility between donor and recipient is necessary but not sufficient to elicit GVHD. Therefore, we tested the hypothesis that some donors may be "stronger alloresponders" than others, and consequently more likely to elicit GVHD. METHODS AND FINDINGS: To this end, we measured the gene-expression profiles of CD4(+ and CD8(+ T cells from 50 AHCT donors with microarrays. We report that pre-AHCT gene-expression profiling segregates donors whose recipient suffered from GVHD or not. Using quantitative PCR, established statistical tests, and analysis of multiple independent training-test datasets, we found that for chronic GVHD the "dangerous donor" trait (occurrence of GVHD in the recipient is under polygenic control and is shaped by the activity of genes that regulate transforming growth factor-beta signaling and cell proliferation. CONCLUSIONS: These findings strongly suggest that the donor gene-expression profile has a dominant influence on the occurrence of GVHD in the recipient. The ability to discriminate strong and weak alloresponders using gene-expression profiling could pave the way to personalized transplantation medicine.

  16. Profiles of Observed Infant Anger Predict Preschool Behavior Problems: Moderation by Life Stress

    Science.gov (United States)

    Brooker, Rebecca J.; Buss, Kristin A.; Lemery-Chalfant, Kathryn; Aksan, Nazan; Davidson, Richard J.; Goldsmith, H. Hill

    2014-01-01

    Using both traditional composites and novel profiles of anger, we examined associations between infant anger and preschool behavior problems in a large, longitudinal data set (N = 966). We also tested the role of life stress as a moderator of the link between early anger and the development of behavior problems. Although traditional measures of…

  17. Predicting fatty acid profiles in blood based on food intake and the FADS1 rs174546 SNP.

    Science.gov (United States)

    Hallmann, Jacqueline; Kolossa, Silvia; Gedrich, Kurt; Celis-Morales, Carlos; Forster, Hannah; O'Donovan, Clare B; Woolhead, Clara; Macready, Anna L; Fallaize, Rosalind; Marsaux, Cyril F M; Lambrinou, Christina-Paulina; Mavrogianni, Christina; Moschonis, George; Navas-Carretero, Santiago; San-Cristobal, Rodrigo; Godlewska, Magdalena; Surwiłło, Agnieszka; Mathers, John C; Gibney, Eileen R; Brennan, Lorraine; Walsh, Marianne C; Lovegrove, Julie A; Saris, Wim H M; Manios, Yannis; Martinez, Jose Alfredo; Traczyk, Iwona; Gibney, Michael J; Daniel, Hannelore

    2015-12-01

    A high intake of n-3 PUFA provides health benefits via changes in the n-6/n-3 ratio in blood. In addition to such dietary PUFAs, variants in the fatty acid desaturase 1 (FADS1) gene are also associated with altered PUFA profiles. We used mathematical modeling to predict levels of PUFA in whole blood, based on multiple hypothesis testing and bootstrapped LASSO selected food items, anthropometric and lifestyle factors, and the rs174546 genotypes in FADS1 from 1607 participants (Food4Me Study). The models were developed using data from the first reported time point (training set) and their predictive power was evaluated using data from the last reported time point (test set). Among other food items, fish, pizza, chicken, and cereals were identified as being associated with the PUFA profiles. Using these food items and the rs174546 genotypes as predictors, models explained 26-43% of the variability in PUFA concentrations in the training set and 22-33% in the test set. Selecting food items using multiple hypothesis testing is a valuable contribution to determine predictors, as our models' predictive power is higher compared to analogue studies. As unique feature, we additionally confirmed our models' power based on a test set. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Concomitant prediction of function and fold at the domain level with GO-based profiles.

    Science.gov (United States)

    Lopez, Daniel; Pazos, Florencio

    2013-01-01

    Predicting the function of newly sequenced proteins is crucial due to the pace at which these raw sequences are being obtained. Almost all resources for predicting protein function assign functional terms to whole chains, and do not distinguish which particular domain is responsible for the allocated function. This is not a limitation of the methodologies themselves but it is due to the fact that in the databases of functional annotations these methods use for transferring functional terms to new proteins, these annotations are done on a whole-chain basis. Nevertheless, domains are the basic evolutionary and often functional units of proteins. In many cases, the domains of a protein chain have distinct molecular functions, independent from each other. For that reason resources with functional annotations at the domain level, as well as methodologies for predicting function for individual domains adapted to these resources are required.We present a methodology for predicting the molecular function of individual domains, based on a previously developed database of functional annotations at the domain level. The approach, which we show outperforms a standard method based on sequence searches in assigning function, concomitantly predicts the structural fold of the domains and can give hints on the functionally important residues associated to the predicted function.

  19. Taxonomic and predicted metabolic profiles of the human gut microbiome in pre-Columbian mummies.

    Science.gov (United States)

    Santiago-Rodriguez, Tasha M; Fornaciari, Gino; Luciani, Stefania; Dowd, Scot E; Toranzos, Gary A; Marota, Isolina; Cano, Raul J

    2016-11-01

    Characterization of naturally mummified human gut remains could potentially provide insights into the preservation and evolution of commensal and pathogenic microorganisms, and metabolic profiles. We characterized the gut microbiome of two pre-Columbian Andean mummies dating to the 10-15th centuries using 16S rRNA gene high-throughput sequencing and metagenomics, and compared them to a previously characterized gut microbiome of an 11th century AD pre-Columbian Andean mummy. Our previous study showed that the Clostridiales represented the majority of the bacterial communities in the mummified gut remains, but that other microbial communities were also preserved during the process of natural mummification, as shown with the metagenomics analyses. The gut microbiome of the other two mummies were mainly comprised by Clostridiales or Bacillales, as demonstrated with 16S rRNA gene amplicon sequencing, many of which are facultative anaerobes, possibly consistent with the process of natural mummification requiring low oxygen levels. Metagenome analyses showed the presence of other microbial groups that were positively or negatively correlated with specific metabolic profiles. The presence of sequences similar to both Trypanosoma cruzi and Leishmania donovani could suggest that these pathogens were prevalent in pre-Columbian individuals. Taxonomic and functional profiling of mummified human gut remains will aid in the understanding of the microbial ecology of the process of natural mummification. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Ovary transcriptome profiling via artificial intelligence reveals a transcriptomic fingerprint predicting egg quality in striped bass, Morone saxatilis.

    Directory of Open Access Journals (Sweden)

    Robert W Chapman

    Full Text Available Inherited gene transcripts deposited in oocytes direct early embryonic development in all vertebrates, but transcript profiles indicative of embryo developmental competence have not previously been identified. We employed artificial intelligence to model profiles of maternal ovary gene expression and their relationship to egg quality, evaluated as production of viable mid-blastula stage embryos, in the striped bass (Morone saxatilis, a farmed species with serious egg quality problems. In models developed using artificial neural networks (ANNs and supervised machine learning, collective changes in the expression of a limited suite of genes (233 representing 90% of the eventual variance in embryo survival. Egg quality related to minor changes in gene expression (<0.2-fold, with most individual transcripts making a small contribution (<1% to the overall prediction of egg quality. These findings indicate that the predictive power of the transcriptome as regards egg quality resides not in levels of individual genes, but rather in the collective, coordinated expression of a suite of transcripts constituting a transcriptomic "fingerprint". Correlation analyses of the corresponding candidate genes indicated that dysfunction of the ubiquitin-26S proteasome, COP9 signalosome, and subsequent control of the cell cycle engenders embryonic developmental incompetence. The affected gene networks are centrally involved in regulation of early development in all vertebrates, including humans. By assessing collective levels of the relevant ovarian transcripts via ANNs we were able, for the first time in any vertebrate, to accurately predict the subsequent embryo developmental potential of eggs from individual females. Our results show that the transcriptomic fingerprint evidencing developmental dysfunction is highly predictive of, and therefore likely to regulate, egg quality, a biologically complex trait crucial to reproductive fitness.

  1. Reduced model prediction of electron temperature profiles in microtearing-dominated National Spherical Torus eXperiment plasmas

    Energy Technology Data Exchange (ETDEWEB)

    Kaye, S. M., E-mail: skaye@pppl.gov; Guttenfelder, W.; Bell, R. E.; Gerhardt, S. P.; LeBlanc, B. P.; Maingi, R. [Princeton Plasma Physics Laboratory, Princeton University, Princeton, New Jersey 08543 (United States)

    2014-08-15

    A representative H-mode discharge from the National Spherical Torus eXperiment is studied in detail to utilize it as a basis for a time-evolving prediction of the electron temperature profile using an appropriate reduced transport model. The time evolution of characteristic plasma variables such as β{sub e}, ν{sub e}{sup ∗}, the MHD α parameter, and the gradient scale lengths of T{sub e}, T{sub i}, and n{sub e} were examined as a prelude to performing linear gyrokinetic calculations to determine the fastest growing micro instability at various times and locations throughout the discharge. The inferences from the parameter evolutions and the linear stability calculations were consistent. Early in the discharge, when β{sub e} and ν{sub e}{sup ∗} were relatively low, ballooning parity modes were dominant. As time progressed and both β{sub e} and ν{sub e}{sup ∗} increased, microtearing became the dominant low-k{sub θ} mode, especially in the outer half of the plasma. There are instances in time and radius, however, where other modes, at higher-k{sub θ}, may, in addition to microtearing, be important for driving electron transport. Given these results, the Rebut-Lallia-Watkins (RLW) electron thermal diffusivity model, which is based on microtearing-induced transport, was used to predict the time-evolving electron temperature across most of the profile. The results indicate that RLW does a good job of predicting T{sub e} for times and locations where microtearing was determined to be important, but not as well when microtearing was predicted to be stable or subdominant.

  2. A biomarker profile for predicting efficacy of cisplatin-vinorelbine therapy in malignant pleural mesothelioma

    DEFF Research Database (Denmark)

    Zimling, Zarah Glad; Sørensen, Jens Benn; Gerds, Thomas Alexander

    2012-01-01

    Malignant pleural mesothelioma (MPM) has a dismal prognosis. Treatment results may be improved by biomarker-directed therapy. We investigated the baseline expression and impact on outcome of predictive biomarkers ERCC1, BRCA1, and class III β-tubulin in a cohort of MPM patients treated with cispl......Malignant pleural mesothelioma (MPM) has a dismal prognosis. Treatment results may be improved by biomarker-directed therapy. We investigated the baseline expression and impact on outcome of predictive biomarkers ERCC1, BRCA1, and class III β-tubulin in a cohort of MPM patients treated...

  3. Prediction du profil de durete de l'acier AISI 4340 traite thermiquement au laser

    Science.gov (United States)

    Maamri, Ilyes

    Les traitements thermiques de surfaces sont des procedes qui visent a conferer au coeur et a la surface des pieces mecaniques des proprietes differentes. Ils permettent d'ameliorer la resistance a l'usure et a la fatigue en durcissant les zones critiques superficielles par des apports thermiques courts et localises. Parmi les procedes qui se distinguent par leur capacite en terme de puissance surfacique, le traitement thermique de surface au laser offre des cycles thermiques rapides, localises et precis tout en limitant les risques de deformations indesirables. Les proprietes mecaniques de la zone durcie obtenue par ce procede dependent des proprietes physicochimiques du materiau a traiter et de plusieurs parametres du procede. Pour etre en mesure d'exploiter adequatement les ressources qu'offre ce procede, il est necessaire de developper des strategies permettant de controler et regler les parametres de maniere a produire avec precision les caracteristiques desirees pour la surface durcie sans recourir au classique long et couteux processus essai-erreur. L'objectif du projet consiste donc a developper des modeles pour predire le profil de durete dans le cas de traitement thermique de pieces en acier AISI 4340. Pour comprendre le comportement du procede et evaluer les effets des differents parametres sur la qualite du traitement, une etude de sensibilite a ete menee en se basant sur une planification experimentale structuree combinee a des techniques d'analyse statistiques eprouvees. Les resultats de cette etude ont permis l'identification des variables les plus pertinentes a exploiter pour la modelisation. Suite a cette analyse et dans le but d'elaborer un premier modele, deux techniques de modelisation ont ete considerees, soient la regression multiple et les reseaux de neurones. Les deux techniques ont conduit a des modeles de qualite acceptable avec une precision d'environ 90%. Pour ameliorer les performances des modeles a base de reseaux de neurones, deux

  4. Amazon forest carbon dynamics predicted by profiles of canopy leaf area and light environment

    Science.gov (United States)

    S. C. Stark; V. Leitold; J. L. Wu; M. O. Hunter; C. V. de Castilho; F. R. C. Costa; S. M. McMahon; G. G. Parker; M. Takako Shimabukuro; M. A. Lefsky; M. Keller; L. F. Alves; J. Schietti; Y. E. Shimabukuro; D. O. Brandao; T. K. Woodcock; N. Higuchi; P. B de Camargo; R. C. de Oliveira; S. R. Saleska

    2012-01-01

    Tropical forest structural variation across heterogeneous landscapes may control above-ground carbon dynamics. We tested the hypothesis that canopy structure (leaf area and light availability) – remotely estimated from LiDAR – control variation in above-ground coarse wood production (biomass growth). Using a statistical model, these factors predicted biomass growth...

  5. Late-Onset Alzheimer's Disease Polygenic Risk Profile Score Predicts Hippocampal Function.

    Science.gov (United States)

    Xiao, Ena; Chen, Qiang; Goldman, Aaron L; Tan, Hao Yang; Healy, Kaitlin; Zoltick, Brad; Das, Saumitra; Kolachana, Bhaskar; Callicott, Joseph H; Dickinson, Dwight; Berman, Karen F; Weinberger, Daniel R; Mattay, Venkata S

    2017-11-01

    We explored the cumulative effect of several late-onset Alzheimer's disease (LOAD) risk loci using a polygenic risk profile score (RPS) approach on measures of hippocampal function, cognition, and brain morphometry. In a sample of 231 healthy control subjects (19-55 years of age), we used an RPS to study the effect of several LOAD risk loci reported in a recent meta-analysis on hippocampal function (determined by its engagement with blood oxygen level-dependent functional magnetic resonance imaging during episodic memory) and several cognitive metrics. We also studied effects on brain morphometry in an overlapping sample of 280 subjects. There was almost no significant association of LOAD-RPS with cognitive or morphometric measures. However, there was a significant negative relationship between LOAD-RPS and hippocampal function (familywise error [small volume correction-hippocampal region of interest] p risk score based on APOE haplotype, and for a combined LOAD-RPS + APOE haplotype risk profile score (p risk genes on hippocampal function even in healthy volunteers. The effect of LOAD-RPS on hippocampal function in the relative absence of any effect on cognitive and morphometric measures is consistent with the reported temporal characteristics of LOAD biomarkers with the earlier manifestation of synaptic dysfunction before morphometric and cognitive changes. Copyright © 2017 Society of Biological Psychiatry. All rights reserved.

  6. Magnetic resonance spectroscopy metabolite profiles predict survival in paediatric brain tumours.

    Science.gov (United States)

    Wilson, Martin; Cummins, Carole L; Macpherson, Lesley; Sun, Yu; Natarajan, Kal; Grundy, Richard G; Arvanitis, Theodoros N; Kauppinen, Risto A; Peet, Andrew C

    2013-01-01

    Brain tumours cause the highest mortality and morbidity rate of all childhood tumour groups and new methods are required to improve clinical management. (1)H magnetic resonance spectroscopy (MRS) allows non-invasive concentration measurements of small molecules present in tumour tissue, providing clinically useful imaging biomarkers. The primary aim of this study was to investigate whether MRS detectable molecules can predict the survival of paediatric brain tumour patients. Short echo time (30ms) single voxel (1)H MRS was performed on children attending Birmingham Children's Hospital with a suspected brain tumour and 115 patients were included in the survival analysis. Patients were followed-up for a median period of 35 months and Cox-Regression was used to establish the prognostic value of individual MRS detectable molecules. A multivariate model of survival was also investigated to improve prognostic power. Lipids and scyllo-inositol predicted poor survival whilst glutamine and N-acetyl aspartate predicted improved survival (pmodel of survival based on three MRS biomarkers predicted survival with a similar accuracy to histologic grading (p5e-5). A negative correlation between lipids and glutamine was found, suggesting a functional link between these molecules. MRS detectable biomolecules have been identified that predict survival of paediatric brain tumour patients across a range of tumour types. The evaluation of these biomarkers in large prospective studies of specific tumour types should be undertaken. The correlation between lipids and glutamine provides new insight into paediatric brain tumour metabolism that may present novel targets for therapy. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Expression profiling to predict the clinical behaviour of ovarian cancer fails independent evaluation

    International Nuclear Information System (INIS)

    Gevaert, Olivier; De Smet, Frank; Van Gorp, Toon; Pochet, Nathalie; Engelen, Kristof; Amant, Frederic; De Moor, Bart; Timmerman, Dirk; Vergote, Ignace

    2008-01-01

    In a previously published pilot study we explored the performance of microarrays in predicting clinical behaviour of ovarian tumours. For this purpose we performed microarray analysis on 20 patients and estimated that we could predict advanced stage disease with 100% accuracy and the response to platin-based chemotherapy with 76.92% accuracy using leave-one-out cross validation techniques in combination with Least Squares Support Vector Machines (LS-SVMs). In the current study we evaluate whether tumour characteristics in an independent set of 49 patients can be predicted using the pilot data set with principal component analysis or LS-SVMs. The results of the principal component analysis suggest that the gene expression data from stage I, platin-sensitive advanced stage and platin-resistant advanced stage tumours in the independent data set did not correspond to their respective classes in the pilot study. Additionally, LS-SVM models built using the data from the pilot study – although they only misclassified one of four stage I tumours and correctly classified all 45 advanced stage tumours – were not able to predict resistance to platin-based chemotherapy. Furthermore, models based on the pilot data and on previously published gene sets related to ovarian cancer outcomes, did not perform significantly better than our models. We discuss possible reasons for failure of the model for predicting response to platin-based chemotherapy and conclude that existing results based on gene expression patterns of ovarian tumours need to be thoroughly scrutinized before these results can be accepted to reflect the true performance of microarray technology

  8. Relationship between the prognostic and predictive value of the intrinsic subtypes and a validated gene profile predictive of loco-regional control and benefit from post-mastectomy radiotherapy in patients with high-risk breast cancer

    DEFF Research Database (Denmark)

    Tramm, Trine; Kyndi, Marianne; Myhre, Simen

    2014-01-01

    , and has shown prognostic impact in terms of loco-regional failure and predictive impact for PMRT. Reports have also shown predictive value in terms of benefit of PMRT from intrinsic subtypes and derived approximations. The aim of this study was to examine: 1) the agreement between various methods...... for determining the intrinsic subtypes; and 2) the relationship between the prognostic and predictive impact of the DBCG-RT profile and the intrinsic subtypes. MATERIAL AND METHODS: Intrinsic subtypes and the DBCG-RT profile was determined from microarray analysis based on fresh frozen tissue from 191 patients...... and predictive information obtained from the DBCG-RT profile cannot be substituted by any approximation of the tumors intrinsic subtype. The predictive value of the intrinsic subtypes in terms of PMRT was influenced by the method used for assignment to the intrinsic subtypes....

  9. Assessment of leisure-time physical activity for the prediction of inflammatory status and cardiometabolic profile.

    Science.gov (United States)

    Pires, Milena Monfort; Salvador, Emanuel P; Siqueira-Catania, Antonela; Folchetti, Luciana D; Cezaretto, Adriana; Ferreira, Sandra Roberta G

    2012-11-01

    Associations of leisure-time physical activity (LTPA), commuting and total physical activity with inflammatory markers, insulin resistance and metabolic profile in individuals at high cardiometabolic risk were investigated. This was a cross-sectional study. A total of 193 prediabetic adults were compared according to physical activity levels measured by the international physical activity questionnaire; p for trend and logistic regression was employed. The most active subset showed lower BMI and abdominal circumference, reaching significance only for LTPA (p for trend=0.02). Lipid profile improved with increased physical activity levels. Interleukin-6 decreased with increased total physical activity and LTPA (p for trend=0.02 and 0.03, respectively), while adiponectin increased in more active subsets for LTPA (p for trend=0.03). Elevation in adjusted OR for hypercholesterolemia was significant for lower LTPA durations (p for trend=0.04). High apolipoprotein B/apolipoprotein A ratio was inversely associated with LTPA, commuting and total physical activity. Increase in adjusted OR for insulin resistance was found from the highest to the lowest category of LTPA (p for trend=0.04) but significance disappeared after adjustments for BMI and energy intake. No association of increased C-reactive protein with physical activity domains was observed. In general, the associations of LTPA, but not commuting or total physical activity, with markers of cardiometabolic risk reinforces the importance of initiatives to increase this domain in programs for the prevention of lifestyle-related diseases. Copyright © 2012 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.

  10. Mathematical model to predict temperature profile and air–fuel equivalence ratio of a downdraft gasification process

    International Nuclear Information System (INIS)

    Jaojaruek, Kitipong

    2014-01-01

    Highlights: • A mathematical model based on finite computation analysis was developed. • Model covers all zones of gasification process which will be useful to improve gasifier design. • Model can predict temperature profile, feedstock consumption rate and reaction equivalent ratio (ϕ). • Model-predicted parameters fitted well with experimental values. - Abstract: A mathematical model for the entire length of a downdraft gasifier was developed using thermochemical principles to derive energy and mass conversion equations. Analysis of heat transfer (conduction, convection and radiation) and chemical kinetic technique were applied to predict the temperature profile, feedstock consumption rate (FCR) and reaction equivalence ratio (RER). The model will be useful for designing gasifiers, estimating output gas composition and gas production rate (GPR). Implicit finite difference method solved the equations on the considered reactor length (50 cm) and diameter (20 cm). Conversion criteria for calculation of temperature and feedstock consumption rate were 1 × 10 −6 °C and 1 × 10 −6 kg/h, respectively. Experimental validation showed that model outputs fitted well with experimental data. Maximum deviation between model and experimental data of temperature, FCR and RER were 52 °C at combustion temperature 663 °C, 0.7 kg/h at the rate 8.1 kg/h and 0.03 at the RER 0.42, respectively. Experimental uncertainty of temperature, FCR and RER were 24.4 °C, 0.71 kg/h and 0.04, respectively, on confidence level of 95%

  11. In-flight measurements and RCS-predictions: A comparison on broad-side radar range profiles of a Boeing 737

    NARCIS (Netherlands)

    Heiden, R. van der; Ewijk, L.J. van; Groen, F.C.A.

    1997-01-01

    The validation of Radar Cross Section (RCS) prediction techniques against real measurements is crucial to acquire confidence in predictions when measurements are not available. In this paper we present the first results of a comparison on one dimensional images, i.e., radar range profiles. The

  12. High-Throughput Gene Expression Profiles to Define Drug Similarity and Predict Compound Activity.

    Science.gov (United States)

    De Wolf, Hans; Cougnaud, Laure; Van Hoorde, Kirsten; De Bondt, An; Wegner, Joerg K; Ceulemans, Hugo; Göhlmann, Hinrich

    2018-04-01

    By adding biological information, beyond the chemical properties and desired effect of a compound, uncharted compound areas and connections can be explored. In this study, we add transcriptional information for 31K compounds of Janssen's primary screening deck, using the HT L1000 platform and assess (a) the transcriptional connection score for generating compound similarities, (b) machine learning algorithms for generating target activity predictions, and (c) the scaffold hopping potential of the resulting hits. We demonstrate that the transcriptional connection score is best computed from the significant genes only and should be interpreted within its confidence interval for which we provide the stats. These guidelines help to reduce noise, increase reproducibility, and enable the separation of specific and promiscuous compounds. The added value of machine learning is demonstrated for the NR3C1 and HSP90 targets. Support Vector Machine models yielded balanced accuracy values ≥80% when the expression values from DDIT4 & SERPINE1 and TMEM97 & SPR were used to predict the NR3C1 and HSP90 activity, respectively. Combining both models resulted in 22 new and confirmed HSP90-independent NR3C1 inhibitors, providing two scaffolds (i.e., pyrimidine and pyrazolo-pyrimidine), which could potentially be of interest in the treatment of depression (i.e., inhibiting the glucocorticoid receptor (i.e., NR3C1), while leaving its chaperone, HSP90, unaffected). As such, the initial hit rate increased by a factor 300, as less, but more specific chemistry could be screened, based on the upfront computed activity predictions.

  13. Performance of CT ASPECTS and Collateral Score in Risk Stratification: Can Target Perfusion Profiles Be Predicted without Perfusion Imaging?

    Science.gov (United States)

    Dehkharghani, S; Bammer, R; Straka, M; Bowen, M; Allen, J W; Rangaraju, S; Kang, J; Gleason, T; Brasher, C; Nahab, F

    2016-08-01

    Endovascular trials suggest that revascularization benefits a subset of acute ischemic stroke patients with large-artery occlusion and small-core infarct volumes. The objective of our study was to identify thresholds of noncontrast CT-ASPECTS and collateral scores on CT angiography that best predict ischemic core volume thresholds quantified by CT perfusion among patients with acute ischemic stroke. Fifty-four patients with acute ischemic stroke (collateral score of 3 had 100% specificity for identifying patients with a CBF core volume of ≤50 mL. NCCT-ASPECTS of ≤6 had 100% specificity for identifying patients with a CBF core volume of >50 mL. In our cohort, 44 (81%) patients had an NCCT-ASPECTS of ≥9, a CTA collateral score of 3, or an NCCT-ASPECTS of ≤6. Using an NCCT-ASPECTS of ≥9 or a CTA collateral score of 3 best predicts CBF core volume infarct of ≤50 mL, while an NCCT-ASPECTS of ≤6 best predicts a CBF core volume infarct of >50 mL. Together these thresholds suggest that a specific population of patients with acute ischemic stroke not meeting such profiles may benefit most from CTP imaging to determine candidacy for revascularization. © 2016 by American Journal of Neuroradiology.

  14. Effectiveness of gene expression profiling for response prediction of rectal cancer to preoperative radiotherapy

    International Nuclear Information System (INIS)

    Ojima, Eiki; Inoue, Yasuhiro; Miki, Chikao; Kusunoki, Masato; Mori, Masaki

    2007-01-01

    Our aim was to determine whether the expression levels of specific genes could predict clinical radiosensitivity in human colorectal cancer. Radioresistant colorectal cancer cell lines were established by repeated X-ray exposure (total, 100 Gy), and the gene expressions of the parent and radioresistant cell lines were compared in a microarray analysis. To verify the microarray data, we carried out a reverse transcriptase-polymerase chain reaction analysis of identified genes in clinical samples from 30 irradiated rectal cancer patients. A comparison of the intensity data for the parent and three radioresistant cell lines revealed 17 upregulated and 142 downregulated genes in all radioresistant cell lines. Next, we focused on two upregulated genes, PTMA (prothymosin α) and EIF5a2 (eukaryotic translation initiation factor 5A), in the radioresistant cell lines. In clinical samples, the expression of PTMA was significantly higher in the minor effect group than in the major effect group (P=0.004), but there were no significant differences in EIF5a2 expression between the two groups. We identified radiation-related genes in colorectal cancer and demonstrated that PTMA may play an important role in radiosensitivity. Our findings suggest that PTMA may be a novel marker for predicting the effectiveness of radiotherapy in clinical cases. (author)

  15. Use of Life Course Work–Family Profiles to Predict Mortality Risk Among US Women

    Science.gov (United States)

    Guevara, Ivan Mejía; Glymour, M. Maria; Berkman, Lisa F.

    2015-01-01

    Objectives. We examined relationships between US women’s exposure to midlife work–family demands and subsequent mortality risk. Methods. We used data from women born 1935 to 1956 in the Health and Retirement Study to calculate employment, marital, and parenthood statuses for each age between 16 and 50 years. We used sequence analysis to identify 7 prototypical work–family trajectories. We calculated age-standardized mortality rates and hazard ratios (HRs) for mortality associated with work–family sequences, with adjustment for covariates and potentially explanatory later-life factors. Results. Married women staying home with children briefly before reentering the workforce had the lowest mortality rates. In comparison, after adjustment for age, race/ethnicity, and education, HRs for mortality were 2.14 (95% confidence interval [CI] = 1.58, 2.90) among single nonworking mothers, 1.48 (95% CI = 1.06, 1.98) among single working mothers, and 1.36 (95% CI = 1.02, 1.80) among married nonworking mothers. Adjustment for later-life behavioral and economic factors partially attenuated risks. Conclusions. Sequence analysis is a promising exposure assessment tool for life course research. This method permitted identification of certain lifetime work–family profiles associated with mortality risk before age 75 years. PMID:25713976

  16. Predicting Delirium Duration in Elderly Hip-Surgery Patients: Does Early Symptom Profile Matter?

    Directory of Open Access Journals (Sweden)

    Chantal J. Slor

    2013-01-01

    Full Text Available Background. Features that may allow early identification of patients at risk of prolonged delirium, and therefore of poorer outcomes, are not well understood. The aim of this study was to determine if preoperative delirium risk factors and delirium symptoms (at onset and clinical symptomatology during the course of delirium are associated with delirium duration. Methods. This study was conducted in prospectively identified cases of incident delirium. We compared patients experiencing delirium of short duration (1 or 2 days with patients who had more prolonged delirium (≥3 days with regard to DRS-R-98 (Delirium Rating Scale Revised-98 symptoms on the first delirious day. Delirium symptom profile was evaluated daily during the delirium course. Results. In a homogenous population of 51 elderly hip-surgery patients, we found that the severity of individual delirium symptoms on the first day of delirium was not associated with duration of delirium. Preexisting cognitive decline was associated with prolonged delirium. Longitudinal analysis using the generalised estimating equations method (GEE identified that more severe impairment of long-term memory across the whole delirium episode was associated with longer duration of delirium. Conclusion. Preexisting cognitive decline rather than severity of individual delirium symptoms at onset is strongly associated with delirium duration.

  17. Use of life course work-family profiles to predict mortality risk among US women.

    Science.gov (United States)

    Sabbath, Erika L; Guevara, Ivan Mejía; Glymour, M Maria; Berkman, Lisa F

    2015-04-01

    We examined relationships between US women's exposure to midlife work-family demands and subsequent mortality risk. We used data from women born 1935 to 1956 in the Health and Retirement Study to calculate employment, marital, and parenthood statuses for each age between 16 and 50 years. We used sequence analysis to identify 7 prototypical work-family trajectories. We calculated age-standardized mortality rates and hazard ratios (HRs) for mortality associated with work-family sequences, with adjustment for covariates and potentially explanatory later-life factors. Married women staying home with children briefly before reentering the workforce had the lowest mortality rates. In comparison, after adjustment for age, race/ethnicity, and education, HRs for mortality were 2.14 (95% confidence interval [CI] = 1.58, 2.90) among single nonworking mothers, 1.48 (95% CI = 1.06, 1.98) among single working mothers, and 1.36 (95% CI = 1.02, 1.80) among married nonworking mothers. Adjustment for later-life behavioral and economic factors partially attenuated risks. Sequence analysis is a promising exposure assessment tool for life course research. This method permitted identification of certain lifetime work-family profiles associated with mortality risk before age 75 years.

  18. Predicting the oral pharmacokinetic profiles of multiple-unit (pellet) dosage forms using a modeling and simulation approach coupled with biorelevant dissolution testing: case example diclofenac sodium.

    Science.gov (United States)

    Kambayashi, Atsushi; Blume, Henning; Dressman, Jennifer B

    2014-07-01

    The objective of this research was to characterize the dissolution profile of a poorly soluble drug, diclofenac, from a commercially available multiple-unit enteric coated dosage form, Diclo-Puren® capsules, and to develop a predictive model for its oral pharmacokinetic profile. The paddle method was used to obtain the dissolution profiles of this dosage form in biorelevant media, with the exposure to simulated gastric conditions being varied in order to simulate the gastric emptying behavior of pellets. A modified Noyes-Whitney theory was subsequently fitted to the dissolution data. A physiologically-based pharmacokinetic (PBPK) model for multiple-unit dosage forms was designed using STELLA® software and coupled with the biorelevant dissolution profiles in order to simulate the plasma concentration profiles of diclofenac from Diclo-Puren® capsule in both the fasted and fed state in humans. Gastric emptying kinetics relevant to multiple-units pellets were incorporated into the PBPK model by setting up a virtual patient population to account for physiological variations in emptying kinetics. Using in vitro biorelevant dissolution coupled with in silico PBPK modeling and simulation it was possible to predict the plasma profile of this multiple-unit formulation of diclofenac after oral administration in both the fasted and fed state. This approach might be useful to predict variability in the plasma profiles for other drugs housed in multiple-unit dosage forms. Copyright © 2014 Elsevier B.V. All rights reserved.

  19. Maternal cytokine profiles during pregnancy predict asthma in children of nonasthmatic mothers.

    Science.gov (United States)

    Rothers, Janet; Stern, Debra A; Lohman, I Carla; Spangenberg, Amber; Wright, Anne L; DeVries, Avery; Vercelli, Donata; Halonen, Marilyn

    2018-06-04

    Little is known about whether maternal immune status during pregnancy influences asthma development in the child. We measured cytokine production in supernatants from mitogen-stimulated peripheral blood immune cells collected during and after pregnancy from the mothers of children enrolled in the Tucson Infant Immune Study, a non-selected birth cohort. Physician-diagnosed active asthma in children through age 9 and a history of asthma in their mothers were assessed through questionnaires. Maternal production of each of the cytokines IL-13, IL-4, IL-5, IFN-γ, IL-10, and IL-17 during pregnancy was unrelated to childhood asthma. However, IFN-γ/IL-13 and IFN-γ/IL-4 ratios during pregnancy were associated with decreased in risk of childhood asthma (N=381; OR=0.33; 95%CI=0.17-0.66, p=0.002 and N=368; OR=0.36; 95%CI=0.18-0.71, p=0.003, respectively). The inverse relations of these two ratios with childhood asthma were only evident in nonasthmatic mothers ( N=309; OR=0.18; 95% CI=0.08-0.42, p=0.00007 and N=299; OR=0.17; 95% CI=0.07-0.39, p=0.00003, respectively) and not in asthmatic mother (N=72 and 69, respectively; p for interaction by maternal asthma=0.036 and 0.002, respectively). Paternal cytokine ratios were unrelated to childhood asthma. Maternal cytokine ratios in nonasthmatic mothers were unrelated to the child's skin test reactivity, total IgE, physician-confirmed allergic rhinitis at age 5, or eczema in infancy. To our knowledge this study provides the first evidence that cytokine profiles in pregnant nonasthmatic mothers relate to risk for childhood asthma but not allergy and suggests a process of asthma development that begins in utero and is independent of allergy.

  20. Analysis and Prediction of the Billet Butt and Transverse Weld in the Continuous Extrusion Process of a Hollow Aluminum Profile

    Science.gov (United States)

    Lou, Shumei; Wang, Yongxiao; Liu, Chuanxi; Lu, Shuai; Liu, Sujun; Su, Chunjian

    2017-08-01

    In continuous extrusions of aluminum profiles, the thickness of the billet butt and the length of the discarded extrudate containing the transverse weld play key roles in reducing material loss and improving product quality. The formation and final distribution of the billet butt and transverse weld depend entirely on the flow behavior of the billet skin material. This study examined the flow behavior of the billet skin material as well as the formation and evolution of the billet butt and the transverse weld in detail through numerical simulation and a series of experiments. In practical extrusions, even if the billet skin is removed by lathe turning shortly before extrusion, billet skin impurities are still distributed around the transverse weld and in the billet butt. The thickness of the scrap billet butt and the length of the discarded extrudate containing the transverse weld can be exactly predicted via simulation.

  1. Lyα Profile, Dust, and Prediction of Lyα Escape Fraction in Green Pea Galaxies

    Science.gov (United States)

    Yang, Huan; Malhotra, Sangeeta; Gronke, Max; Rhoads, James E.; Leitherer, Claus; Wofford, Aida; Jiang, Tianxing; Dijkstra, Mark; Tilvi, V.; Wang, Junxian

    2017-08-01

    We studied Lyman-α (Lyα) escape in a statistical sample of 43 Green Peas with HST/COS Lyα spectra. Green Peas are nearby star-forming galaxies with strong [O III]λ5007 emission lines. Our sample is four times larger than the previous sample and covers a much more complete range of Green Pea properties. We found that about two-thirds of Green Peas are strong Lyα line emitters with rest-frame Lyα equivalent width > 20 \\mathringA . The Lyα profiles of Green Peas are diverse. The Lyα escape fraction, defined as the ratio of observed Lyα flux to intrinsic Lyα flux, shows anti-correlations with a few Lyα kinematic features—both the blue peak and red peak velocities, the peak separations, and the FWHM of the red portion of the Lyα profile. Using properties measured from Sloan Digital Sky Survey optical spectra, we found many correlations—the Lyα escape fraction generally increases at lower dust reddening, lower metallicity, lower stellar mass, and higher [O III]/[O II] ratio. We fit their Lyα profiles with the H I shell radiative transfer model and found that the Lyα escape fraction is anti-correlated with the best-fit N H I . Finally, we fit an empirical linear relation to predict {f}{esc}{Lyα } from the dust extinction and Lyα red peak velocity. The standard deviation of this relation is about 0.3 dex. This relation can be used to isolate the effect of intergalactic medium (IGM) scatterings from Lyα escape and to probe the IGM optical depth along the line of sight of each z> 7 Lyα emission-line galaxy in the James Webb Space Telescope era.

  2. Predicting protein-ATP binding sites from primary sequence through fusing bi-profile sampling of multi-view features

    Directory of Open Access Journals (Sweden)

    Zhang Ya-Nan

    2012-05-01

    Full Text Available Abstract Background Adenosine-5′-triphosphate (ATP is one of multifunctional nucleotides and plays an important role in cell biology as a coenzyme interacting with proteins. Revealing the binding sites between protein and ATP is significantly important to understand the functionality of the proteins and the mechanisms of protein-ATP complex. Results In this paper, we propose a novel framework for predicting the proteins’ functional residues, through which they can bind with ATP molecules. The new prediction protocol is achieved by combination of sequence evolutional information and bi-profile sampling of multi-view sequential features and the sequence derived structural features. The hypothesis for this strategy is single-view feature can only represent partial target’s knowledge and multiple sources of descriptors can be complementary. Conclusions Prediction performances evaluated by both 5-fold and leave-one-out jackknife cross-validation tests on two benchmark datasets consisting of 168 and 227 non-homologous ATP binding proteins respectively demonstrate the efficacy of the proposed protocol. Our experimental results also reveal that the residue structural characteristics of real protein-ATP binding sites are significant different from those normal ones, for example the binding residues do not show high solvent accessibility propensities, and the bindings prefer to occur at the conjoint points between different secondary structure segments. Furthermore, results also show that performance is affected by the imbalanced training datasets by testing multiple ratios between positive and negative samples in the experiments. Increasing the dataset scale is also demonstrated useful for improving the prediction performances.

  3. PROSPECT improves cis-acting regulatory element prediction by integrating expression profile data with consensus pattern searches

    Science.gov (United States)

    Fujibuchi, Wataru; Anderson, John S. J.; Landsman, David

    2001-01-01

    Consensus pattern and matrix-based searches designed to predict cis-acting transcriptional regulatory sequences have historically been subject to large numbers of false positives. We sought to decrease false positives by incorporating expression profile data into a consensus pattern-based search method. We have systematically analyzed the expression phenotypes of over 6000 yeast genes, across 121 expression profile experiments, and correlated them with the distribution of 14 known regulatory elements over sequences upstream of the genes. Our method is based on a metric we term probabilistic element assessment (PEA), which is a ranking of potential sites based on sequence similarity in the upstream regions of genes with similar expression phenotypes. For eight of the 14 known elements that we examined, our method had a much higher selectivity than a naïve consensus pattern search. Based on our analysis, we have developed a web-based tool called PROSPECT, which allows consensus pattern-based searching of gene clusters obtained from microarray data. PMID:11574681

  4. Predicting survival in patients with metastatic kidney cancer by gene-expression profiling in the primary tumor.

    Science.gov (United States)

    Vasselli, James R; Shih, Joanna H; Iyengar, Shuba R; Maranchie, Jodi; Riss, Joseph; Worrell, Robert; Torres-Cabala, Carlos; Tabios, Ray; Mariotti, Andra; Stearman, Robert; Merino, Maria; Walther, McClellan M; Simon, Richard; Klausner, Richard D; Linehan, W Marston

    2003-06-10

    To identify potential molecular determinants of tumor biology and possible clinical outcomes, global gene-expression patterns were analyzed in the primary tumors of patients with metastatic renal cell cancer by using cDNA microarrays. We used grossly dissected tumor masses that included tumor, blood vessels, connective tissue, and infiltrating immune cells to obtain a gene-expression "profile" from each primary tumor. Two patterns of gene expression were found within this uniformly staged patient population, which correlated with a significant difference in overall survival between the two patient groups. Subsets of genes most significantly associated with survival were defined, and vascular cell adhesion molecule-1 (VCAM-1) was the gene most predictive for survival. Therefore, despite the complex biological nature of metastatic cancer, basic clinical behavior as defined by survival may be determined by the gene-expression patterns expressed within the compilation of primary gross tumor cells. We conclude that survival in patients with metastatic renal cell cancer can be correlated with the expression of various genes based solely on the expression profile in the primary kidney tumor.

  5. HPV and high-risk gene expression profiles predict response to chemoradiotherapy in head and neck cancer, independent of clinical factors

    International Nuclear Information System (INIS)

    Jong, Monique C. de; Pramana, Jimmy; Knegjens, Joost L.; Balm, Alfons J.M.; Brekel, Michiel W.M. van den; Hauptmann, Michael; Begg, Adrian C.; Rasch, Coen R.N.

    2010-01-01

    Purpose: The purpose of this study was to combine gene expression profiles and clinical factors to provide a better prediction model of local control after chemoradiotherapy for advanced head and neck cancer. Material and methods: Gene expression data were available for a series of 92 advanced stage head and neck cancer patients treated with primary chemoradiotherapy. The effect of the Chung high-risk and Slebos HPV expression profiles on local control was analyzed in a model with age at diagnosis, gender, tumor site, tumor volume, T-stage and N-stage and HPV profile status. Results: Among 75 patients included in the study, the only factors significantly predicting local control were tumor site (oral cavity vs. Pharynx, hazard ratio 4.2 [95% CI 1.4-12.5]), Chung gene expression status (high vs. Low risk profile, hazard ratio 4.4 [95% CI 1.5-13.3]) and HPV profile (negative vs. Positive profile, hazard ratio 6.2 [95% CI 1.7-22.5]). Conclusions: Chung high-risk expression profile and a negative HPV expression profile were significantly associated with increased risk of local recurrence after chemoradiotherapy in advanced pharynx and oral cavity tumors, independent of clinical factors.

  6. Predicting the impact of vegetations in open channels with different distributaries' operations on water surface profile using artificial neural networks

    International Nuclear Information System (INIS)

    Abdeen, Mostafa A. M.

    2008-01-01

    Most of the open water irrigation channels in Egypt suffer from the infestation of aquatic weeds, especially the submerged ones that cause numerous hydraulic problems for the open channels themselves and their water distributaries such as increasing water losses, obstructing water flow, and reducing channels' water distribution efficiencies. Accurate simulation and prediction of flow behavior in such channels is very essential for water distribution decision makers. Artificial neural networks (ANN) have proven to be very successful in the simulation of several physical phenomena, in general, and in the water research field in particular. Therefore, the current study aims towards introducing the utilization of ANN in simulating the impact of vegetation in main open channel, which supplies water to different distributaries, on the water surface profile in this main channel. Specifically, the study, presented in the current paper utilizes ANN technique for the development of various models to simulate the impact of different submerged weeds' densities, different flow discharges, and different distributaries operation scheduling on the water surface profile in an experimental main open channel that supplies water to different distributaries. In the investigated experiment, the submerged weeds were simulated as branched flexible elements. The investigated experiment was considered as an example for implementing the same methodology and technique in a real open channel system. The results showed that the ANN technique is very successful in simulating the flow behavior of the pre-mentioned open channel experiment with the existence of the submerged weeds. In addition, the developed ANN models were capable of predicting the open channel flow behavior in all the submerged weeds' cases that were considered in the ANN development process

  7. Predicting clinical concussion measures at baseline based on motivation and academic profile.

    Science.gov (United States)

    Trinidad, Katrina J; Schmidt, Julianne D; Register-Mihalik, Johna K; Groff, Diane; Goto, Shiho; Guskiewicz, Kevin M

    2013-11-01

    The purpose of this study was to predict baseline neurocognitive and postural control performance using a measure of motivation, high school grade point average (hsGPA), and Scholastic Aptitude Test (SAT) score. Cross-sectional. Clinical research center. Eighty-eight National Collegiate Athletic Association Division I incoming student-athletes (freshman and transfers). Participants completed baseline clinical concussion measures, including a neurocognitive test battery (CNS Vital Signs), a balance assessment [Sensory Organization Test (SOT)], and motivation testing (Rey Dot Counting). Participants granted permission to access hsGPA and SAT total score. Standard scores for each CNS Vital Signs domain and SOT composite score. Baseline motivation, hsGPA, and SAT explained a small percentage of the variance of complex attention (11%), processing speed (12%), and composite SOT score (20%). Motivation, hsGPA, and total SAT score do not explain a significant amount of the variance in neurocognitive and postural control measures but may still be valuable to consider when interpreting neurocognitive and postural control measures.

  8. Dopamine Gene Profiling to Predict Impulse Control and Effects of Dopamine Agonist Ropinirole.

    Science.gov (United States)

    MacDonald, Hayley J; Stinear, Cathy M; Ren, April; Coxon, James P; Kao, Justin; Macdonald, Lorraine; Snow, Barry; Cramer, Steven C; Byblow, Winston D

    2016-07-01

    Dopamine agonists can impair inhibitory control and cause impulse control disorders for those with Parkinson disease (PD), although mechanistically this is not well understood. In this study, we hypothesized that the extent of such drug effects on impulse control is related to specific dopamine gene polymorphisms. This double-blind, placebo-controlled study aimed to examine the effect of single doses of 0.5 and 1.0 mg of the dopamine agonist ropinirole on impulse control in healthy adults of typical age for PD onset. Impulse control was measured by stop signal RT on a response inhibition task and by an index of impulsive decision-making on the Balloon Analogue Risk Task. A dopamine genetic risk score quantified basal dopamine neurotransmission from the influence of five genes: catechol-O-methyltransferase, dopamine transporter, and those encoding receptors D1, D2, and D3. With placebo, impulse control was better for the high versus low genetic risk score groups. Ropinirole modulated impulse control in a manner dependent on genetic risk score. For the lower score group, both doses improved response inhibition (decreased stop signal RT) whereas the lower dose reduced impulsiveness in decision-making. Conversely, the higher score group showed a trend for worsened response inhibition on the lower dose whereas both doses increased impulsiveness in decision-making. The implications of the present findings are that genotyping can be used to predict impulse control and whether it will improve or worsen with the administration of dopamine agonists.

  9. Therapeutic profile of single-fraction radiosurgery of vestibular schwannoma: unrelated malignancy predicts tumor control

    Science.gov (United States)

    Wowra, Berndt; Muacevic, Alexander; Fürweger, Christoph; Schichor, Christian; Tonn, Jörg-Christian

    2012-01-01

    Radiosurgery has become an accepted treatment option for vestibular schwannomas. Nevertheless, predictors of tumor control and treatment toxicity in current radiosurgery of vestibular schwannomas are not well understood. To generate new information on predictors of tumor control and cranial nerve toxicity of single-fraction radiosurgery of vestibular schwannomas, we conducted a single-institution long-term observational study of radiosurgery for sporadic vestibular schwannomas. Minimum follow-up was 3 years. Investigated as potential predictors of tumor control and cranial nerve toxicity were treatment technology; tumor resection preceding radiosurgery; tumor size; gender; patient age; history of cancer, vascular disease, or metabolic disease; tumor volume; radiosurgical prescription dose; and isodose line. Three hundred eighty-six patients met inclusion criteria. Treatment failure was observed in 27 patients. History of unrelated cancer (strongest predictor) and prescription dose significantly predicted tumor control. The cumulative incidence of treatment failure was 30% after 6.5 years in patients with unrelated malignancy and 10% after ≥15 years in patients without such cancer (P making in ambiguous cases. PMID:22561798

  10. Current and Future Applications of Biomedical Engineering for Proteomic Profiling: Predictive Biomarkers in Neuro-Traumatology

    Directory of Open Access Journals (Sweden)

    Mario Ganau

    2018-02-01

    Full Text Available This systematic review aims to summarize the impact of nanotechnology and biomedical engineering in defining clinically meaningful predictive biomarkers in patients with traumatic brain injury (TBI, a critical worldwide health problem with an estimated 10 billion people affected annually worldwide. Data were collected through a review of the existing English literature performed on Scopus, MEDLINE, MEDLINE in Process, EMBASE, and/or Cochrane Central Register of Controlled Trials. Only experimental articles revolving around the management of TBI, in which the role of new devices based on innovative discoveries coming from the field of nanotechnology and biomedical engineering were highlighted, have been included and analyzed in this study. Based on theresults gathered from this research on innovative methods for genomics, epigenomics, and proteomics, their future application in this field seems promising. Despite the outstanding technical challenges of identifying reliable biosignatures for TBI and the mixed nature of studies herein described (single cells proteomics, biofilms, sensors, etc., the clinical implementation of those discoveries will allow us to gain confidence in the use of advanced neuromonitoring modalities with a potential dramatic improvement in the management of those patients.

  11. Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel.

    Science.gov (United States)

    Kharaziha, Pedram; Chioureas, Dimitris; Rutishauser, Dorothea; Baltatzis, George; Lennartsson, Lena; Fonseca, Pedro; Azimi, Alireza; Hultenby, Kjell; Zubarev, Roman; Ullén, Anders; Yachnin, Jeffrey; Nilsson, Sten; Panaretakis, Theocharis

    2015-08-28

    Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.

  12. Comparison of ring-focus image profile with predictions for the AXAF VETA-I test

    Science.gov (United States)

    Zissa, David E.

    1993-01-01

    The X-ray test of the largest pair of nearly cylindrical mirrors for the Advanced X-ray Astrophysics Facility (AXAF) was completed in October 1991 at Marshall Space Flight Center. The test assembly was named the Verification Engineering Test Article I (VETA-I). The ring-focus portion of the test measured the imaging quality of azimuthal sections of VETA-I. This gives information about the core of the on-orbit image. The finite source distance, VETA-I mirror spacing, and VETA-I structural deformation caused the core of the image to be spread over a diameter of nearly 4 arc seconds at the VETA-I overall focus. The results of a preliminary analysis of the ring-focus data and the implications for the on-orbit image of the telescope are discussed. An upper limit for the on-orbit encircled-energy fraction at 1 arc second diameter was determined to be 0.82 at 0.277 keV X-ray energy. This assumes that the bottoms of the mirrors in the VETA-I arrangement are representative of the mirror surfaces and that the on-orbit system would be aligned using a combination of preliminary measurements and predictions for the mirror surface shapes.

  13. Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.

    Directory of Open Access Journals (Sweden)

    Joseph N Jarvis

    2015-04-01

    Full Text Available Understanding the host immune response during cryptococcal meningitis (CM is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA. PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1 and macrophage inflammatory protein-1α (MIP-1α. High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS. In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS, more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and

  14. Early second-trimester serum miRNA profiling predicts gestational diabetes mellitus.

    Directory of Open Access Journals (Sweden)

    Chun Zhao

    Full Text Available BACKGROUND: Gestational diabetes mellitus (GDM is one type of diabetes that presents during pregnancy and significantly increases the risk of a number of adverse consequences for the fetus and mother. The microRNAs (miRNA have recently been demonstrated to abundantly and stably exist in serum and to be potentially disease-specific. However, no reported study investigates the associations between serum miRNA and GDM. METHODOLOGY/PRINCIPAL FINDINGS: We systematically used the TaqMan Low Density Array followed by individual quantitative reverse transcription polymerase chain reaction assays to screen miRNAs in serum collected at 16-19 gestational weeks. The expression levels of three miRNAs (miR-132, miR-29a and miR-222 were significantly decreased in GDM women with respect to the controls in similar gestational weeks in our discovery evaluation and internal validation, and two miRNAs (miR-29a and miR-222 were also consistently validated in two-centric external validation sample sets. In addition, the knockdown of miR-29a could increase Insulin-induced gene 1 (Insig1 expression level and subsequently the level of Phosphoenolpyruvate Carboxy Kinase2 (PCK2 in HepG2 cell lines. CONCLUSIONS/SIGNIFICANCE: Serum miRNAs are differentially expressed between GDM women and controls and could be candidate biomarkers for predicting GDM. The utility of miR-29a, miR-222 and miR-132 as serum-based non-invasive biomarkers warrants further evaluation and optimization.

  15. Integrating circadian activity and gene expression profiles to predict chronotoxicity of Drosophila suzukii response to insecticides.

    Science.gov (United States)

    Hamby, Kelly A; Kwok, Rosanna S; Zalom, Frank G; Chiu, Joanna C

    2013-01-01

    Native to Southeast Asia, Drosophila suzukii (Matsumura) is a recent invader that infests intact ripe and ripening fruit, leading to significant crop losses in the U.S., Canada, and Europe. Since current D. suzukii management strategies rely heavily on insecticide usage and insecticide detoxification gene expression is under circadian regulation in the closely related Drosophila melanogaster, we set out to determine if integrative analysis of daily activity patterns and detoxification gene expression can predict chronotoxicity of D. suzukii to insecticides. Locomotor assays were performed under conditions that approximate a typical summer or winter day in Watsonville, California, where D. suzukii was first detected in North America. As expected, daily activity patterns of D. suzukii appeared quite different between 'summer' and 'winter' conditions due to differences in photoperiod and temperature. In the 'summer', D. suzukii assumed a more bimodal activity pattern, with maximum activity occurring at dawn and dusk. In the 'winter', activity was unimodal and restricted to the warmest part of the circadian cycle. Expression analysis of six detoxification genes and acute contact bioassays were performed at multiple circadian times, but only in conditions approximating Watsonville summer, the cropping season, when most insecticide applications occur. Five of the genes tested exhibited rhythmic expression, with the majority showing peak expression at dawn (ZT0, 6am). We observed significant differences in the chronotoxicity of D. suzukii towards malathion, with highest susceptibility at ZT0 (6am), corresponding to peak expression of cytochrome P450s that may be involved in bioactivation of malathion. High activity levels were not found to correlate with high insecticide susceptibility as initially hypothesized. Chronobiology and chronotoxicity of D. suzukii provide valuable insights for monitoring and control efforts, because insect activity as well as insecticide timing

  16. Sleep-wake profiles predict longitudinal changes in manic symptoms and memory in young people with mood disorders.

    Science.gov (United States)

    Robillard, Rébecca; Hermens, Daniel F; Lee, Rico S C; Jones, Andrew; Carpenter, Joanne S; White, Django; Naismith, Sharon L; Southan, James; Whitwell, Bradley; Scott, Elizabeth M; Hickie, Ian B

    2016-10-01

    Mood disorders are characterized by disabling symptoms and cognitive difficulties which may vary in intensity throughout the course of the illness. Sleep-wake cycles and circadian rhythms influence emotional regulation and cognitive functions. However, the relationships between the sleep-wake disturbances experienced commonly by people with mood disorders and the longitudinal changes in their clinical and cognitive profile are not well characterized. This study investigated associations between initial sleep-wake patterns and longitudinal changes in mood symptoms and cognitive functions in 50 young people (aged 13-33 years) with depression or bipolar disorder. Data were based on actigraphy monitoring conducted over approximately 2 weeks and clinical and neuropsychological assessment. As part of a longitudinal cohort study, these assessments were repeated after a mean follow-up interval of 18.9 months. No significant differences in longitudinal clinical changes were found between the participants with depression and those with bipolar disorder. Lower sleep efficiency was predictive of longitudinal worsening in manic symptoms (P = 0.007). Shorter total sleep time (P = 0.043) and poorer circadian rhythmicity (P = 0.045) were predictive of worsening in verbal memory. These findings suggest that some sleep-wake and circadian disturbances in young people with mood disorders may be associated with less favourable longitudinal outcomes, notably for subsequent manic symptoms and memory difficulties. © 2016 European Sleep Research Society.

  17. Profiling crop pollinators: life history traits predict habitat use and crop visitation by Mediterranean wild bees.

    Science.gov (United States)

    Pisanty, Gideon; Mandelik, Yael

    2015-04-01

    Wild pollinators, bees in particular, may greatly contribute to crop pollination and provide a safety net against declines in commercial pollinators. However, the identity, life history traits, and environmental sensitivities of main crop pollinator species.have received limited attention. These are crucial for predicting pollination services of different communities and for developing management practices that enhance crop pollinators. We sampled wild bees in three crop systems (almond, confection sunflower, and seed watermelon) in a mosaic Israeli Mediterranean landscape. Bees were sampled in field/orchard edges and interiors, and in seminatural scrub surrounding the fields/orchards. We also analyzed land cover at 50-2500 m radii around fields/orchards. We used this data to distinguish crop from non-crop pollinators based on a set of life history traits (nesting, lecty, sociality, body size) linked to habitat preference and crop visitation. Bee abundance and species richness decreased from the surrounding seminatural habitat to the field/orchard interior, especially across the seminatural habitat-field edge ecotone. Thus, although rich bee communities were found near fields, only small fractions crossed the ecotone and visited crop flowers in substantial numbers. The bee assemblage in agricultural fields/orchards and on crop flowers was dominated by ground-nesting bees of the tribe Halictini, which tend to nest within fields. Bees' habitat preferences were determined mainly by nesting guild, whereas crop visitation was determined mainly by sociality. Lecty and body size also affected both measures. The percentage of surrounding seminatural habitat at 250-2500 m radii had a positive effect on wild bee diversity in field edges, for all bee guilds, while at 50-100 m radii, only aboveground nesters were positively affected. In sum, we found that crop and non-crop pollinators are distinguished by behavioral and morphological traits. Hence, analysis of life

  18. Photoperiodic Regulation of Behavioral Responsiveness to Proinflammatory Cytokines

    OpenAIRE

    Wen, Jarvi C.; Prendergast, Brian J.

    2007-01-01

    Symptoms of bacterial infection include decreases in body mass (cachexia), induction of depressive-like hedonic tone (anhedonia), decreases in food intake (anorexia), and increases in body temperature (fever). Recognition of bacteria by the innate immune system triggers the release of proinflammatory cytokines which induce these sickness behaviors via central and peripheral substrates. In Siberian hamsters, exposure to short day lengths decreases both the production of proinflammatory cytokin...

  19. Pro-inflammatory capacity of classically activated monocytes relates positively to muscle mass and strength.

    Science.gov (United States)

    Beenakker, Karel G M; Westendorp, Rudi G J; de Craen, Anton J M; Slagboom, Pieternella E; van Heemst, Diana; Maier, Andrea B

    2013-08-01

    In mice, monocytes that exhibit a pro-inflammatory profile enter muscle tissue after muscle injury and are crucial for clearance of necrotic tissue and stimulation of muscle progenitor cell proliferation and differentiation. The aim of this study was to test if pro-inflammatory capacity of classically activated (M1) monocytes relates to muscle mass and strength in humans. This study included 191 male and 195 female subjects (mean age 64.2 years (SD 6.4) and 61.9 ± 6.4, respectively) of the Leiden Longevity Study. Pro-inflammatory capacity of M1 monocytes was assessed by ex vivo stimulation of whole blood with Toll-like receptor (TLR) 4 agonist lipopolysaccharide (LPS) and TLR-2/1 agonist tripalmitoyl-S-glycerylcysteine (Pam₃Cys-SK₄), both M1 phenotype activators. Cytokines that stimulate M1 monocyte response (IFN-γ and GM-CSF) as well as cytokines that are secreted by M1 monocytes (IL-6, TNF-α, IL-12, and IL-1β) were measured. Analyses were adjusted for age, height, and body fat mass. Upon stimulation with LPS, the cytokine production capacity of INF-γ, GM-CSF, and TNF-α was significantly positively associated with lean body mass, appendicular lean mass and handgrip strength in men, but not in women. Upon stimulation with Pam₃Cys-SK₄, IL-6; TNF-α; and Il-1β were significantly positively associated with lean body mass and appendicular lean in women, but not in men. Taken together, this study shows that higher pro-inflammatory capacity of M1 monocytes upon stimulation is associated with muscle characteristics and sex dependent. © 2013 John Wiley & Sons Ltd and the Anatomical Society.

  20. Cytokines in systemic lupus erythematosus: far beyond Th1/Th2 dualism lupus: cytokine profiles.

    Science.gov (United States)

    Guimarães, Poliana Macedo; Scavuzzi, Bruna Miglioranza; Stadtlober, Nicole Perugini; Franchi Santos, Lorena Flor da Rosa; Lozovoy, Marcell Alysson Batisti; Iriyoda, Tatiana Mayumi Veiga; Costa, Neide Tomimura; Reiche, Edna Maria Vissoci; Maes, Michael; Dichi, Isaias; Simão, Andréa Name Colado

    2017-10-01

    The aims of this study were to delineate cytokine profiles of systemic lupus erythematosus (SLE), construct prediction models for diagnosis and disease activity using those profiles, and to examine the associations between TNFB Ncol polymorphism, body mass index (BMI) and vitamin D levels with cytokine levels. Two hundred SLE patients and 196 healthy controls participated in this case-control study. Plasma cytokines levels of tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-1β, IL- 4, IL-6, IL-10, IL-12 and IL-17 were measured and cytokines profiles were computed. IL-6, IL-12, IL-17, IFN-γ and IL-10 levels were significantly higher in SLE, while IL-4 was lower in SLE. The Th1/Th2 and Th1+Th17/Th2 profiles were significantly higher in SLE than in healthy controls, whereas there were no significant differences in the proinflammatory cytokine profile (TNFα+IL-6+IL-1β). In total, 90.4% of all subjects were correctly classified using Th1+Th17 profile and IL-10 (positively associated) and IL-4 (negatively associated) as predictor variables (sensitivity=66.7% and specificity=96.9%). In all, 20.9% of the variance in the SLE Disease Activity Index was predicted by the Th1+Th17/Th2 ratio, IL-10 and BMI (all positively) and proinflammatory profile (inversely associated). B1/B1 genotype is accompanied by increased IL-17 and Th17/Th2 ratio, while B1/B2 genotype is accompanied by higher IL-4 and IFNγ values. 25-OH vitamin D was inversely associated with IFN-γ levels. SLE is accompanied by Th1, Th17 and Treg profile and lowered IL-4 production. Lowered vitamin D levels and B1/B1 genotype, but not BMI, contribute to changes in cytokines profiles. Future treatments should target Th1, Th2 and Th17 profiles rather than inflammatory cytokines.

  1. Gene Expression Profiling to Predict Clinical Outcome of Breast Cancer: reproducing, analyzing and extending the Nature publication by vhVeer et al

    NARCIS (Netherlands)

    Li R.; Visser, H.M.

    2010-01-01

    Chemotherapy and hormonal therapy as adjuvant systemic therapies to inhibit breast cancer recurrence are not necessary for each patient. In Veer's paper "Gene expression profiling predicts clinical outcome of breast cancer" (Nature 2002, PMID: 11823860), they introduced a method based on DNA

  2. Prediction of the hardness profile of an AISI 4340 steel cylinder heat-treated by laser - 3D and artificial neural networks modelling and experimental validation

    Energy Technology Data Exchange (ETDEWEB)

    Hadhri, Mahdi; Ouafi, Abderazzak El; Barka, Noureddine [University of Quebec, Rimouski (Canada)

    2017-02-15

    This paper presents a comprehensive approach developed to design an effective prediction model for hardness profile in laser surface transformation hardening process. Based on finite element method and Artificial neural networks, the proposed approach is built progressively by (i) examining the laser hardening parameters and conditions known to have an influence on the hardened surface attributes through a structured experimental investigation, (ii) investigating the laser hardening parameters effects on the hardness profile through extensive 3D modeling and simulation efforts and (ii) integrating the hardening process parameters via neural network model for hardness profile prediction. The experimental validation conducted on AISI4340 steel using a commercial 3 kW Nd:Yag laser, confirm the feasibility and efficiency of the proposed approach leading to an accurate and reliable hardness profile prediction model. With a maximum relative error of about 10 % under various practical conditions, the predictive model can be considered as effective especially in the case of a relatively complex system such as laser surface transformation hardening process.

  3. Prediction of the hardness profile of an AISI 4340 steel cylinder heat-treated by laser - 3D and artificial neural networks modelling and experimental validation

    International Nuclear Information System (INIS)

    Hadhri, Mahdi; Ouafi, Abderazzak El; Barka, Noureddine

    2017-01-01

    This paper presents a comprehensive approach developed to design an effective prediction model for hardness profile in laser surface transformation hardening process. Based on finite element method and Artificial neural networks, the proposed approach is built progressively by (i) examining the laser hardening parameters and conditions known to have an influence on the hardened surface attributes through a structured experimental investigation, (ii) investigating the laser hardening parameters effects on the hardness profile through extensive 3D modeling and simulation efforts and (ii) integrating the hardening process parameters via neural network model for hardness profile prediction. The experimental validation conducted on AISI4340 steel using a commercial 3 kW Nd:Yag laser, confirm the feasibility and efficiency of the proposed approach leading to an accurate and reliable hardness profile prediction model. With a maximum relative error of about 10 % under various practical conditions, the predictive model can be considered as effective especially in the case of a relatively complex system such as laser surface transformation hardening process

  4. Real Time Hybrid Model Predictive Control for the Current Profile of the Tokamak à Configuration Variable (TCV

    Directory of Open Access Journals (Sweden)

    Izaskun Garrido

    2016-08-01

    Full Text Available Plasma stability is one of the obstacles in the path to the successful operation of fusion devices. Numerical control-oriented codes as it is the case of the widely accepted RZIp may be used within Tokamak simulations. The novelty of this article relies in the hierarchical development of a dynamic control loop. It is based on a current profile Model Predictive Control (MPC algorithm within a multiloop structure, where a MPC is developed at each step so as to improve the Proportional Integral Derivative (PID global scheme. The inner control loop is composed of a PID-based controller that acts over the Multiple Input Multiple Output (MIMO system resulting from the RZIp plasma model of the Tokamak à Configuration Variable (TCV. The coefficients of this PID controller are initially tuned using an eigenmode reduction over the passive structure model. The control action corresponding to the state of interest is then optimized in the outer MPC loop. For the sake of comparison, both the traditionally used PID global controller as well as the multiloop enhanced MPC are applied to the same TCV shot. The results show that the proposed control algorithm presents a superior performance over the conventional PID algorithm in terms of convergence. Furthermore, this enhanced MPC algorithm contributes to extend the discharge length and to overcome the limited power availability restrictions that hinder the performance of advanced tokamaks.

  5. Proinflammatory cytokine levels in patients with conversion disorder.

    Science.gov (United States)

    Tiyekli, Utkan; Calıyurt, Okan; Tiyekli, Nimet Dilek

    2013-06-01

    It was aimed to evaluate the relationship between proinflammatory cytokine levels and conversion disorder both commonly known as stress regulated. Baseline proinflammatory cytokine levels-[Tumour necrosis factor alpha (TNF-α), Interleukin-1 beta (IL-1β), Interleukin-6 (IL-6)]-were evaluated with enzyme-linked immunosorbent assay in 35 conversion disorder patients and 30 healthy controls. Possible changes in proinflammatory cytokine levels were evaluated again, after their acute phase in conversion disorder patients. Statistically significant decreased serum TNF-α levels were obtained in acute phase of conversion disorder. Those levels increased after acute conversion phase. There were no statistically significant difference observed between groups in serum IL-1β and (IL-6) levels. Stress associated with conversion disorder may suppress immune function in acute conversion phase and may have diagnostic and therapeutic value.

  6. Cancer as a Proinflammatory Environment: Metastasis and Cachexia

    Science.gov (United States)

    Inácio Pinto, Nelson; Carnier, June; Oyama, Lila M.; Otoch, Jose Pinhata; Alcântara, Paulo Sergio; Tokeshi, Flavio; Nascimento, Claudia M.

    2015-01-01

    The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines. PMID:26508818

  7. Cancer as a Proinflammatory Environment: Metastasis and Cachexia

    Directory of Open Access Journals (Sweden)

    Nelson Inácio Pinto

    2015-01-01

    Full Text Available The development of the syndrome of cancer cachexia and that of metastasis are related with a poor prognostic for cancer patients. They are considered multifactorial processes associated with a proinflammatory environment, to which tumour microenvironment and other tissues from the tumour bearing individuals contribute. The aim of the present review is to address the role of ghrelin, myostatin, leptin, HIF, IL-6, TNF-α, and ANGPTL-4 in the regulation of energy balance, tumour development, and tumoural cell invasion. Hypoxia induced factor plays a prominent role in tumour macro- and microenvironment, by modulating the release of proinflammatory cytokines.

  8. Injury profile SIMulator, a Qualitative aggregative modelling framework to predict injury profile as a function of cropping practices, and abiotic and biotic environment. II. Proof of concept: design of IPSIM-wheat-eyespot.

    Science.gov (United States)

    Robin, Marie-Hélène; Colbach, Nathalie; Lucas, Philippe; Montfort, Françoise; Cholez, Célia; Debaeke, Philippe; Aubertot, Jean-Noël

    2013-01-01

    IPSIM (Injury Profile SIMulator) is a generic modelling framework presented in a companion paper. It aims at predicting a crop injury profile as a function of cropping practices and abiotic and biotic environment. IPSIM's modelling approach consists of designing a model with an aggregative hierarchical tree of attributes. In order to provide a proof of concept, a model, named IPSIM-Wheat-Eyespot, has been developed with the software DEXi according to the conceptual framework of IPSIM to represent final incidence of eyespot on wheat. This paper briefly presents the pathosystem, the method used to develop IPSIM-Wheat-Eyespot using IPSIM's modelling framework, simulation examples, an evaluation of the predictive quality of the model with a large dataset (526 observed site-years) and a discussion on the benefits and limitations of the approach. IPSIM-Wheat-Eyespot proved to successfully represent the annual variability of the disease, as well as the effects of cropping practices (Efficiency = 0.51, Root Mean Square Error of Prediction = 24%; bias = 5.0%). IPSIM-Wheat-Eyespot does not aim to precisely predict the incidence of eyespot on wheat. It rather aims to rank cropping systems with regard to the risk of eyespot on wheat in a given production situation through ex ante evaluations. IPSIM-Wheat-Eyespot can also help perform diagnoses of commercial fields. Its structure is simple and permits to combine available knowledge in the scientific literature (data, models) and expertise. IPSIM-Wheat-Eyespot is now available to help design cropping systems with a low risk of eyespot on wheat in a wide range of production situations, and can help perform diagnoses of commercial fields. In addition, it provides a proof of concept with regard to the modelling approach of IPSIM. IPSIM-Wheat-Eyespot will be a sub-model of IPSIM-Wheat, a model that will predict injury profile on wheat as a function of cropping practices and the production situation.

  9. Dysregulated proinflammatory and fibrogenic phenotype of fibroblasts in cystic fibrosis.

    Directory of Open Access Journals (Sweden)

    François Huaux

    Full Text Available Morbi-mortality in cystic fibrosis (CF is mainly related to chronic lung infection and inflammation, uncontrolled tissue rearrangements and fibrosis, and yet the underlying mechanisms remain largely unknown. We evaluated inflammatory and fibrosis responses to bleomycin in F508del homozygous and wild-type mice, and phenotype of fibroblasts explanted from mouse lungs and skin. The effect of vardenafil, a cGMP-specific phosphodiesterase type 5 inhibitor, was tested in vivo and in culture. Responses of proinflammatory and fibrotic markers to bleomycin were enhanced in lungs and skin of CF mice and were prevented by treatment with vardenafil. Purified lung and skin fibroblasts from CF mice proliferated and differentiated into myofibroblasts more prominently and displayed higher sensitivity to growth factors than those recovered from wild-type littermates. Under inflammatory stimulation, mRNA and protein expression of proinflammatory mediators were higher in CF than in wild-type fibroblasts, in which CFTR expression reached similar levels to those observed in other non-epithelial cells, such as macrophages. Increased proinflammatory responses in CF fibroblasts were reduced by half with submicromolar concentrations of vardenafil. Proinflammatory and fibrogenic functions of fibroblasts are upregulated in CF and are reduced by vardenafil. This study provides compelling new support for targeting cGMP signaling pathway in CF pharmacotherapy.

  10. Tenocytes, pro-inflammatory cytokines and leukocytes: a relationship?

    OpenAIRE

    Al-Sadi, Onays; Schulze-Tanzil, Gundula; Kohl, Benjamin; Lohan, Anke; Lemke, Marion; Ertel, Wolfgang; John, Thilo

    2012-01-01

    Leukocyte derived pro-inflammatory mediators could be involved in tendon healing and scar formation. Hence, the effect of autologous leukocytes (PBMCs, peripheral blood mononuclear cells and neutrophils) on primary rabbit Achilles tenocytes gene expression was tested in insert assisted co-cultures.

  11. Proinflammatory proteins in female and male patients with primary antiphospholipid syndrome: preliminary data.

    Science.gov (United States)

    Bećarević, Mirjana; Ignjatović, Svetlana

    2016-10-01

    The latest classification criteria for the diagnosis of the antiphospholipid syndrome (APS, an autoimmune disease characterized by thromboses, miscarriages and presence of antiphospholipid antibodies (Abs)) emphasized that thrombotic manifestations of APS should be without any signs of an inflammatory process. However, atherosclerosis (a chronic inflammatory response to the accumulation of lipoproteins in the walls of arteries) and APS are characterized by some similar features. We evaluated whether proinflammatory proteins were associated with the features of the primary APS (PAPS). PAPS patients without obstetric complications and with impaired lipid profile were included in the study. Antiphospholipid antibodies, TNF-alpha, and apo(a) were determined by ELISA. Complement components and hsCRP were measured by immunonephelometry. Decreased C3c was observed in female patients with increased titers of IgG anti-β2gpI (χ(2) = 3.939, P = 0.047) and in male patients with increased IgM anticardiolipin Abs (χ(2) = 4.286, P = 0.038). Pulmonary emboli were associated with interleukin (IL)-6 in male (χ(2) = 6.519, P = 0.011) and in female (χ(2) = 10.405, P = 0.001) patients. Cerebrovascular insults were associated with LDL-cholesterol (P = 0.05, 95 % CI: 1.003 - 12.739) in female and with apo(a) (P = 0.016, 95 % CI: 0.000-0.003) in male patients. Older female patients had increased LDL-cholesterol levels and frequency of myocardial infarctions. Proinflammatory proteins were associated with features of primary APS. No real gender differences in regard to proinflammatory protein levels were observed. Premenopausal state of female PAPS patients confers lower cardiovascular risk.

  12. NFAT5-Regulated Macrophage Polarization Supports the Proinflammatory Function of Macrophages and T Lymphocytes.

    Science.gov (United States)

    Tellechea, Mónica; Buxadé, Maria; Tejedor, Sonia; Aramburu, Jose; López-Rodríguez, Cristina

    2018-01-01

    Macrophages are exquisite sensors of tissue homeostasis that can rapidly switch between pro- and anti-inflammatory or regulatory modes to respond to perturbations in their microenvironment. This functional plasticity involves a precise orchestration of gene expression patterns whose transcriptional regulators have not been fully characterized. We had previously identified the transcription factor NFAT5 as an activator of TLR-induced responses, and in this study we explore its contribution to macrophage functions in different polarization settings. We found that both in classically and alternatively polarized macrophages, NFAT5 enhanced functions associated with a proinflammatory profile such as bactericidal capacity and the ability to promote Th1 polarization over Th2 responses. In this regard, NFAT5 upregulated the Th1-stimulatory cytokine IL-12 in classically activated macrophages, whereas in alternatively polarized ones it enhanced the expression of the pro-Th1 mediators Fizz-1 and arginase 1, indicating that it could promote proinflammatory readiness by regulating independent genes in differently polarized macrophages. Finally, adoptive transfer assays in vivo revealed a reduced antitumor capacity in NFAT5-deficient macrophages against syngeneic Lewis lung carcinoma and ID8 ovarian carcinoma cells, a defect that in the ID8 model was associated with a reduced accumulation of effector CD8 T cells at the tumor site. Altogether, detailed analysis of the effect of NFAT5 in pro- and anti-inflammatory macrophages uncovered its ability to regulate distinct genes under both polarization modes and revealed its predominant role in promoting proinflammatory macrophage functions. Copyright © 2017 by The American Association of Immunologists, Inc.

  13. Ground-based remote sensing profiling and numerical weather prediction model to manage nuclear power plants meteorological surveillance in Switzerland

    Directory of Open Access Journals (Sweden)

    B. Calpini

    2011-08-01

    Full Text Available The meteorological surveillance of the four nuclear power plants in Switzerland is of first importance in a densely populated area such as the Swiss Plateau. The project "Centrales Nucléaires et Météorologie" CN-MET aimed at providing a new security tool based on one hand on the development of a high resolution numerical weather prediction (NWP model. The latter is providing essential nowcasting information in case of a radioactive release from a nuclear power plant in Switzerland. On the other hand, the model input over the Swiss Plateau is generated by a dedicated network of surface and upper air observations including remote sensing instruments (wind profilers and temperature/humidity passive microwave radiometers. This network is built upon three main sites ideally located for measuring the inflow/outflow and central conditions of the main wind field in the planetary boundary layer over the Swiss Plateau, as well as a number of surface automatic weather stations (AWS. The network data are assimilated in real-time into the fine grid NWP model using a rapid update cycle of eight runs per day (one forecast every three hours. This high resolution NWP model has replaced the former security tool based on in situ observations (in particular one meteorological mast at each of the power plants and a local dispersion model. It is used to forecast the dynamics of the atmosphere in the planetary boundary layer (typically the first 4 km above ground layer and over a time scale of 24 h. This tool provides at any time (e.g. starting at the initial time of a nuclear power plant release the best picture of the 24-h evolution of the air mass over the Swiss Plateau and furthermore generates the input data (in the form of simulated values substituting in situ observations required for the local dispersion model used at each of the nuclear power plants locations. This paper is presenting the concept and two validation studies as well as the results of an

  14. FUNCTIONAL SUBCLONE PROFILING FOR PREDICTION OF TREATMENT-INDUCED INTRA-TUMOR POPULATION SHIFTS AND DISCOVERY OF RATIONAL DRUG COMBINATIONS IN HUMAN GLIOBLASTOMA

    Science.gov (United States)

    Reinartz, Roman; Wang, Shanshan; Kebir, Sied; Silver, Daniel J.; Wieland, Anja; Zheng, Tong; Küpper, Marius; Rauschenbach, Laurèl; Fimmers, Rolf; Shepherd, Timothy M.; Trageser, Daniel; Till, Andreas; Schäfer, Niklas; Glas, Martin; Hillmer, Axel M.; Cichon, Sven; Smith, Amy A.; Pietsch, Torsten; Liu, Ying; Reynolds, Brent A.; Yachnis, Anthony; Pincus, David W.; Simon, Matthias; Brüstle, Oliver; Steindler, Dennis A.; Scheffler, Björn

    2016-01-01

    Purpose Investigation of clonal heterogeneity may be key to understanding mechanisms of therapeutic failure in human cancer. However, little is known on the consequences of therapeutic intervention on the clonal composition of solid tumors. Experimental Design Here, we used 33 single cell-derived subclones generated from five clinical glioblastoma specimens for exploring intra- and inter-individual spectra of drug resistance profiles in vitro. In a personalized setting, we explored whether differences in pharmacological sensitivity among subclones could be employed to predict drug-dependent changes to the clonal composition of tumors. Results Subclones from individual tumors exhibited a remarkable heterogeneity of drug resistance to a library of potential anti-glioblastoma compounds. A more comprehensive intra-tumoral analysis revealed that stable genetic and phenotypic characteristics of co-existing subclones could be correlated with distinct drug sensitivity profiles. The data obtained from differential drug response analysis could be employed to predict clonal population shifts within the naïve parental tumor in vitro and in orthotopic xenografts. Furthermore, the value of pharmacological profiles could be shown for establishing rational strategies for individualized secondary lines of treatment. Conclusions Our data provide a previously unrecognized strategy for revealing functional consequences of intra-tumor heterogeneity by enabling predictive modeling of treatment-related subclone dynamics in human glioblastoma. PMID:27521447

  15. Evaluation of feasible machine learning techniques for predicting the time to fly and aircraft speed profile on final approach : Predictive dynamic support tool on final approach

    NARCIS (Netherlands)

    Herrema, Herrema Floris; Treve, V; Curran, R.; Visser, H.G.; Lovell, D.; Fricke, H.

    2016-01-01

    currently, at many airports, the runway throughput is the limiting factor for the overall capacity. Among the most important constraining parameters is the separation minima expressed in distance. On the top of these minima, the difference of the leader and follower aircraft speed profiles imposes

  16. Predictive modelling of grain size distributions from marine electromagnetic profiling data using end-member analysis and a radial basis function network

    Science.gov (United States)

    Baasch, B.; M"uller, H.; von Dobeneck, T.

    2018-04-01

    In this work we present a new methodology to predict grain-size distributions from geophysical data. Specifically, electric conductivity and magnetic susceptibility of seafloor sediments recovered from electromagnetic profiling data are used to predict grain-size distributions along shelf-wide survey lines. Field data from the NW Iberian shelf are investigated and reveal a strong relation between the electromagnetic properties and grain-size distribution. The here presented workflow combines unsupervised and supervised machine learning techniques. Nonnegative matrix factorisation is used to determine grain-size end-members from sediment surface samples. Four end-members were found which well represent the variety of sediments in the study area. A radial-basis function network modified for prediction of compositional data is then used to estimate the abundances of these end-members from the electromagnetic properties. The end-members together with their predicted abundances are finally back transformed to grain-size distributions. A minimum spatial variation constraint is implemented in the training of the network to avoid overfitting and to respect the spatial distribution of sediment patterns. The predicted models are tested via leave-one-out cross-validation revealing high prediction accuracy with coefficients of determination (R2) between 0.76 and 0.89. The predicted grain-size distributions represent the well-known sediment facies and patterns on the NW Iberian shelf and provide new insights into their distribution, transition and dynamics. This study suggests that electromagnetic benthic profiling in combination with machine learning techniques is a powerful tool to estimate grain-size distribution of marine sediments.

  17. Profiling cancer

    DEFF Research Database (Denmark)

    Ciro, Marco; Bracken, Adrian P; Helin, Kristian

    2003-01-01

    In the past couple of years, several very exciting studies have demonstrated the enormous power of gene-expression profiling for cancer classification and prediction of patient survival. In addition to promising a more accurate classification of cancer and therefore better treatment of patients......, gene-expression profiling can result in the identification of novel potential targets for cancer therapy and a better understanding of the molecular mechanisms leading to cancer....

  18. Predicting the educational performance of Isfahan University students of medical sciences based on their behaviour profile, mental health and demographic characteristic.

    Science.gov (United States)

    Samouei, Rahele; Fooladvand, Maryam; Janghorban, Shahla; Khorvash, Fariba

    2015-01-01

    The issue of students' academic failure is one of the most important educational, economic, and social issues. Cognizance of the factors related to academic downfall is so efficient in its prevention and control and leads to protecting governmental assets and labor force. In order to achieve this goal, this study intends to determine the predictive factors of the students' academic performance in Isfahan University of Medical Sciences in terms of their personality profile, mental health, and their demographic characteristics. This study was a descriptive-correlation study on 771 students who entered Isfahan University of Medical Sciences between 2005 and 2007. The information was gathered through using the students' educational and clinical files (for measuring personality characteristics and mental health) and SAMA Software (To get the mean scores). Minnesota Multiphasic Personality Inventory short form and General Health Questionnaire were used for collecting clinical data. The data were analyzed using SPSS 15 (stepwise regression coefficient, variance analysis, Student's t-test, and Spearman correlation coefficient). The results showed that the aforementioned students obtained a normal average for their personality profile and mental health indicators. Of all the reviewed variables, education, age, gender, depression, and hypochondria were the predictive factors of the students' educational performance. It could be concluded that some of the personality features, mental health indicators, and personality profile play such a significant role in the students' educational life that the disorder in any of them affects the students' educational performance and academic failure.

  19. Gray model prediction of the sea wall profile survey in the first process of Qinshan Nuclear Power Plant

    International Nuclear Information System (INIS)

    Zang Deyan

    1998-01-01

    Based on gray system theory, the information about deformation observation of the first stage Qinshan nuclear power plant is analysed and predicted as well. The gray system theory is applied to engineering prediction and a large-scale building deformation observation. It is convenient to apply the model and it a has high degree of accuracy

  20. The affective profiles, psychological well-being, and harmony: environmental mastery and self-acceptance predict the sense of a harmonious life

    Directory of Open Access Journals (Sweden)

    Danilo Garcia

    2014-02-01

    explained by the dimensions of psychological well-being within the four affective profiles. Specifically, harmony in life was significantly predicted by environmental mastery and self-acceptance across all affective profiles. However, for the low affective group high purpose in life predicted low levels of harmony in life.Conclusions. The results demonstrated that affective profiles systematically relate to psychological well-being and harmony in life. Notably, individuals categorised as self-fulfilling tended to report higher levels of both psychological well-being and harmony in life when compared with the other profiles. Meanwhile individuals in the self-destructive group reported the lowest levels of psychological well-being and harmony when compared with the three other profiles. It is proposed that self-acceptance and environmental acceptance might enable individuals to go from self-destructive to a self-fulfilling state that also involves harmony in life.

  1. Aqueous proinflammatory cytokines in acute primary angle-closure eyes

    Directory of Open Access Journals (Sweden)

    Yao-Ming Liu

    2017-05-01

    Full Text Available AIM: To evaluate changes of proinflammatory cytokines in aqueous humor of patients with acute primary angle-closure (APAC and age-related cataracts. METHODS: Twenty eyes of 20 APAC patients and 15 eyes of 15 age-related cataract patients were included in this cross-sectional study. Aqueous humor samples were collected prospectively. The levels of 20 proinflammatory cytokines were evaluated in the aqueous humor of the APAC and cataract patients using the multiplex bead immunoassay technique. Clinical data were collected for correlation analysis. RESULTS: Seven of the 20 proinflammatory cytokines included in the magnetic bead panel were detectable in both APAC eyes and cataract eyes: interleukin (IL-10, IL-12, IL-15, IL-21, IL-6, chemokine (C-C motif ligand 20, and tumor necrosis factor alpha (TNF-α. IL-27 was only detectable in APAC eyes. Compared with the cataract eyes, the APAC eyes had significantly elevated concentrations of IL-12 (P=0.036, IL-15 (P=0.001, IL-6 (P=0.012, and IL-27 (only detectable in APAC eyes. Age was positively correlated with IL-12 (P=0.022 and IL-6 (P=0.037, and time elapsed between APAC onset and aqueous humor samples collection was positively correlated with IL-15 (P=0.037, IL-27 (P=0.040, and TNF-α (P=0.042. CONCLUSION: Several proinflammatory cytokines including IL-12,IL-15, IL-6 and IL-27, were elevated in the APAC eyes and may be implicated in its pathologic mechanism.

  2. The Pro-inflammatory Effects of Glucocorticoids in the Brain

    Science.gov (United States)

    Duque, Erica de Almeida; Munhoz, Carolina Demarchi

    2016-01-01

    Glucocorticoids are a class of steroid hormones derived from cholesterol. Their actions are mediated by the glucocorticoid and mineralocorticoid receptors, members of the superfamily of nuclear receptors, which, once bound to their ligands, act as transcription factors that can directly modulate gene expression. Through protein–protein interactions with other transcription factors, they can also regulate the activity of many genes in a composite or tethering way. Rapid non-genomic signaling was also demonstrated since glucocorticoids can act through membrane receptors and activate signal transduction pathways, such as protein kinases cascades, to modulate other transcriptions factors and activate or repress various target genes. By all these different mechanisms, glucocorticoids regulate numerous important functions in a large variety of cells, not only in the peripheral organs but also in the central nervous system during development and adulthood. In general, glucocorticoids are considered anti-inflammatory and protective agents due to their ability to inhibit gene expression of pro-inflammatory mediators and other possible damaging molecules. Nonetheless, recent studies have uncovered situations in which these hormones can act as pro-inflammatory agents depending on the dose, chronicity of exposure, and the structure/organ analyzed. In this review, we will provide an overview of the conditions under which these phenomena occur, a discussion that will serve as a basis for exploring the mechanistic foundation of glucocorticoids pro-inflammatory gene regulation in the brain. PMID:27445981

  3. Biochemical Profile of Heritage and Modern Apple Cultivars and Application of Machine Learning Methods To Predict Usage, Age, and Harvest Season.

    Science.gov (United States)

    Anastasiadi, Maria; Mohareb, Fady; Redfern, Sally P; Berry, Mark; Simmonds, Monique S J; Terry, Leon A

    2017-07-05

    The present study represents the first major attempt to characterize the biochemical profile in different tissues of a large selection of apple cultivars sourced from the United Kingdom's National Fruit Collection comprising dessert, ornamental, cider, and culinary apples. Furthermore, advanced machine learning methods were applied with the objective to identify whether the phenolic and sugar composition of an apple cultivar could be used as a biomarker fingerprint to differentiate between heritage and mainstream commercial cultivars as well as govern the separation among primary usage groups and harvest season. A prediction accuracy of >90% was achieved with the random forest method for all three models. The results highlighted the extraordinary phytochemical potency and unique profile of some heritage, cider, and ornamental apple cultivars, especially in comparison to more mainstream apple cultivars. Therefore, these findings could guide future cultivar selection on the basis of health-promoting phytochemical content.

  4. DMPD: Post-transcriptional regulation of proinflammatory proteins. [Dynamic Macrophage Pathway CSML Database

    Lifescience Database Archive (English)

    Full Text Available 15075353 Post-transcriptional regulation of proinflammatory proteins. Anderson P, P...l) (.csml) Show Post-transcriptional regulation of proinflammatory proteins. PubmedID 15075353 Title Post-tr...anscriptional regulation of proinflammatory proteins. Authors Anderson P, Phillip

  5. Non-invasive metabolomic profiling of embryo culture media and morphology grading to predict implantation outcome in frozen-thawed embryo transfer cycles.

    Science.gov (United States)

    Li, Xiong; Xu, Yan; Fu, Jing; Zhang, Wen-Bi; Liu, Su-Ying; Sun, Xiao-Xi

    2015-11-01

    Assessment of embryo viability is a crucial component of in vitro fertilization and currently relies largely on embryo morphology and cleavage rate. Because morphological assessment remains highly subjective, it can be unreliable in predicting embryo viability. This study investigated the metabolomic profiling of embryo culture media using near-infrared (NIR) spectroscopy for predicting the implantation potential of human embryos in frozen-thawed embryo transfer (FET) cycles. Spent embryo culture media was collected on day 4 after thawed embryo transfer (n = 621) and analysed using NIR spectroscopy. Viability scores were calculated using a predictive multivariate algorithm of fresh embryos with known pregnancy outcomes. The mean viability indices of embryos resulting in clinical pregnancy following FET were significantly higher than those of non-implanted embryos and differed between the 0, 50, and 100 % implantation groups. Notably, the 0 % group index was significantly lower than the 100 % implantation group index (-0.787 ± 0.382 vs. 1.064 ± 0.331, P  0.05). NIR metabolomic profiling of thawed embryo culture media is independent of morphology and correlates with embryo implantation potential in FET cycles. The viability score alone or in conjunction with morphologic grading is a more objective marker for implantation outcome in FET cycles than morphology alone.

  6. Use of Artificial Intelligence and Machine Learning Algorithms with Gene Expression Profiling to Predict Recurrent Nonmuscle Invasive Urothelial Carcinoma of the Bladder.

    Science.gov (United States)

    Bartsch, Georg; Mitra, Anirban P; Mitra, Sheetal A; Almal, Arpit A; Steven, Kenneth E; Skinner, Donald G; Fry, David W; Lenehan, Peter F; Worzel, William P; Cote, Richard J

    2016-02-01

    Due to the high recurrence risk of nonmuscle invasive urothelial carcinoma it is crucial to distinguish patients at high risk from those with indolent disease. In this study we used a machine learning algorithm to identify the genes in patients with nonmuscle invasive urothelial carcinoma at initial presentation that were most predictive of recurrence. We used the genes in a molecular signature to predict recurrence risk within 5 years after transurethral resection of bladder tumor. Whole genome profiling was performed on 112 frozen nonmuscle invasive urothelial carcinoma specimens obtained at first presentation on Human WG-6 BeadChips (Illumina®). A genetic programming algorithm was applied to evolve classifier mathematical models for outcome prediction. Cross-validation based resampling and gene use frequencies were used to identify the most prognostic genes, which were combined into rules used in a voting algorithm to predict the sample target class. Key genes were validated by quantitative polymerase chain reaction. The classifier set included 21 genes that predicted recurrence. Quantitative polymerase chain reaction was done for these genes in a subset of 100 patients. A 5-gene combined rule incorporating a voting algorithm yielded 77% sensitivity and 85% specificity to predict recurrence in the training set, and 69% and 62%, respectively, in the test set. A singular 3-gene rule was constructed that predicted recurrence with 80% sensitivity and 90% specificity in the training set, and 71% and 67%, respectively, in the test set. Using primary nonmuscle invasive urothelial carcinoma from initial occurrences genetic programming identified transcripts in reproducible fashion, which were predictive of recurrence. These findings could potentially impact nonmuscle invasive urothelial carcinoma management. Copyright © 2016 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.

  7. A predictive model to evaluate the impact of the cooling profile on growth of psychrotrophic bacteria in raw milk from conventional and robotic milking.

    Science.gov (United States)

    Christiansson, Anders

    2017-08-01

    This Research Communication explores the usefulness of predictive modelling to explain bacterial behaviour during cooling. A simple dynamic lag phase model was developed and validated. The model takes into account the effect of the cooling profile on the lag phase and growth in bulk tank milk. The time before the start of cooling was the most critical and should not exceed 1 h. The cooling rate between 30 and approximately 10 °C was the second most critical period. Cooling from 30 to 10 °C within 2 h ensured minimal growth of psychrotrophic bacteria in the milk. The cooling rate between 10 and 4 °C (the slowest phase of cooling) was of surprisingly little importance. Given a normal cooling profile to 10 °C, several hours of prolonged cooling time made practically no difference in psychrotrophic counts. This behaviour can be explained by the time/temperature dependence of the work needed by the bacteria to complete the lag phase at low temperature. For milk quality advisors, it is important to know that slow cooling below 10 °C does not result in high total counts of bacteria. In practice, slow cooling is occasionally found at farms with robotic milking. However, when comparing psychrotrophic growth in bulk milk tanks designed for robotic milking or conventional milking, the model predicted less growth for robotic milking for identical cooling profiles. It is proposed that due to the different rates of milk entering the tank, fewer bacteria will exit the lag phase during robotic milking and they will be more diluted than in conventional milking systems. At present, there is no international standard that specifies the cooling profile in robotic systems. The information on the insignificant effect of the cooling rate below 10 °C may be useful in the development of a standard.

  8. Serum protein profiling using an aptamer array predicts clinical outcomes of stage IIA colon cancer: A leave-one-out crossvalidation

    Science.gov (United States)

    Huh, Jung Wook; Kim, Sung Chun; Sohn, Insuk; Jung, Sin-Ho; Kim, Hee Cheol

    2016-01-01

    Background In this study, we established and validated a model for predicting prognosis of stage IIA colon cancer patients based on expression profiles of aptamers in serum. Methods Bloods samples were collected from 227 consecutive patients with pathologic T3N0M0 (stage IIA) colon cancer. We incubated 1,149 serum molecule-binding aptamer pools of clinical significance with serum from patients to obtain aptamers bound to serum molecules, which were then amplified and marked. Oligonucleotide arrays were constructed with the base sequences of the 1,149 aptamers, and the marked products identified above were reacted with one another to produce profiles of the aptamers bound to serum molecules. These profiles were organized into low- and high-risk groups of colon cancer patients based on clinical information for the serum samples. Cox proportional hazards model and leave-one-out cross-validation (LOOCV) were used to evaluate predictive performance. Results During a median follow-up period of 5 years, 29 of the 227 patients (11.9%) experienced recurrence. There were 212 patients (93.4%) in the low-risk group and 15 patients (6.6%) in the high-risk group in our aptamer prognosis model. Postoperative recurrence significantly correlated with age and aptamer risk stratification (p = 0.046 and p = 0.001, respectively). In multivariate analysis, aptamer risk stratification (p recurrence. Disease-free survival curves calculated according to aptamer risk level predicted through a LOOCV procedure and age showed significant differences (p < 0.001 from permutations). Conclusion Aptamer risk stratification can be a valuable prognostic factor in stage II colon cancer patients. PMID:26908450

  9. Segmenting by Risk Perceptions: Predicting Young Adults’ Genetic-Belief Profiles with Health and Opinion-Leader Covariates

    Science.gov (United States)

    Smith, Rachel A.; Greenberg, Marisa; Parrott, Roxanne L.

    2014-01-01

    With a growing interest in using genetic information to motivate young adults’ health behaviors, audience segmentation is needed for effective campaign design. Using latent class analysis, this study identifies segments based on young adults’ (N = 327) beliefs about genetic threats to their health and personal efficacy over genetic influences on their health. A four-class model was identified. The model indicators fit the risk perception attitude framework (Rimal & Real, 2003), but the covariates (e.g., current health behaviors) did not. In addition, opinion leader qualities covaried with one profile: those in this profile engaged in fewer preventative behaviors and more dangerous treatment options, and also liked to persuade others, making them a particularly salient group for campaign efforts. The implications for adult-onset disorders, like alpha-1 antitrypsin deficiency are discussed. PMID:24111749

  10. A Binomial Modeling Approach for Upscaling Colloid Transport Under Unfavorable Attachment Conditions: Emergent Prediction of Nonmonotonic Retention Profiles

    Science.gov (United States)

    Hilpert, Markus; Johnson, William P.

    2018-01-01

    We used a recently developed simple mathematical network model to upscale pore-scale colloid transport information determined under unfavorable attachment conditions. Classical log-linear and nonmonotonic retention profiles, both well-reported under favorable and unfavorable attachment conditions, respectively, emerged from our upscaling. The primary attribute of the network is colloid transfer between bulk pore fluid, the near-surface fluid domain (NSFD), and attachment (treated as irreversible). The network model accounts for colloid transfer to the NSFD of downgradient grains and for reentrainment to bulk pore fluid via diffusion or via expulsion at rear flow stagnation zones (RFSZs). The model describes colloid transport by a sequence of random trials in a one-dimensional (1-D) network of Happel cells, which contain a grain and a pore. Using combinatorial analysis that capitalizes on the binomial coefficient, we derived from the pore-scale information the theoretical residence time distribution of colloids in the network. The transition from log-linear to nonmonotonic retention profiles occurs when the conditions underlying classical filtration theory are not fulfilled, i.e., when an NSFD colloid population is maintained. Then, nonmonotonic retention profiles result potentially both for attached and NSFD colloids. The concentration maxima shift downgradient depending on specific parameter choice. The concentration maxima were also shown to shift downgradient temporally (with continued elution) under conditions where attachment is negligible, explaining experimentally observed downgradient transport of retained concentration maxima of adhesion-deficient bacteria. For the case of zero reentrainment, we develop closed-form, analytical expressions for the shape, and the maximum of the colloid retention profile.

  11. A model for prediction of profile and flatness of hot and cold rolled flat products in four-high mills

    Science.gov (United States)

    Overhagen, Christian; Mauk, Paul Josef

    2018-05-01

    For flat rolled products, the thickness profile in the transversal direction is one of the most important product properties. For further processing, a defined crown of the product is necessary. In the rolling process, several mechanical and thermal influences interact with each other to form the strip shape at the roll gap exit. In the present analysis, a process model for rolling of strip and sheet is presented. The core feature of the process model is a two-dimensional stress distribution model based on von Karman's differential equation. Sub models for the mechanical influences of work roll flattening as well as work and backup roll deflection and the thermal influence of work roll expansion have been developed or extended. The two-dimensional stress distribution serves as an input parameter for the roll deformation models. For work roll flattening, a three-dimensional model based on the Boussinesq problem is adopted, while the work and backup roll deflection, including contact flattening is calculated by means of finite beam elements. The thermal work roll crown is calculated with help of an axisymmetric numerical solution of the heat equation for the work roll, considering azimuthal averaging for the boundary conditions at the work roll surface. Results are presented for hot rolling of a strip in a seven-stand finishing train of a hot strip mill, showing the calculated evolution of the strip profile. A variation of the strip profile from the first to the 20th rolled strip is shown. This variation is addressed to the progressive increase of work roll temperature during the first 20 strips. It is shown that a CVC® system can lead to improvements in strip profile and therefore flatness.

  12. Morphogen and proinflammatory cytokine release kinetics from PRGF-Endoret fibrin scaffolds: evaluation of the effect of leukocyte inclusion.

    Science.gov (United States)

    Anitua, E; Zalduendo, M M; Prado, R; Alkhraisat, M H; Orive, G

    2015-03-01

    The potential influence of leukocyte incorporation in the kinetic release of growth factors from platelet-rich plasma (PRP) may explain the conflicting efficiency of leukocyte platelet-rich plasma (L-PRP) scaffolds in tissue regeneration. To assess this hypothesis, leukocyte-free (PRGF-Endoret) and L-PRP fibrin scaffolds were prepared, and both morphogen and proinflammatory cytokine release kinetics were analyzed. Clots were incubated with culture medium to monitor protein release over 8 days. Furthermore, the different fibrin scaffolds were morphologically characterized. Results show that leukocyte-free fibrin matrices were homogenous while leukocyte-containing ones were heterogeneous, loose and cellular. Leukocyte incorporation produced a significant increase in the contents of proinflammatory cytokines interleukin (IL)-1β and IL-16 but not in the platelet-derived growth factors release (PRGF-Endoret, the inclusion of leukocytes induced a major increase in these cytokines, which was characterized by the presence of a latent period. The PRGF-Endoret matrices were stable during the 8 days of incubation. The inclusion of leukocytes alters the growth factors release profile and also increased the dose of proinflammatory cytokines. © 2014 Wiley Periodicals, Inc.

  13. Diffusion profiling of tumor volumes using a histogram approach can predict proliferation and further microarchitectural features in medulloblastoma.

    Science.gov (United States)

    Schob, Stefan; Beeskow, Anne; Dieckow, Julia; Meyer, Hans-Jonas; Krause, Matthias; Frydrychowicz, Clara; Hirsch, Franz-Wolfgang; Surov, Alexey

    2018-05-31

    Medulloblastomas are the most common central nervous system tumors in childhood. Treatment and prognosis strongly depend on histology and transcriptomic profiling. However, the proliferative potential also has prognostical value. Our study aimed to investigate correlations between histogram profiling of diffusion-weighted images and further microarchitectural features. Seven patients (age median 14.6 years, minimum 2 years, maximum 20 years; 5 male, 2 female) were included in this retrospective study. Using a Matlab-based analysis tool, histogram analysis of whole apparent diffusion coefficient (ADC) volumes was performed. ADC entropy revealed a strong inverse correlation with the expression of the proliferation marker Ki67 (r = - 0.962, p = 0.009) and with total nuclear area (r = - 0.888, p = 0.044). Furthermore, ADC percentiles, most of all ADCp90, showed significant correlations with Ki67 expression (r = 0.902, p = 0.036). Diffusion histogram profiling of medulloblastomas provides valuable in vivo information which potentially can be used for risk stratification and prognostication. First of all, entropy revealed to be the most promising imaging biomarker. However, further studies are warranted.

  14. Predicting the liquefaction phenomena from shear velocity profiling: Empirical approach to 6.3 Mw, May 2006 Yogyakarta earthquake

    Energy Technology Data Exchange (ETDEWEB)

    Hartantyo, Eddy, E-mail: hartantyo@ugm.ac.id [PhD student, Physics Department, FMIPA, UGM. Sekip Utara Yogyakarta 55281 Indonesia (Indonesia); Brotopuspito, Kirbani S.; Sismanto; Waluyo [Geophysics Laboratory, FMIPA, Universitas Gadjah Mada, Sekip Utara Yogyakarta 55281 (Indonesia)

    2015-04-24

    The liquefactions phenomena have been reported after a shocking 6.5Mw earthquake hit Yogyakarta province in the morning at 27 May 2006. Several researchers have reported the damage, casualties, and soil failure due to the quake, including the mapping and analyzing the liquefaction phenomena. Most of them based on SPT test. The study try to draw the liquefaction susceptibility by means the shear velocity profiling using modified Multichannel Analysis of Surface Waves (MASW). This paper is a preliminary report by using only several measured MASW points. The study built 8-channel seismic data logger with 4.5 Hz geophones for this purpose. Several different offsets used to record the high and low frequencies of surface waves. The phase-velocity diagrams were stacked in the frequency domain rather than in time domain, for a clearer and easier dispersion curve picking. All codes are implementing in Matlab. From these procedures, shear velocity profiling was collected beneath each geophone’s spread. By mapping the minimum depth of shallow water table, calculating PGA with soil classification, using empirical formula for saturated soil weight from shear velocity profile, and calculating CRR and CSR at every depth, the liquefaction characteristic can be identify in every layer. From several acquired data, a liquefiable potential at some depth below water table was obtained.

  15. ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation.

    Directory of Open Access Journals (Sweden)

    Adrian Nahirnyj

    Full Text Available Astrocytes are the most abundant glial cell in the retinal nerve fiber layer (NFL and optic nerve head (ONH, and perform essential roles in maintaining retinal ganglion cell (RGC detoxification and homeostasis. Mature astrocytes are relatively quiescent, but rapidly undergo a phenotypic switch in response to insult, characterized by upregulation of intermediate filament proteins, loss of glutamate buffering, secretion of pro-inflammatory cytokines, and increased antioxidant production. These changes result in both positive and negative influences on RGCs. However, the mechanism regulating these responses is still unclear, and pharmacologic strategies to modulate select aspects of this switch have not been thoroughly explored. Here we describe a system for rapid culture of mature astrocytes from the adult rat retina that remain relatively quiescent, but respond robustly when challenged with oxidative damage, a key pathogenic stress associated with inner retinal injury. When primary astrocytes were exposed to reactive oxygen species (ROS we consistently observed characteristic changes in activation markers, along with increased expression of detoxifying genes, and secretion of proinflammatory cytokines. This in vitro model was then used for a pilot chemical screen to target specific aspects of this switch. Increased activity of p38α and β Mitogen Activated Protein Kinases (MAPKs were identified as a necessary signal regulating expression of MnSOD, and heme oxygenase 1 (HO-1, with consequent changes in ROS-mediated injury. Additionally, multiplex cytokine profiling detected p38 MAPK-dependent secretion of IL-6, MCP-1, and MIP-2α, which are proinflammatory signals recently implicated in damage to the inner retina. These data provide a mechanism to link increased oxidative stress to proinflammatory signaling by astrocytes, and establish this assay as a useful model to further dissect factors regulating the reactive switch.

  16. Predicting multi-level drug response with gene expression profile in multiple myeloma using hierarchical ordinal regression.

    Science.gov (United States)

    Zhang, Xinyan; Li, Bingzong; Han, Huiying; Song, Sha; Xu, Hongxia; Hong, Yating; Yi, Nengjun; Zhuang, Wenzhuo

    2018-05-10

    Multiple myeloma (MM), like other cancers, is caused by the accumulation of genetic abnormalities. Heterogeneity exists in the patients' response to treatments, for example, bortezomib. This urges efforts to identify biomarkers from numerous molecular features and build predictive models for identifying patients that can benefit from a certain treatment scheme. However, previous studies treated the multi-level ordinal drug response as a binary response where only responsive and non-responsive groups are considered. It is desirable to directly analyze the multi-level drug response, rather than combining the response to two groups. In this study, we present a novel method to identify significantly associated biomarkers and then develop ordinal genomic classifier using the hierarchical ordinal logistic model. The proposed hierarchical ordinal logistic model employs the heavy-tailed Cauchy prior on the coefficients and is fitted by an efficient quasi-Newton algorithm. We apply our hierarchical ordinal regression approach to analyze two publicly available datasets for MM with five-level drug response and numerous gene expression measures. Our results show that our method is able to identify genes associated with the multi-level drug response and to generate powerful predictive models for predicting the multi-level response. The proposed method allows us to jointly fit numerous correlated predictors and thus build efficient models for predicting the multi-level drug response. The predictive model for the multi-level drug response can be more informative than the previous approaches. Thus, the proposed approach provides a powerful tool for predicting multi-level drug response and has important impact on cancer studies.

  17. Comparison of percentage body fat and body mass index for the prediction of inflammatory and atherogenic lipid risk profiles in elderly women.

    Science.gov (United States)

    Funghetto, Silvana Schwerz; Silva, Alessandro de Oliveira; de Sousa, Nuno Manuel Frade; Stival, Marina Morato; Tibana, Ramires Alsamir; Pereira, Leonardo Costa; Antunes, Marja Letícia Chaves; de Lima, Luciano Ramos; Prestes, Jonato; Oliveira, Ricardo Jacó; Dutra, Maurílio Tiradentes; Souza, Vinícius Carolino; Nascimento, Dahan da Cunha; Karnikowski, Margô Gomes de Oliveira

    2015-01-01

    To compare the clinical classification of the body mass index (BMI) and percentage body fat (PBF) for the prediction of inflammatory and atherogenic lipid profile risk in older women. Cross-sectional analytical study with 277 elderly women from a local community in the Federal District, Brazil. PBF and fat-free mass (FFM) were determined by dual energy X-ray absorptiometry. The investigated inflammatory parameters were interleukin 6 and C-reactive protein. Twenty-five percent of the elderly women were classified as normal weight, 50% overweight, and 25% obese by the BMI. The obese group had higher levels of triglycerides and very low-density lipoproteins than did the normal weight group (P≤0.05) and lower levels of high-density lipoproteins (HDL) than did the overweight group (P≤0.05). According to the PBF, 49% of the elderly women were classified as eutrophic, 28% overweight, and 23% obese. In the binomial logistic regression analyses including age, FFM, and lipid profile, only FFM (odds ratio [OR]=0.809, 95% confidence interval [CI]: 0.739-0.886; Pprofile is key to assessing the risk of cardiometabolic diseases. Classification based on dual energy X-ray absorptiometry measures, along with biochemical and inflammatory parameters, seems to have a great clinical importance, since it allows the lipid profile eutrophic distinction in elderly overweight women.

  18. Predicting the profile of nutrients available for absorption: from nutrient requirement to animal response and environmental impact

    NARCIS (Netherlands)

    Dijkstra, J.; Kebreab, E.; Mills, J.A.N.; Pellikaan, W.F.; López, S.; Bannink, A.; France, J.

    2007-01-01

    Current feed evaluation systems for dairy cattle aim to match nutrient requirements with nutrient intake at pre-defined production levels. These systems were not developed to address, and are not suitable to predict, the responses to dietary changes in terms of production level and product

  19. Accurate diffraction data integration by the EVAL15 profile prediction method : Application in chemical and biological crystallography

    NARCIS (Netherlands)

    Xian, X.

    2009-01-01

    Accurate integration of reflection intensities plays an essential role in structure determination of the crystallized compound. A new diffraction data integration method, EVAL15, is presented in this thesis. This method uses the principle of general impacts to predict ab inito three-dimensional

  20. Scalable and Cost-Effective Assignment of Mobile Crowdsensing Tasks Based on Profiling Trends and Prediction: The ParticipAct Living Lab Experience.

    Science.gov (United States)

    Bellavista, Paolo; Corradi, Antonio; Foschini, Luca; Ianniello, Raffaele

    2015-07-30

    Nowadays, sensor-rich smartphones potentially enable the harvesting of huge amounts of valuable sensing data in urban environments, by opportunistically involving citizens to play the role of mobile virtual sensors to cover Smart City areas of interest. This paper proposes an in-depth study of the challenging technical issues related to the efficient assignment of Mobile Crowd Sensing (MCS) data collection tasks to volunteers in a crowdsensing campaign. In particular, the paper originally describes how to increase the effectiveness of the proposed sensing campaigns through the inclusion of several new facilities, including accurate participant selection algorithms able to profile and predict user mobility patterns, gaming techniques, and timely geo-notification. The reported results show the feasibility of exploiting profiling trends/prediction techniques from volunteers' behavior; moreover, they quantitatively compare different MCS task assignment strategies based on large-scale and real MCS data campaigns run in the ParticipAct living lab, an ongoing MCS real-world experiment that involved more than 170 students of the University of Bologna for more than one year.

  1. Scalable and Cost-Effective Assignment of Mobile Crowdsensing Tasks Based on Profiling Trends and Prediction: The ParticipAct Living Lab Experience

    Directory of Open Access Journals (Sweden)

    Paolo Bellavista

    2015-07-01

    Full Text Available Nowadays, sensor-rich smartphones potentially enable the harvesting of huge amounts of valuable sensing data in urban environments, by opportunistically involving citizens to play the role of mobile virtual sensors to cover Smart City areas of interest. This paper proposes an in-depth study of the challenging technical issues related to the efficient assignment of Mobile Crowd Sensing (MCS data collection tasks to volunteers in a crowdsensing campaign. In particular, the paper originally describes how to increase the effectiveness of the proposed sensing campaigns through the inclusion of several new facilities, including accurate participant selection algorithms able to profile and predict user mobility patterns, gaming techniques, and timely geo-notification. The reported results show the feasibility of exploiting profiling trends/prediction techniques from volunteers’ behavior; moreover, they quantitatively compare different MCS task assignment strategies based on large-scale and real MCS data campaigns run in the ParticipAct living lab, an ongoing MCS real-world experiment that involved more than 170 students of the University of Bologna for more than one year.

  2. Diagnostic value of the flow profile in the distal descending aorta by phase-contrast magnetic resonance for predicting severe coarctation of the aorta.

    Science.gov (United States)

    Muzzarelli, Stefano; Ordovas, Karen Gomes; Hope, Michael D; Meadows, Jeffery J; Higgins, Charles B; Meadows, Alison Knauth

    2011-06-01

    To compare aortic flow profiles at the level of the proximal descending (PDAo) and distal descending aorta (DDAo) in patients investigated for coarctation of the aorta (CoA), and compare their respective diagnostic value for predicting severe CoA. Diastolic flow decay in the PDAo predicts severe CoA, but flow measurements at this level are limited by flow turbulence, aliasing, and stent-related artifacts. We studied 49 patients evaluated for CoA with phase contrast magnetic resonance imaging (PC-MRI). Parameters of diastolic flow decay in the PDAo and DDAo were compared. Their respective diagnostic value was compared with the standard reference of transcatheter peak gradient ≥20 mmHg. Flow measurement in the PDAo required repeated acquisition with adjustment of encoding velocity or location of the imaging plane in 69% of patients; measurement in the DDAo was achieved in single acquisition in all cases. Parameters of diastolic flow decay in the PDAo and DDAo, including rate-corrected (RC) deceleration time and RC flow deceleration yielded a good correlation (r = 0.78; P RC deceleration time at DDAo (sensitivity 85%, specificity 85%). Characterization of aortic flow profiles at the DDAo offers a quick and reliable noninvasive means of assessing hemodynamically significant CoA. Copyright © 2011 Wiley-Liss, Inc.

  3. What does optimization theory actually predict about crown profiles of photosynthetic capacity when models incorporate greater realism?

    Science.gov (United States)

    Buckley, Thomas N; Cescatti, Alessandro; Farquhar, Graham D

    2013-08-01

    Measured profiles of photosynthetic capacity in plant crowns typically do not match those of average irradiance: the ratio of capacity to irradiance decreases as irradiance increases. This differs from optimal profiles inferred from simple models. To determine whether this could be explained by omission of physiological or physical details from such models, we performed a series of thought experiments using a new model that included more realism than previous models. We used ray-tracing to simulate irradiance for 8000 leaves in a horizontally uniform canopy. For a subsample of 500 leaves, we simultaneously optimized both nitrogen allocation (among pools representing carboxylation, electron transport and light capture) and stomatal conductance using a transdermally explicit photosynthesis model. Few model features caused the capacity/irradiance ratio to vary systematically with irradiance. However, when leaf absorptance varied as needed to optimize distribution of light-capture N, the capacity/irradiance ratio increased up through the crown - that is, opposite to the observed pattern. This tendency was counteracted by constraints on stomatal or mesophyll conductance, which caused chloroplastic CO(2) concentration to decline systematically with increasing irradiance. Our results suggest that height-related constraints on stomatal conductance can help to reconcile observations with the hypothesis that photosynthetic N is allocated optimally. © 2013 John Wiley & Sons Ltd.

  4. Improving spatial prediction of Schistosoma haematobium prevalence in southern Ghana through new remote sensors and local water access profiles.

    Science.gov (United States)

    Kulinkina, Alexandra V; Walz, Yvonne; Koch, Magaly; Biritwum, Nana-Kwadwo; Utzinger, Jürg; Naumova, Elena N

    2018-06-04

    Schistosomiasis is a water-related neglected tropical disease. In many endemic low- and middle-income countries, insufficient surveillance and reporting lead to poor characterization of the demographic and geographic distribution of schistosomiasis cases. Hence, modeling is relied upon to predict areas of high transmission and to inform control strategies. We hypothesized that utilizing remotely sensed (RS) environmental data in combination with water, sanitation, and hygiene (WASH) variables could improve on the current predictive modeling approaches. Schistosoma haematobium prevalence data, collected from 73 rural Ghanaian schools, were used in a random forest model to investigate the predictive capacity of 15 environmental variables derived from RS data (Landsat 8, Sentinel-2, and Global Digital Elevation Model) with fine spatial resolution (10-30 m). Five methods of variable extraction were tested to determine the spatial linkage between school-based prevalence and the environmental conditions of potential transmission sites, including applying the models to known human water contact locations. Lastly, measures of local water access and groundwater quality were incorporated into RS-based models to assess the relative importance of environmental and WASH variables. Predictive models based on environmental characterization of specific locations where people contact surface water bodies offered some improvement as compared to the traditional approach based on environmental characterization of locations where prevalence is measured. A water index (MNDWI) and topographic variables (elevation and slope) were important environmental risk factors, while overall, groundwater iron concentration predominated in the combined model that included WASH variables. The study helps to understand localized drivers of schistosomiasis transmission. Specifically, unsatisfactory water quality in boreholes perpetuates reliance of surface water bodies, indirectly increasing

  5. The molecular basis for development of proinflammatory autoantibodies to progranulin.

    Science.gov (United States)

    Thurner, Lorenz; Fadle, Natalie; Regitz, Evi; Kemele, Maria; Klemm, Philipp; Zaks, Marina; Stöger, Elisabeth; Bette, Birgit; Carbon, Gabi; Zimmer, Vincent; Assmann, Gunter; Murawski, Niels; Kubuschok, Boris; Held, Gerhard; Preuss, Klaus-Dieter; Pfreundschuh, Michael

    2015-07-01

    Recently we identified in a wide spectrum of autoimmune diseases frequently occurring proinflammatory autoantibodies directed against progranulin, a direct inhibitor of TNFR1 & 2 and of DR3. In the present study we investigated the mechanisms for the breakdown of self-tolerance against progranulin. Isoelectric focusing identified a second, differentially electrically charged progranulin isoform exclusively present in progranulin-antibody-positive patients. Alkaline phosphatase treatment revealed this additional progranulin isoform to be hyperphosphorylated. Subsequently Ser81, which is located within the epitope region of progranulin-antibodies, was identified as hyperphosphorylated serine residue by site directed mutagenesis of candidate phosphorylation sites. Hyperphosphorylated progranulin was detected exclusively in progranulin-antibody-positive patients during the courses of their diseases. The occurrence of hyperphosphorylated progranulin preceded seroconversions of progranulin-antibodies, indicating adaptive immune response. Utilizing panels of kinase and phosphatase inhibitors, PKCβ1 was identified as the relevant kinase and PP1 as the relevant phosphatase for phosphorylation and dephosphorylation of Ser81. In contrast to normal progranulin, hyperphosphorylated progranulin interacted exclusively with inactivated (pThr320) PP1, suggesting inactivated PP1 to cause the detectable occurrence of phosphorylated Ser81 PGRN. Investigation of possible functional alterations of PGRN due to Ser81 phosphorylation revealed, that hyperphosphorylation prevents the interaction and thus direct inhibition of TNFR1, TNFR2 and DR3, representing an additional direct proinflammatory effect. Finally phosphorylation of Ser81 PGRN alters the conversion pattern of PGRN. In conclusion, inactivated PP1 induces hyperphosphorylation of progranulin in a wide spectrum of autoimmune diseases. This hyperphosphorylation prevents direct inhibition of TNFR1, TNFR2 and DR3 by PGRN, alters the

  6. Histogram Profiling of Postcontrast T1-Weighted MRI Gives Valuable Insights into Tumor Biology and Enables Prediction of Growth Kinetics and Prognosis in Meningiomas.

    Science.gov (United States)

    Gihr, Georg Alexander; Horvath-Rizea, Diana; Kohlhof-Meinecke, Patricia; Ganslandt, Oliver; Henkes, Hans; Richter, Cindy; Hoffmann, Karl-Titus; Surov, Alexey; Schob, Stefan

    2018-06-14

    Meningiomas are the most frequently diagnosed intracranial masses, oftentimes requiring surgery. Especially procedure-related morbidity can be substantial, particularly in elderly patients. Hence, reliable imaging modalities enabling pretherapeutic prediction of tumor grade, growth kinetic, realistic prognosis, and-as a consequence-necessity of surgery are of great value. In this context, a promising diagnostic approach is advanced analysis of magnetic resonance imaging data. Therefore, our study investigated whether histogram profiling of routinely acquired postcontrast T1-weighted images is capable of separating low-grade from high-grade lesions and whether histogram parameters reflect Ki-67 expression in meningiomas. Pretreatment T1-weighted postcontrast volumes of 44 meningioma patients were used for signal intensity histogram profiling. WHO grade, tumor volume, and Ki-67 expression were evaluated. Comparative and correlative statistics investigating the association between histogram profile parameters and neuropathology were performed. None of the investigated histogram parameters revealed significant differences between low-grade and high-grade meningiomas. However, significant correlations were identified between Ki-67 and the histogram parameters skewness and entropy as well as between entropy and tumor volume. Contrary to previously reported findings, pretherapeutic postcontrast T1-weighted images can be used to predict growth kinetics in meningiomas if whole tumor histogram analysis is employed. However, no differences between distinct WHO grades were identifiable in out cohort. As a consequence, histogram analysis of postcontrast T1-weighted images is a promising approach to obtain quantitative in vivo biomarkers reflecting the proliferative potential in meningiomas. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

  7. Predicting the Equilibrium Deuterium-Tritium Fuel Layer Thickness Profile in an Indirect-Drive Hohlraum Capsule

    International Nuclear Information System (INIS)

    Sanchez, Jorge J.; Giedt, Warren H.

    2004-01-01

    A numerical procedure for calculating the equilibrium thickness distribution of a thin layer of deuterium and tritium on the inner surface of an indirect drive target sphere (∼2.0 mm in diameter) is described. Starting with an assumed uniform thickness layer and with specified thermal boundary conditions, the temperature distribution throughout the capsule and hohlraum (including natural convection in the hohlraum gas) is calculated. Results are used to make a first estimate of the final non-uniform thickness distribution of the layer. This thickness distribution is then used to make a second calculation of the temperature distribution with the same boundary conditions. Legendre polynomial coefficients are evaluated for the two temperature distributions and the two thickness profiles. Final equilibrium Legendre coefficients are determined by linear extrapolation. From these coefficients, the equilibrium layer thickness can be computed

  8. Immediate Postoperative Pain Scores Predict Neck Pain Profile up to 1 Year Following Anterior Cervical Discectomy and Fusion.

    Science.gov (United States)

    Adogwa, Owoicho; Elsamadicy, Aladine A; Vuong, Victoria D; Mehta, Ankit I; Vasquez, Raul A; Cheng, Joseph; Bagley, Carlos A; Karikari, Isaac O

    2018-05-01

    Retrospective cohort review. To assess whether immediate postoperative neck pain scores accurately predict 12-month visual analog scale-neck pain (VAS-NP) outcomes following Anterior Cervical Discectomy and Fusion surgery (ACDF). This was a retrospective study of 82 patients undergoing elective ACDF surgery at a major academic medical center. Patient reported outcomes measures VAS-NP scores were recorded on the first postoperative day, then at 6-weeks, 3, 6, and 12-months after surgery. Multivariate correlation and logistic regression methods were utilized to determine whether immediate postoperative VAS-NP score accurately predicted 1-year patient reported VAS-NP Scores. Overall, 46.3% male, 25.6% were smokers, and the mean age and body mass index (BMI) were 53.7 years and 28.28 kg/m 2 , respectively. There were significant correlations between immediate postoperative pain scores and neck pain scores at 6 weeks VAS-NP ( P = .0015), 6 months VAS-NP ( P = .0333), and 12 months VAS-NP ( P = .0247) after surgery. Furthermore, immediate postoperative pain score is an independent predictor of 6 weeks, 6 months, and 1 year VAS-NP scores. Our study suggests that immediate postoperative patient reported neck pain scores accurately predicts and correlates with 12-month VAS-NP scores after an ACDF procedure. Patients with high neck pain scores after surgery are more likely to report persistent neck pain 12 months after index surgery.

  9. Transcriptional profiling of human brain endothelial cells reveals key properties crucial for predictive in vitro blood-brain barrier models.

    Directory of Open Access Journals (Sweden)

    Eduard Urich

    Full Text Available Brain microvascular endothelial cells (BEC constitute the blood-brain barrier (BBB which forms a dynamic interface between the blood and the central nervous system (CNS. This highly specialized interface restricts paracellular diffusion of fluids and solutes including chemicals, toxins and drugs from entering the brain. In this study we compared the transcriptome profiles of the human immortalized brain endothelial cell line hCMEC/D3 and human primary BEC. We identified transcriptional differences in immune response genes which are directly related to the immortalization procedure of the hCMEC/D3 cells. Interestingly, astrocytic co-culturing reduced cell adhesion and migration molecules in both BECs, which possibly could be related to regulation of immune surveillance of the CNS controlled by astrocytic cells within the neurovascular unit. By matching the transcriptome data from these two cell lines with published transcriptional data from freshly isolated mouse BECs, we discovered striking differences that could explain some of the limitations of using cultured BECs to study BBB properties. Key protein classes such as tight junction proteins, transporters and cell surface receptors show differing expression profiles. For example, the claudin-5, occludin and JAM2 expression is dramatically reduced in the two human BEC lines, which likely explains their low transcellular electric resistance and paracellular leakiness. In addition, the human BEC lines express low levels of unique brain endothelial transporters such as Glut1 and Pgp. Cell surface receptors such as LRP1, RAGE and the insulin receptor that are involved in receptor-mediated transport are also expressed at very low levels. Taken together, these data illustrate that BECs lose their unique protein expression pattern outside of their native environment and display a more generic endothelial cell phenotype. A collection of key genes that seems to be highly regulated by the local

  10. β-Catenin promotes colitis and colon cancer through imprinting of proinflammatory properties in T cells.

    Science.gov (United States)

    Keerthivasan, Shilpa; Aghajani, Katayoun; Dose, Marei; Molinero, Luciana; Khan, Mohammad W; Venkateswaran, Vysak; Weber, Christopher; Emmanuel, Akinola Olumide; Sun, Tianjao; Bentrem, David J; Mulcahy, Mary; Keshavarzian, Ali; Ramos, Elena M; Blatner, Nichole; Khazaie, Khashayarsha; Gounari, Fotini

    2014-02-26

    The density and type of lymphocytes that infiltrate colon tumors are predictive of the clinical outcome of colon cancer. High densities of T helper 17 (T(H)17) cells and inflammation predict poor outcome, whereas infiltration by T regulatory cells (Tregs) that naturally suppress inflammation is associated with longer patient survival. However, the role of Tregs in cancer remains controversial. We recently reported that Tregs in colon cancer patients can become proinflammatory and tumor-promoting. These properties were directly linked with their expression of RORγt (retinoic acid-related orphan receptor-γt), the signature transcription factor of T(H)17 cells. We report that Wnt/β-catenin signaling in T cells promotes expression of RORγt. Expression of β-catenin was elevated in T cells, including Tregs, of patients with colon cancer. Genetically engineered activation of β-catenin in mouse T cells resulted in enhanced chromatin accessibility in the proximity of T cell factor-1 (Tcf-1) binding sites genome-wide, induced expression of T(H)17 signature genes including RORγt, and promoted T(H)17-mediated inflammation. Strikingly, the mice had inflammation of small intestine and colon and developed lesions indistinguishable from colitis-induced cancer. Activation of β-catenin only in Tregs was sufficient to produce inflammation and initiate cancer. On the basis of these findings, we conclude that activation of Wnt/β-catenin signaling in effector T cells and/or Tregs is causatively linked with the imprinting of proinflammatory properties and the promotion of colon cancer.

  11. Antimicrobial peptides and pro-inflammatory cytokines are differentially regulated across epidermal layers following bacterial stimuli.

    Science.gov (United States)

    Percoco, Giuseppe; Merle, Chloé; Jaouen, Thomas; Ramdani, Yasmina; Bénard, Magalie; Hillion, Mélanie; Mijouin, Lily; Lati, Elian; Feuilloley, Marc; Lefeuvre, Luc; Driouich, Azeddine; Follet-Gueye, Marie-Laure

    2013-12-01

    The skin is a natural barrier between the body and the environment and is colonised by a large number of microorganisms. Here, we report a complete analysis of the response of human skin explants to microbial stimuli. Using this ex vivo model, we analysed at both the gene and protein level the response of epidermal cells to Staphylococcus epidermidis (S. epidermidis) and Pseudomonas fluorescens (P. fluorescens), which are present in the cutaneous microbiota. We showed that both bacterial species affect the structure of skin explants without penetrating the living epidermis. We showed by real-time quantitative polymerase chain reaction (qPCR) that S. epidermidis and P. fluorescens increased the levels of transcripts that encode antimicrobial peptides (AMPs), including human β defensin (hBD)2 and hBD3, and the pro-inflammatory cytokines interleukin (IL)-1α and (IL)-1-β, as well as IL-6. In addition, we analysed the effects of bacterial stimuli on the expression profiles of genes related to innate immunity and the inflammatory response across the epidermal layers, using laser capture microdissection (LCM) coupled to qPCR. We showed that AMP transcripts were principally upregulated in suprabasal keratinocytes. Conversely, the expression of pro-inflammatory cytokines was upregulated in the lower epidermis. These findings were confirmed by protein localisation using specific antibodies coupled to optical or electron microscopy. This work underscores the potential value of further studies that use LCM on human skin explants model to study the roles and effects of the epidermal microbiota on human skin physiology. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. Polycystic Ovary Syndrome as a Proinflammatory State: The Role of Adipokines.

    Science.gov (United States)

    Dimitriadis, Georgios K; Kyrou, Ioannis; Randeva, Harpal S

    2016-01-01

    Polycystic Ovary Syndrome (PCOS) is a complex heterogeneous disorder and the most common endocrinopathy amongst women of reproductive age. It is characterized by androgen excess, chronic anovulation and an altered cardiometabolic profile. PCOS is linked to impaired adipose tissue (AT) physiology and women with this disorder present with greater risk for insulin resistance (IR), hyperinsulinemia, central adiposity, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) than matched for age and body mass index (BMI) women without PCOS. Hyperandrogenaemia appears to be driving adipocyte hypertrophy observed in PCOS under the influence of a hyperinsulinaemic state. Changes in the function of adipocytes have an impact on the secretion of adipokines, adipose tissue-derived proinflammatory factors promoting susceptibility to low grade inflammation. In this article, we review the existing knowledge on the interplay between hyperandrogenaemia, insulin resistance, impaired adipocyte biology, adipokines and chronic low-grade inflammation in PCOS. In PCOS, more than one mechanisms have been suggested in the development of a chronic low-grade inflammation state with the most prevalent being that of a direct effect of the immune system on adipose tissue functions as previously reported in obese women without PCOS. Despite the lack of conclusive evidence regarding a direct mechanism linking hyperandrogenaemia to pro-inflammation in PCOS, there have been recent findings indicating that hyperandrogenaemia might be involved in chronic inflammation by exerting an effect on adipocytes morphology and attributes. Increasing evidence suggests that there is an important connection and interaction between proinflammatory pathways, hyperinsulinemia, androgen excess and adipose tissue hypertrophy and, dysfunction in PCOS. While lifestyle changes and individualized prescription of insulin-sensitizing drugs are common in managing PCOS, further studies are warranted to

  13. Comparison of midlatitude ionospheric F region peak parameters and topside Ne profiles from IRI2012 model prediction with ground-based ionosonde and Alouette II observations

    Science.gov (United States)

    Gordiyenko, G. I.; Yakovets, A. F.

    2017-07-01

    The ionospheric F2 peak parameters recorded by a ground-based ionosonde at the midlatitude station Alma-Ata [43.25N, 76.92E] were compared with those obtained using the latest version of the IRI model (http://omniweb.gsfc.nasa.gov/vitmo/iri2012_vitmo.html). It was found that for the Alma-Ata (Kazakhstan) location, the IRI2012 model describes well the morphology of seasonal and diurnal variations of the ionospheric critical frequency (foF2) and peak density height (hmF2) monthly medians. The model errors in the median foF2 prediction (percentage deviations between the median foF2 values and their model predictions) were found to vary approximately in the range from about -20% to 34% and showed a stable overestimation in the median foF2 values for daytime in January and July and underestimation for day- and nighttime hours in the equinoctial months. The comparison between the ionosonde hmF2 and IRI results clearly showed that the IRI overestimates the nighttime hmF2 values for March and September months, and the difference is up to 30 km. The daytime Alma-Ata hmF2 data were found to be close to the IRI predictions (deviations are approximately ±10-15 km) in winter and equinoctial months, except in July when the observed hmF2 values were much more (from approximately 50-200 km). The comparison between the Alouette foF2 data and IRI predictions showed mixed results. In particular, the Alouette foF2 data showed a tendency to be overestimated for daytime in winter months similar to the ionosonde data; however, the overestimated foF2 values for nighttime in the autumn equinox were in disagreement with the ionosonde observations. There were large deviations between the observed hmF2 values and their model predictions. The largest deviations were found during winter and summer (up to -90 km). The comparison of the Alouette II electron density profiles with those predicted by the adapted IRI2012 model in the altitude range hmF2 of the satellite position showed a great

  14. Profiling of volatile organic compounds in exhaled breath as a strategy to find early predictive signatures of asthma in children.

    Directory of Open Access Journals (Sweden)

    Agnieszka Smolinska

    Full Text Available Wheezing is one of the most common respiratory symptoms in preschool children under six years old. Currently, no tests are available that predict at early stage who will develop asthma and who will be a transient wheezer. Diagnostic tests of asthma are reliable in adults but the same tests are difficult to use in children, because they are invasive and require active cooperation of the patient. A non-invasive alternative is needed for children. Volatile Organic Compounds (VOCs excreted in breath could yield such non-invasive and patient-friendly diagnostic. The aim of this study was to identify VOCs in the breath of preschool children (inclusion at age 2-4 years that indicate preclinical asthma. For that purpose we analyzed the total array of exhaled VOCs with Gas Chromatography time of flight Mass Spectrometry of 252 children between 2 and 6 years of age. Breath samples were collected at multiple time points of each child. Each breath-o-gram contained between 300 and 500 VOCs; in total 3256 different compounds were identified across all samples. Using two multivariate methods, Random Forests and dissimilarity Partial Least Squares Discriminant Analysis, we were able to select a set of 17 VOCs which discriminated preschool asthmatic children from transient wheezing children. The correct prediction rate was equal to 80% in an independent test set. These VOCs are related to oxidative stress caused by inflammation in the lungs and consequently lipid peroxidation. In conclusion, we showed that VOCs in the exhaled breath predict the subsequent development of asthma which might guide early treatment.

  15. Predicting Recurrence and Progression of Noninvasive Papillary Bladder Cancer at Initial Presentation Based on Quantitative Gene Expression Profiles

    DEFF Research Database (Denmark)

    Birkhahn, M.; Mitra, A.P.; Williams, Johan

    2010-01-01

    Background: Currently, tumor grade is the best predictor of outcome at first presentation of noninvasive papillary (Ta) bladder cancer. However, reliable predictors of Ta tumor recurrence and progression for individual patients, which could optimize treatment and follow-up schedules based...... on specific tumor biology, are yet to be identified. Objective: To identify genes predictive for recurrence and progression in Ta bladder cancer at first presentation using a quantitative, pathway-specific approach. Design, setting, and participants: Retrospective study of patients with Ta G2/3 bladder tumors...... at initial presentation with three distinct clinical outcomes: absence of recurrence (n = 16), recurrence without progression (n = 16), and progression to carcinoma in situ or invasive disease (n = 16). Measurements: Expressions of 24 genes that feature in relevant pathways that are deregulated in bladder...

  16. Distinct lipid profiles predict improved glycemic control in obese, nondiabetic patients after a low-caloric diet intervention

    DEFF Research Database (Denmark)

    Valsesia, Armand; Saris, Wim Hm; Astrup, Arne

    2016-01-01

    BACKGROUND: An aim of weight loss is to reduce the risk of type 2 diabetes (T2D) in obese subjects. However, the relation with long-term glycemic improvement remains unknown. OBJECTIVE: We evaluated the changes in lipid composition during weight loss and their association with long-term glycemic...... improvement. DESIGN: We investigated the plasma lipidome of 383 obese, nondiabetic patients within a randomized, controlled dietary intervention in 8 European countries at baseline, after an 8-wk low-caloric diet (LCD) (800-1000 kcal/d), and after 6 mo of weight maintenance. RESULTS: After weight loss......: In this study, we report a lipid signature of LCD success (for weight and glycemic outcome) in obese, nondiabetic patients. Lipid changes during an 8-wk LCD allowed us to predict insulin-resistant patients after 6 mo of weight maintenance. The determination of the lipid composition during an LCD enables...

  17. Gene Expression Profiles for Predicting Metastasis in Breast Cancer: A Cross-Study Comparison of Classification Methods

    Directory of Open Access Journals (Sweden)

    Mark Burton

    2012-01-01

    Full Text Available Machine learning has increasingly been used with microarray gene expression data and for the development of classifiers using a variety of methods. However, method comparisons in cross-study datasets are very scarce. This study compares the performance of seven classification methods and the effect of voting for predicting metastasis outcome in breast cancer patients, in three situations: within the same dataset or across datasets on similar or dissimilar microarray platforms. Combining classification results from seven classifiers into one voting decision performed significantly better during internal validation as well as external validation in similar microarray platforms than the underlying classification methods. When validating between different microarray platforms, random forest, another voting-based method, proved to be the best performing method. We conclude that voting based classifiers provided an advantage with respect to classifying metastasis outcome in breast cancer patients.

  18. Whole genome transcript profiling of drug induced steatosis in rats reveals a gene signature predictive of outcome.

    Directory of Open Access Journals (Sweden)

    Nishika Sahini

    Full Text Available Drug induced steatosis (DIS is characterised by excess triglyceride accumulation in the form of lipid droplets (LD in liver cells. To explore mechanisms underlying DIS we interrogated the publically available microarray data from the Japanese Toxicogenomics Project (TGP to study comprehensively whole genome gene expression changes in the liver of treated rats. For this purpose a total of 17 and 12 drugs which are diverse in molecular structure and mode of action were considered based on their ability to cause either steatosis or phospholipidosis, respectively, while 7 drugs served as negative controls. In our efforts we focused on 200 genes which are considered to be mechanistically relevant in the process of lipid droplet biogenesis in hepatocytes as recently published (Sahini and Borlak, 2014. Based on mechanistic considerations we identified 19 genes which displayed dose dependent responses while 10 genes showed time dependency. Importantly, the present study defined 9 genes (ANGPTL4, FABP7, FADS1, FGF21, GOT1, LDLR, GK, STAT3, and PKLR as signature genes to predict DIS. Moreover, cross tabulation revealed 9 genes to be regulated ≥10 times amongst the various conditions and included genes linked to glucose metabolism, lipid transport and lipogenesis as well as signalling events. Additionally, a comparison between drugs causing phospholipidosis and/or steatosis revealed 26 genes to be regulated in common including 4 signature genes to predict DIS (PKLR, GK, FABP7 and FADS1. Furthermore, a comparison between in vivo single dose (3, 6, 9 and 24 h and findings from rat hepatocyte studies (2 h, 8 h, 24 h identified 10 genes which are regulated in common and contained 2 DIS signature genes (FABP7, FGF21. Altogether, our studies provide comprehensive information on mechanistically linked gene expression changes of a range of drugs causing steatosis and phospholipidosis and encourage the screening of DIS signature genes at the preclinical stage.

  19. Physical fitness predicts technical-tactical and time-motion profile in simulated Judo and Brazilian Jiu-Jitsu matches

    Directory of Open Access Journals (Sweden)

    Victor S. Coswig

    2018-05-01

    Full Text Available Background Among combat sports, Judo and Brazilian Jiu-Jitsu (BJJ present elevated physical fitness demands from the high-intensity intermittent efforts. However, information regarding how metabolic and neuromuscular physical fitness is associated with technical-tactical performance in Judo and BJJ fights is not available. This study aimed to relate indicators of physical fitness with combat performance variables in Judo and BJJ. Methods The sample consisted of Judo (n = 16 and BJJ (n = 24 male athletes. At the first meeting, the physical tests were applied and, in the second, simulated fights were performed for later notational analysis. Results The main findings indicate: (i high reproducibility of the proposed instrument and protocol used for notational analysis in a mobile device; (ii differences in the technical-tactical and time-motion patterns between modalities; (iii performance-related variables are different in Judo and BJJ; and (iv regression models based on metabolic fitness variables may account for up to 53% of the variances in technical-tactical and/or time-motion variables in Judo and up to 31% in BJJ, whereas neuromuscular fitness models can reach values up to 44 and 73% of prediction in Judo and BJJ, respectively. When all components are combined, they can explain up to 90% of high intensity actions in Judo. Discussion In conclusion, performance prediction models in simulated combat indicate that anaerobic, aerobic and neuromuscular fitness variables contribute to explain time-motion variables associated with high intensity and technical-tactical variables in Judo and BJJ fights.

  20. Sensitivity and specificity of a brief personality screening instrument in predicting future substance use, emotional, and behavioral problems: 18-month predictive validity of the Substance Use Risk Profile Scale.

    Science.gov (United States)

    Castellanos-Ryan, Natalie; O'Leary-Barrett, Maeve; Sully, Laura; Conrod, Patricia

    2013-01-01

    This study assessed the validity, sensitivity, and specificity of the Substance Use Risk Profile Scale (SURPS), a measure of personality risk factors for substance use and other behavioral problems in adolescence. The concurrent and predictive validity of the SURPS was tested in a sample of 1,162 adolescents (mean age: 13.7 years) using linear and logistic regressions, while its sensitivity and specificity were examined using the receiver operating characteristics curve analyses. Concurrent and predictive validity tests showed that all 4 brief scales-hopelessness (H), anxiety sensitivity (AS), impulsivity (IMP), and sensation seeking (SS)-were related, in theoretically expected ways, to measures of substance use and other behavioral and emotional problems. Results also showed that when using the 4 SURPS subscales to identify adolescents "at risk," one can identify a high number of those who developed problems (high sensitivity scores ranging from 72 to 91%). And, as predicted, because each scale is related to specific substance and mental health problems, good specificity was obtained when using the individual personality subscales (e.g., most adolescents identified at high risk by the IMP scale developed conduct or drug use problems within the next 18 months [a high specificity score of 70 to 80%]). The SURPS is a valuable tool for identifying adolescents at high risk for substance misuse and other emotional and behavioral problems. Implications of findings for the use of this measure in future research and prevention interventions are discussed. Copyright © 2012 by the Research Society on Alcoholism.

  1. The Hierarchy of Proinflammatory Cytokines in Ocular Inflammation.

    Science.gov (United States)

    Da Cunha, A P; Zhang, Q; Prentiss, M; Wu, X Q; Kainz, V; Xu, Y Y; Vrouvlianis, J; Li, H; Rangaswamy, N; Leehy, B; McGee, T L; Bell, C L; Bigelow, C E; Kansara, V; Medley, Q; Huang, Q; Wu, H Y

    2018-04-01

    The concept of tissue-dependent cytokine hierarchy has been demonstrated in a number of diseases, but it has not been investigated in ophthalmic diseases. Here, we evaluated the functional hierarchy of interleukin-1β (IL-1β), IL-6, IL-17A, and tumor necrosis factor (TNF) in the induction of ocular inflammation. We delivered adeno-associated virus (AAV) vectors expressing IL-1β, IL-6, IL-17A, or TNF intravitreally in naïve C57/BL6 mice and compared and contrasted the inflammatory effects in the eye 5 weeks after AAV-mediated gene transfer. We also used an in vitro human system to test the effect of cytokines on barrier function. We found that IL-1β had the highest ability to initiate ocular inflammation. The continuous overexpression of IL-1β resulted in a significant upregulation of additional proinflammatory mediators in the eye. Using scanning laser ophthalmoscope and optical coherence tomography imaging techniques, we showed that a low dose of AAVIL-1β was sufficient and was as pathogenic as a high dose of TNF in inducing vascular leakage, retinal degeneration, and cellular infiltration. Furthermore, only a marginal increase in IL-1β was enough to cause cellular infiltration, thus confirming the highly pathogenic nature of IL-1β in the eye. Contrary to our expectation, IL-6 or IL-17A had minimal or no effect in the eye. To examine the clinical relevance of our findings, we used an impedance assay to show that IL-1β alone or TNF alone was able to cause primary human retinal endothelial cell barrier dysfunction in vitro. Again, IL-6 alone or IL-17A alone had no effect on barrier function; however, in the presence of IL-1β or TNF, IL-17A but not IL-6 may provide additive proinflammatory effects. Our studies demonstrate the existence of a functional hierarchy of proinflammatory cytokines in the eye, and we show that IL-1β is the most pathogenic when it is continuously expressed in the eye.

  2. TP53, STK11 and EGFR Mutations Predict Tumor Immune Profile and the Response to anti-PD-1 in Lung Adenocarcinoma.

    Science.gov (United States)

    Biton, Jerome; Mansuet-Lupo, Audrey; Pécuchet, Nicolas; Alifano, Marco; Ouakrim, Hanane; Arrondeau, Jennifer; Boudou-Rouquette, Pascaline; Goldwasser, Francois; Leroy, Karen; Goc, Jeremy; Wislez, Marie; Germain, Claire; Laurent-Puig, Pierre; Dieu-Nosjean, Marie-Caroline; Cremer, Isabelle; Herbst, Ronald; Blons, Hélène F; Damotte, Diane

    2018-05-15

    By unlocking anti-tumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. We performed in depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry and transcriptomic data. Tumor mutational status was investigated using next-generation sequencing. The response to PD-1 blockers was analyzed from a prospective cohort according to tumor mutational profiles and to PD-L1 expression, and a public clinical database was used to validate the results obtained. We showed that distinct combinations of STK11 , EGFR and TP53 mutations, were major determinants of the tumor immune profile (TIP) and of the expression of PD-L1 by malignant cells. Indeed, the presence of TP53 mutations without co-occurring STK11 or EGFR alterations ( TP53 -mut/ STK11 - EGFR -WT), independently of KRAS mutations, identified the group of tumors with the highest CD8 T cell density and PD-L1 expression. In this tumor subtype, pathways related to T cell chemotaxis, immune cell cytotoxicity, and antigen processing were up-regulated. Finally, a prolonged progression-free survival (PFS: HR=0.32; 95% CI, 0.16-0.63, p <0.001) was observed in anti-PD-1 treated patients harboring TP53 -mut/ STK11 - EGFR -WT tumors. This clinical benefit was even more remarkable in patients with associated strong PD-L1 expression. Our study reveals that different combinations of TP53 , EGFR and STK11 mutations , together with PD-L1 expression by tumor cells, represent robust parameters to identify best responders to PD-1 blockade. Copyright ©2018, American Association for Cancer Research.

  3. Prediction of the binding mode and resistance profile for a dual-target pyrrolyl diketo acid scaffold against HIV-1 integrase and reverse-transcriptase-associated ribonuclease H.

    Science.gov (United States)

    Yang, Fengyuan; Zheng, Guoxun; Fu, Tingting; Li, Xiaofeng; Tu, Gao; Li, Ying Hong; Yao, Xiaojun; Xue, Weiwei; Zhu, Feng

    2018-06-27

    The rapid emergence of drug-resistant variants is one of the most common causes of highly active antiretroviral therapeutic (HAART) failure in patients infected with HIV-1. Compared with the existing HAART, the recently developed pyrrolyl diketo acid scaffold targeting both HIV-1 integrase (IN) and reverse transcriptase-associated ribonuclease H (RNase H) is an efficient approach to counteract the failure of anti-HIV treatment due to drug resistance. However, the binding mode and potential resistance profile of these inhibitors with important mechanistic principles remain poorly understood. To address this issue, an integrated computational method was employed to investigate the binding mode of inhibitor JMC6F with HIV-1 IN and RNase H. By using per-residue binding free energy decomposition analysis, the following residues: Asp64, Thr66, Leu68, Asp116, Tyr143, Gln148 and Glu152 in IN, Asp443, Glu478, Trp536, Lys541 and Asp549 in RNase H were identified as key residues for JMC6F binding. And then computational alanine scanning was carried to further verify the key residues. Moreover, the resistance profile of the currently known major mutations in HIV-1 IN and 2 mutations in RNase H against JMC6F was predicted by in silico mutagenesis studies. The results demonstrated that only three mutations in HIV-1 IN (Y143C, Q148R and N155H) and two mutations in HIV-1 RNase H (Y501R and Y501W) resulted in a reduction of JMC6F potency, thus indicating their potential role in providing resistance to JMC6F. These data provided important insights into the binding mode and resistance profile of the inhibitors with a pyrrolyl diketo acid scaffold in HIV-1 IN and RNase H, which would be helpful for the development of more effective dual HIV-1 IN and RNase H inhibitors.

  4. Predictive value of a profile of routine blood measurements on mortality in older persons in the general population: the Leiden 85-plus Study.

    Directory of Open Access Journals (Sweden)

    Anne H van Houwelingen

    Full Text Available BACKGROUND: Various questionnaires and performance tests predict mortality in older people. However, most are heterogeneous, laborious and a validated consensus index is not available yet. Since most older people are regularly monitored by laboratory tests, we compared the predictive value of a profile of seven routine laboratory measurements on mortality in older persons in the general population with other predictors of mortality; gait speed and disability in instrumental activities of daily living (IADL. METHODOLOGY/PRINCIPAL FINDINGS: Within the Leiden 85-plus Study, a prospective population-based study, we followed 562 participants aged 85 years for mortality over five years. At baseline (age 85 years high-density lipoprotein cholesterol, albumin, alanine transaminase, hemoglobin, creatinin clearance, C-reactive protein and homocysteine were measured. Participants were stratified based on their number of laboratory abnormalities (0, 1, 2-4 and 5-7. The predictive capacity was compared with gait speed (6-meter walking test and disability in IADL (Groningen Activity Restriction Scale by C-statistics. At baseline, 418 (74% 85-year old participants had at least one laboratory abnormality. All cause mortality risk increased with increasing number of laboratory abnormalities to a hazard ratio of 5.64 [95% CI 3.49-9.12] for those with 5-7 laboratory abnormalities (p<0.001 compared to those without abnormalities. The c-statistic was 0.66 [95% CI 0.59-0.69], similar to that of gait speed and disability in IADL. CONCLUSIONS/SIGNIFICANCE: In the general population of oldest old, the number of abnormalities in seven routine laboratory measurements predicts five-year mortality as accurately as gait speed and IADL disability.

  5. Simultaneous virtual prediction of anti-Escherichia coli activities and ADMET profiles: A chemoinformatic complementary approach for high-throughput screening.

    Science.gov (United States)

    Speck-Planche, Alejandro; Cordeiro, M N D S

    2014-02-10

    Escherichia coli remains one of the principal pathogens that cause nosocomial infections, medical conditions that are increasingly common in healthcare facilities. E. coli is intrinsically resistant to many antibiotics, and multidrug-resistant strains have emerged recently. Chemoinformatics has been a great ally of experimental methodologies such as high-throughput screening, playing an important role in the discovery of effective antibacterial agents. However, there is no approach that can design safer anti-E. coli agents, because of the multifactorial nature and complexity of bacterial diseases and the lack of desirable ADMET (absorption, distribution, metabolism, elimination, and toxicity) profiles as a major cause of disapproval of drugs. In this work, we introduce the first multitasking model based on quantitative-structure biological effect relationships (mtk-QSBER) for simultaneous virtual prediction of anti-E. coli activities and ADMET properties of drugs and/or chemicals under many experimental conditions. The mtk-QSBER model was developed from a large and heterogeneous data set of more than 37800 cases, exhibiting overall accuracies of >95% in both training and prediction (validation) sets. The utility of our mtk-QSBER model was demonstrated by performing virtual prediction of properties for the investigational drug avarofloxacin (AVX) under 260 different experimental conditions. Results converged with the experimental evidence, confirming the remarkable anti-E. coli activities and safety of AVX. Predictions also showed that our mtk-QSBER model can be a promising computational tool for virtual screening of desirable anti-E. coli agents, and this chemoinformatic approach could be extended to the search for safer drugs with defined pharmacological activities.

  6. A one-dimensional Fickian model to predict the Ga depth profiles in three-stage Cu(In,Ga)Se{sub 2}

    Energy Technology Data Exchange (ETDEWEB)

    Rodriguez-Alvarez, H., E-mail: humberto.rodriguez@helmholtz-berlin.de [International Iberian Nanotechnology Laboratory, Avenida Mestre Jose Veiga s/n, 4715-330 Braga (Portugal); Helmholtz-Zentrum Berlin, Hahn-Meitner Platz 1, 14109 Berlin (Germany); Mainz, R. [Helmholtz-Zentrum Berlin, Hahn-Meitner Platz 1, 14109 Berlin (Germany); Sadewasser, S. [International Iberian Nanotechnology Laboratory, Avenida Mestre Jose Veiga s/n, 4715-330 Braga (Portugal)

    2014-05-28

    We present a one-dimensional Fickian model that predicts the formation of a double Ga gradient during the fabrication of Cu(In,Ga)Se{sub 2} thin films by three-stage thermal co-evaporation. The model is based on chemical reaction equations, structural data, and effective Ga diffusivities. In the model, the Cu(In,Ga)Se{sub 2} surface is depleted from Ga during the deposition of Cu-Se in the second deposition stage, leading to an accumulation of Ga near the back contact. During the third deposition stage, where In-Ga-Se is deposited at the surface, the atomic fluxes within the growing layer are inverted. This results in the formation of a double Ga gradient within the Cu(In,Ga)Se{sub 2} layer and reproduces experimentally observed Ga distributions. The final shape of the Ga depth profile strongly depends on the temperatures, times and deposition rates used. The model is used to evaluate possible paths to flatten the marked Ga depth profile that is obtained when depositing at low substrate temperatures. We conclude that inserting Ga during the second deposition stage is an effective way to achieve this.

  7. A one-dimensional Fickian model to predict the Ga depth profiles in three-stage Cu(In,Ga)Se2

    International Nuclear Information System (INIS)

    Rodriguez-Alvarez, H.; Mainz, R.; Sadewasser, S.

    2014-01-01

    We present a one-dimensional Fickian model that predicts the formation of a double Ga gradient during the fabrication of Cu(In,Ga)Se 2 thin films by three-stage thermal co-evaporation. The model is based on chemical reaction equations, structural data, and effective Ga diffusivities. In the model, the Cu(In,Ga)Se 2 surface is depleted from Ga during the deposition of Cu-Se in the second deposition stage, leading to an accumulation of Ga near the back contact. During the third deposition stage, where In-Ga-Se is deposited at the surface, the atomic fluxes within the growing layer are inverted. This results in the formation of a double Ga gradient within the Cu(In,Ga)Se 2 layer and reproduces experimentally observed Ga distributions. The final shape of the Ga depth profile strongly depends on the temperatures, times and deposition rates used. The model is used to evaluate possible paths to flatten the marked Ga depth profile that is obtained when depositing at low substrate temperatures. We conclude that inserting Ga during the second deposition stage is an effective way to achieve this.

  8. Proinflammatory and anti-inflammatory cytokine profile in pediatric patients with irritable bowel syndrome

    Directory of Open Access Journals (Sweden)

    R. Vázquez-Frias

    2015-01-01

    Conclusions: This study suggests that children with IBS have a state of altered immune regulation. This is consistent with the theory of low-grade inflammatory state in these patients. Further studies are needed to elucidate the role played by these cytokines, specifically TGF-β in the pathogenesis of IBS.

  9. Bacterial vaginosis in pregnant adolescents: proinflammatory cytokine and bacterial sialidase profile. Cross-sectional study

    Directory of Open Access Journals (Sweden)

    Carolina Sanitá Tafner Ferreira

    Full Text Available ABSTRACT CONTEXT AND OBJECTIVE: Bacterial vaginosis occurs frequently in pregnancy and increases susceptibility to sexually transmitted infections (STI. Considering that adolescents are disproportionally affected by STI, the aim of this study was to evaluate the cervicovaginal levels of interleukin (IL-1 beta, IL-6, IL-8 and bacterial sialidase in pregnant adolescents with bacterial vaginosis. DESIGN AND SETTING: Cross-sectional study at mother and child referral units in Belém, Pará, Brazil. METHODS: Vaginal samples from 168 pregnant adolescents enrolled were tested for trichomoniasis and candidiasis. Their vaginal microbiota was classified according to the Nugent criteria (1991 as normal, intermediate or bacterial vaginosis. Cervical infection due to Chlamydia trachomatisand Neisseria gonorrhoeae was also assessed. Cytokine and sialidase levels were measured, respectively, using enzyme-linked immunosorbent assays and MUAN conversion in cervicovaginal lavages. Forty-eight adolescents (28.6% were excluded because they tested positive for some of the infections investigated. The remaining 120 adolescents were grouped according to vaginal flora type: normal (n = 68 or bacterial vaginosis (n = 52. Their cytokine and sialidase levels were compared between the groups using the Mann-Whitney test (P < 0.05. RESULTS: The pregnant adolescents with bacterial vaginosis had higher levels of IL-1 beta, IL-6 and IL-8 (P < 0.05. Sialidase was solely detected in 35 adolescents (67.2% with bacterial vaginosis. CONCLUSIONS: Not only IL-1 beta and sialidase levels, but also IL-6 and IL-8 levels are higher in pregnant adolescents with bacterial vaginosis, thus indicating that this condition elicits a more pronounced inflammatory response in this population, which potentially increases vulnerability to STI acquisition.

  10. An elevated pro-inflammatory cytokine profile in multiple chemical sensitivity

    DEFF Research Database (Denmark)

    Dantoft, Thomas Meinertz; Elberling, J.; Brix, Susanne

    2014-01-01

    BackgroundMultiple chemical sensitivity (MCS) is a medically unexplained condition characterized by reports of recurrent unspecific symptoms attributed to exposure to low levels of common volatile chemicals. The etiology of MCS is poorly understood, but dysregulation of the immune system has been...

  11. Visceral adiposity index (VAI is predictive of an altered adipokine profile in patients with type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Marco C Amato

    Full Text Available AIMS: Although there is still no clear definition of "adipose tissue dysfunction" or ATD, the identification of a clinical marker of altered fat distribution and function may provide the needed tools for early identification of a condition of cardiometabolic risk. Our aim was to evaluate the correlations among various anthropometric indices [BMI, Waist Circumference (WC, Hip Circumference (HC, Waist/Hip ratio (WHR, Body Adiposity Index (BAI and Visceral adiposity Index (VAI] and several adipocytokines [Visfatin, Resistin, Leptin, Soluble leptin receptors (sOB-R, Adiponectin, Ghrelin, Adipsin, PAI-1, vascular endothelial growth factor (VEGF, Hepatocyte growth factor (HGF TNF-α, hs-CRP, IL-6, IL-18] in patients with type 2 diabetes (DM2. MATERIALS AND METHODS: Ninety-one DM2 patients (age: 65.25 ± 6.38 years; 42 men and 49 women in stable treatment for the last six months with metformin in monotherapy (1.5-2 g/day were cross-sectionally studied. Clinical, anthropometric, and metabolic parameters were evaluated. Serum adipocytokine levels were assayed with Luminex based kits. RESULTS: At the Pearson's correlation, among all the indices investigated, VAI showed a significant correlation with almost all adipocytokines analyzed [Visfatin, Resistin and hsCRP (all p<0.001; Adiponectin, sOb-R, IL-6, IL-18, HGF (all p<0.010; Ghrelin and VEGF (both p<0.05]. Through a two-step cluster analysis, 55 patients were identified with the most altered adipocytokine profile (patients with ATD. At a ROC analysis, VAI showed the highest C-statistic [0.767 (95% CI 0.66-0.84] of all the indices. CONCLUSIONS: Our study suggests that the VAI, among the most common indexes of adiposity assessment, shows the best correlation with the best known adipocytokines and cardiometabolic risk serum markers. Although to date we are still far from clearly identifying an ATD, the VAI would be an easy tool for clearly mirroring a condition of cardiometabolic risk, in the absence of an

  12. Proinflammatory effects of cookstove emissions on human bronchial epithelial cells.

    Science.gov (United States)

    Hawley, B; Volckens, J

    2013-02-01

    Approximately half of the world's population uses biomass fuel for indoor cooking and heating. This form of combustion typically occurs in open fires or primitive stoves. Human exposure to emissions from indoor biomass combustion is a global health concern, causing an estimated 1.5 million premature deaths each year. Many 'improved' stoves have been developed to address this concern; however, studies that examine exposure-response with cleaner-burning, more efficient stoves are few. The objective of this research was to evaluate the effects of traditional and cleaner-burning stove emissions on an established model of the bronchial epithelium. We exposed well-differentiated, normal human bronchial epithelial cells to emissions from a single biomass combustion event using either a traditional three-stone fire or one of two energy-efficient stoves. Air-liquid interface cultures were exposed using a novel, aerosol-to-cell deposition system. Cellular expression of a panel of three pro-inflammatory markers was evaluated at 1 and 24 h following exposure. Cells exposed to emissions from the cleaner-burning stoves generated significantly fewer amounts of pro-inflammatory markers than cells exposed to emissions from a traditional three-stone fire. Particulate matter emissions from each cookstove were substantially different, with the three-stone fire producing the largest concentrations of particles (by both number and mass). This study supports emerging evidence that more efficient cookstoves have the potential to reduce respiratory inflammation in settings where solid fuel combustion is used to meet basic domestic needs. Emissions from more efficient, cleaner-burning cookstoves produced less inflammation in well-differentiated bronchial lung cells. The results support evidence that more efficient cookstoves can reduce the health burden associated with exposure to indoor pollution from the combustion of biomass. © 2012 John Wiley & Sons A/S.

  13. Macrophage elastase (MMP-12: a pro-inflammatory mediator?

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    Soazig Nénan

    2005-03-01

    Full Text Available As many metalloproteinases (MMPs, macrophage elastase (MMP-12 is able to degrade extracellular matrix components such as elastin and is involved in tissue remodeling processes. Studies using animal models of acute and chronic pulmonary inflammatory diseases, such as pulmonary fibrosis and chronic obstrutive pulmonary disease (COPD, have given evidences that MMP-12 is an important mediator of the pathogenesis of these diseases. However, as very few data regarding the direct involvement of MMP-12 in inflammatory process in the airways were available, we have instilled a recombinant form of human MMP-12 (rhMMP-12 in mouse airways. Hence, we have demonstrated that this instillation induced a severe inflammatory cell recruitment characterized by an early accumulation of neutrophils correlated with an increase in proinflammatory cytokines and in gelatinases and then by a relatively stable recruitment of macrophages in the lungs over a period of ten days. Another recent study suggests that resident alveolar macrophages and recruited neutrophils are not involved in the delayed macrophage recruitment. However, epithelial cells could be one of the main targets of rhMMP-12 in our model. We have also reported that a corticoid, dexamethasone, phosphodiesterase 4 inhibitor, rolipram and a non-selective MMP inhibitor, marimastat could reverse some of these inflammatory events. These data indicate that our rhMMP-12 model could mimic some of the inflammatory features observed in COPD patients and could be used for the pharmacological evaluation of new anti-inflammatory treatment. In this review, data demonstrating the involvement of MMP-12 in the pathogenesis of pulmonary fibrosis and COPD as well as our data showing a pro-inflammatory role for MMP-12 in mouse airways will be summarized.

  14. The influence of genetic variability and proinflammatory status on the development of bone disease in patients with Gaucher disease.

    Directory of Open Access Journals (Sweden)

    Javier Gervas-Arruga

    Full Text Available Gaucher disease, the most common lysosomal storage disorder, is caused by β-glucocerebrosidase deficiency. Bone complications are the major cause of morbidity in patients with type 1 Gaucher disease (GD1. Genetic components strongly influence bone remodelling. In addition, chronic inflammation produced by Gaucher cells induces the production of several cytokines, which leads to direct changes in the bone remodelling process and can also affect the process indirectly through other immune cells. In this study, we analysed the association between bone mineral density (BMD, bone marrow burden score, and relevant genetic polymorphisms related to bone metabolism, as well as profiles of proinflammatory cytokines in a GD1 cohort. This study included 83 patients distributed according to bone status. BMD was measured with DXA and broadband ultrasound attenuation; bone marrow involvement was evaluated using MRI. We also analysed 26 SNPs located in 14 genes related to bone metabolism. To assess proinflammatory status, we analysed IL-4, IL-6, IL-7, IL-10, IL-13, MIP-1α, MIP-1β, and TNFα in plasma samples from 71 control participants and GD1 patients. SNP genotype proportions and BMD differed significantly between ESRI c.453-397T>C and VDR c.1024+283G>A variants. We also observed significant associations between GD1 genotypes and bone affectation. When patients were stratified by spleen status, we observed significant correlations between non-/splenectomized groups and Spanish MRI (S-MRI score. Across genotype proportions of non-/splenectomized patients and S-MRI, we observed significant differences in ESRI c.453-397T>C, VDR c.-83-25988G>A, and TNFRSF11B c.9C>G polymorphisms. We observed different significant proinflammatory profiles between control participants, treatment-naïve patients, and patients on enzyme replacement therapy (ERT; between non-/splenectomized patients (between untreated and ERT-treated patients and among those with differing GBA

  15. Metabolic profiling and predicting the free radical scavenging activity of guava (Psidium guajava L.) leaves according to harvest time by 1H-nuclear magnetic resonance spectroscopy.

    Science.gov (United States)

    Kim, So-Hyun; Cho, Somi K; Hyun, Sun-Hee; Park, Hae-Eun; Kim, Young-Suk; Choi, Hyung-Kyoon

    2011-01-01

    Guava leaves were classified and the free radical scavenging activity (FRSA) evaluated according to different harvest times by using the (1)H-NMR-based metabolomic technique. A principal component analysis (PCA) of (1)H-NMR data from the guava leaves provided clear clusters according to the harvesting time. A partial least squares (PLS) analysis indicated a correlation between the metabolic profile and FRSA. FRSA levels of the guava leaves harvested during May and August were high, and those leaves contained higher amounts of 3-hydroxybutyric acid, acetic acid, glutamic acid, asparagine, citric acid, malonic acid, trans-aconitic acid, ascorbic acid, maleic acid, cis-aconitic acid, epicatechin, protocatechuic acid, and xanthine than the leaves harvested during October and December. Epicatechin and protocatechuic acid among those compounds seem to have enhanced FRSA of the guava leaf samples harvested in May and August. A PLS regression model was established to predict guava leaf FRSA at different harvesting times by using a (1)H-NMR data set. The predictability of the PLS model was then tested by internal and external validation. The results of this study indicate that (1)H-NMR-based metabolomic data could usefully characterize guava leaves according to their time of harvesting.

  16. Effects of the use of a flat wire electrode in gas metal arc welding and fuzzy logic model for the prediction of weldment shape profile

    Energy Technology Data Exchange (ETDEWEB)

    Karuthapandi, Sripriyan; Thyla, P. R. [PSG College of Technology, Coimbatore (India); Ramu, Murugan [Amrita University, Ettimadai (India)

    2017-05-15

    This paper describes the relationships between the macrostructural characteristics of weld beads and the welding parameters in Gas metal arc welding (GMAW) using a flat wire electrode. Bead-on-plate welds were produced with a flat wire electrode and different combinations of input parameters (i.e., welding current, welding speed, and flat wire electrode orientation). The macrostructural characteristics of the weld beads, namely, deposition, bead width, total bead width, reinforcement height, penetration depth, and depth of HAZ were investigated. A mapping technique was employed to measure these characteristics in various segments of the weldment zones. Results show that the use of a flat wire electrode improves the depth-to-width (D/W) ratio by 16.5 % on average compared with the D/W ratio when a regular electrode is used in GMAW. Furthermore, a fuzzy logic model was established to predict the effects of the use of a flat electrode on the weldment shape profile with varying input parameters. The predictions of the model were compared with the experimental results.

  17. A Metagenomic and in Silico Functional Prediction of Gut Microbiota Profiles May Concur in Discovering New Cystic Fibrosis Patient-Targeted Probiotics.

    Science.gov (United States)

    Vernocchi, Pamela; Del Chierico, Federica; Quagliariello, Andrea; Ercolini, Danilo; Lucidi, Vincenzina; Putignani, Lorenza

    2017-12-09

    Cystic fibrosis (CF) is a life-limiting hereditary disorder that results in aberrant mucosa in the lungs and digestive tract, chronic respiratory infections, chronic inflammation, and the need for repeated antibiotic treatments. Probiotics have been demonstrated to improve the quality of life of CF patients. We investigated the distribution of gut microbiota (GM) bacteria to identify new potential probiotics for CF patients on the basis of GM patterns. Fecal samples of 28 CF patients and 31 healthy controls (HC) were collected and analyzed by 16S rRNA-based pyrosequencing analysis of GM, to produce CF-HC paired maps of the distribution of operational taxonomic units (OTUs), and by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) for Kyoto Encyclopedia of Genes and Genomes (KEGG) biomarker prediction. The maps were scanned to highlight the distribution of bacteria commonly claimed as probiotics, such as bifidobacteria and lactobacilli, and of butyrate-producing colon bacteria, such as Eubacterium spp. and Faecalibacterium prausnitzii. The analyses highlighted 24 OTUs eligible as putative probiotics. Eleven and nine species were prevalently associated with the GM of CF and HC subjects, respectively. Their KEGG prediction provided differential CF and HC pathways, indeed associated with health-promoting biochemical activities in the latter case. GM profiling and KEGG biomarkers concurred in the evaluation of nine bacterial species as novel putative probiotics that could be investigated for the nutritional management of CF patients.

  18. A Metagenomic and in Silico Functional Prediction of Gut Microbiota Profiles May Concur in Discovering New Cystic Fibrosis Patient-Targeted Probiotics

    Directory of Open Access Journals (Sweden)

    Pamela Vernocchi

    2017-12-01

    Full Text Available Cystic fibrosis (CF is a life-limiting hereditary disorder that results in aberrant mucosa in the lungs and digestive tract, chronic respiratory infections, chronic inflammation, and the need for repeated antibiotic treatments. Probiotics have been demonstrated to improve the quality of life of CF patients. We investigated the distribution of gut microbiota (GM bacteria to identify new potential probiotics for CF patients on the basis of GM patterns. Fecal samples of 28 CF patients and 31 healthy controls (HC were collected and analyzed by 16S rRNA-based pyrosequencing analysis of GM, to produce CF-HC paired maps of the distribution of operational taxonomic units (OTUs, and by Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt for Kyoto Encyclopedia of Genes and Genomes (KEGG biomarker prediction. The maps were scanned to highlight the distribution of bacteria commonly claimed as probiotics, such as bifidobacteria and lactobacilli, and of butyrate-producing colon bacteria, such as Eubacterium spp. and Faecalibacterium prausnitzii. The analyses highlighted 24 OTUs eligible as putative probiotics. Eleven and nine species were prevalently associated with the GM of CF and HC subjects, respectively. Their KEGG prediction provided differential CF and HC pathways, indeed associated with health-promoting biochemical activities in the latter case. GM profiling and KEGG biomarkers concurred in the evaluation of nine bacterial species as novel putative probiotics that could be investigated for the nutritional management of CF patients.

  19. Accurate prediction of retention in hydrophilic interaction chromatography by back calculation of high pressure liquid chromatography gradient profiles.

    Science.gov (United States)

    Wang, Nu; Boswell, Paul G

    2017-10-20

    Gradient retention times are difficult to project from the underlying retention factor (k) vs. solvent composition (φ) relationships. A major reason for this difficulty is that gradients produced by HPLC pumps are imperfect - gradient delay, gradient dispersion, and solvent mis-proportioning are all difficult to account for in calculations. However, we recently showed that a gradient "back-calculation" methodology can measure these imperfections and take them into account. In RPLC, when the back-calculation methodology was used, error in projected gradient retention times is as low as could be expected based on repeatability in the k vs. φ relationships. HILIC, however, presents a new challenge: the selectivity of HILIC columns drift strongly over time. Retention is repeatable in short time, but selectivity frequently drifts over the course of weeks. In this study, we set out to understand if the issue of selectivity drift can be avoid by doing our experiments quickly, and if there any other factors that make it difficult to predict gradient retention times from isocratic k vs. φ relationships when gradient imperfections are taken into account with the back-calculation methodology. While in past reports, the accuracy of retention projections was >5%, the back-calculation methodology brought our error down to ∼1%. This result was 6-43 times more accurate than projections made using ideal gradients and 3-5 times more accurate than the same retention projections made using offset gradients (i.e., gradients that only took gradient delay into account). Still, the error remained higher in our HILIC projections than in RPLC. Based on the shape of the back-calculated gradients, we suspect the higher error is a result of prominent gradient distortion caused by strong, preferential water uptake from the mobile phase into the stationary phase during the gradient - a factor our model did not properly take into account. It appears that, at least with the stationary phase

  20. An assessment of predictive value of the biophysical profile in women with preeclampsia using data from the fullPIERS database.

    Science.gov (United States)

    Payne, Beth A; Kyle, Phillipa M; Lim, Kenneth; Lisonkova, Sarka; Magee, Laura A; Pullar, Barbra; Qu, Ziguang; von Dadelszen, Peter

    2013-07-01

    Pre-eclampsia is associated with increased risk to both the mother and fetus. Effective monitoring of the fetal condition is essential to the management of women with pre-eclampsia. The biophysical profile (BPP) is one monitoring tool available to clinicians. To compare the BPP test with cardiotocography/non-stress test (CTG/NST) alone for their ability to predict fetal acidemia at birth or a composite adverse perinatal outcome among women with preeclampsia and to estimate the effect of BPP assessment on mode of delivery and birth outcome. Secondary analysis of a prospective cohort of women with preeclampsia. The predictive ability of the tests was assessed based on sensitivity, specificity, positive and negative likelihood ratios (LR+, LR-). Women assessed with the BPP were compared with matched controls not assessed with the BPP to determine the odds of Cesarean delivery or adverse perinatal outcomes after adjustment for potential confounders. Five out of 89 women (5.6%) had an abnormal BPP; 18 out of 89 (20.2%) had an abnormal CTG/NST. Fetal acidemia was diagnosed in 13 fetuses (14.6%); composite adverse perinatal outcome in 68 fetuses/infants (76.4%). Both tests had relatively poor predictive performance for both outcomes (LR+ between 2.50 and 3.90 and LR- between 0.64 and 0.93). Assessment with the BPP was positively associated with fetal acidemia (adjusted OR 4.84; 95% CI 1.33-17.66). The BPP and CTG/NST alone were poor predictors of perinatal outcome in this cohort; multiple tests should be considered when assessing fetal risk in women with preeclampsia. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  1. Improvement of a predictive model in ovarian cancer patients submitted to platinum-based chemotherapy: implications of a GST activity profile.

    Science.gov (United States)

    Pereira, Deolinda; Assis, Joana; Gomes, Mónica; Nogueira, Augusto; Medeiros, Rui

    2016-05-01

    The success of chemotherapy in ovarian cancer (OC) is directly associated with the broad variability in platinum response, with implications in patients survival. This heterogeneous response might result from inter-individual variations in the platinum-detoxification pathway due to the expression of glutathione-S-transferase (GST) enzymes. We hypothesized that GSTM1 and GSTT1 polymorphisms might have an impact as prognostic and predictive determinants for OC. We conducted a hospital-based study in a cohort of OC patients submitted to platinum-based chemotherapy. GSTM1 and GSTT1 genotypes were determined by multiplex PCR. GSTM1-null genotype patients presented a significantly longer 5-year survival and an improved time to progression when compared with GSTM1-wt genotype patients (log-rank test, P = 0.001 and P = 0.013, respectively). Multivariate Cox regression analysis indicates that the inclusion of genetic information regarding GSTM1 polymorphism increased the predictive ability of risk of death after OC platinum-based chemotherapy (c-index from 0.712 to 0.833). Namely, residual disease (HR, 4.90; P = 0.016) and GSTM1-wt genotype emerged as more important predictors of risk of death (HR, 2.29; P = 0.039; P = 0.036 after bootstrap). No similar effect on survival was observed regarding GSTT1 polymorphism, and there were no statistically significant differences between GSTM1 and GSTT1 genotypes and the assessed patients' clinical-pathological characteristics. GSTM1 polymorphism seems to have an impact in OC prognosis as it predicts a better response to platinum-based chemotherapy and hence an improved survival. The characterization of the GSTM1 genetic profile might be a useful molecular tool and a putative genetic marker for OC clinical outcome.

  2. Better cognitive control of emotional information is associated with reduced pro-inflammatory cytokine reactivity to emotional stress.

    Science.gov (United States)

    Shields, Grant S; Kuchenbecker, Shari Young; Pressman, Sarah D; Sumida, Ken D; Slavich, George M

    2016-01-01

    Stress is strongly associated with several mental and physical health problems that involve inflammation, including asthma, cardiovascular disease, certain types of cancer, and depression. It has been hypothesized that better cognitive control of emotional information may lead to reduced inflammatory reactivity to stress and thus better health, but to date no studies have examined whether differences in cognitive control predict pro-inflammatory cytokine responses to stress. To address this issue, we conducted a laboratory-based experimental study in which we randomly assigned healthy young-adult females to either an acute emotional stress (emotionally evocative video) or no-stress (control video) condition. Salivary levels of the key pro-inflammatory cytokines IL-1β, IL-6, and IL-8 were measured before and after the experimental manipulation, and following the last cytokine sample, we assessed participants' cognitive control of emotional information using an emotional Stroop task. We also assessed participants' cortisol levels before and after the manipulation to verify that documented effects were specific to cytokines and not simply due to increased nonwater salivary output. As hypothesized, the emotional stressor triggered significant increases in IL-1β, IL-6, and IL-8. Moreover, even in fully adjusted models, better cognitive control following the emotional (but not control) video predicted less pronounced cytokine responses to that stressor. In contrast, no effects were observed for cortisol. These data thus indicate that better cognitive control specifically following an emotional stressor is uniquely associated with less pronounced pro-inflammatory cytokine reactivity to such stress. These findings may therefore help explain why superior cognitive control portends better health over the lifespan.

  3. A proposal of predictive methods of crack propagation life and remaining life of structural metal under creep-fatigue interacted conditions by use of X-ray profile analysis

    International Nuclear Information System (INIS)

    Ohnami, M.; Sakane, M.; Nishino, S.

    1987-01-01

    The following two series of studies are described: One is crack propagation life prediction in high-temperature low-cycle fatigue tests under triangular and trapezoidal strain or stress waves for austenitic stainless steel by X-ray fractography. Another is remaining life prediction of the steel under creep-fatigue interacted conditions by applying the concept of the remaining life diagram and X-ray profile analysis. Particle size and microstrain obtained by X-ray profile analysis were effective nondestructive parameters for estimating crack propagation life and remaining life in creep-fatigue interaction

  4. Suppression of Proinflammatory and Prosurvival Biomarkers in Oral Cancer Patients Consuming a Black Raspberry Phytochemical-Rich Troche.

    Science.gov (United States)

    Knobloch, Thomas J; Uhrig, Lana K; Pearl, Dennis K; Casto, Bruce C; Warner, Blake M; Clinton, Steven K; Sardo-Molmenti, Christine L; Ferguson, Jeanette M; Daly, Brett T; Riedl, Kenneth; Schwartz, Steven J; Vodovotz, Yael; Buchta, Anthony J; Schuller, David E; Ozer, Enver; Agrawal, Amit; Weghorst, Christopher M

    2016-02-01

    Black raspberries (BRB) demonstrate potent inhibition of aerodigestive tract carcinogenesis in animal models. However, translational clinical trials evaluating the ability of BRB phytochemicals to impact molecular biomarkers in the oral mucosa remain limited. The present phase 0 study addresses a fundamental question for oral cancer food-based prevention: Do BRB phytochemicals successfully reach the targeted oral tissues and reduce proinflammatory and antiapoptotic gene expression profiles? Patients with biopsy-confirmed oral squamous cell carcinomas (OSCC) administered oral troches containing freeze-dried BRB powder from the time of enrollment to the date of curative intent surgery (13.9 ± 1.27 days). Transcriptional biomarkers were evaluated in patient-matched OSCCs and noninvolved high at-risk mucosa (HARM) for BRB-associated changes. Significant expression differences between baseline OSCC and HARM tissues were confirmed using a panel of genes commonly deregulated during oral carcinogenesis. Following BRB troche administration, the expression of prosurvival genes (AURKA, BIRC5, EGFR) and proinflammatory genes (NFKB1, PTGS2) were significantly reduced. There were no BRB-associated grade 3-4 toxicities or adverse events, and 79.2% (N = 30) of patients successfully completed the study with high levels of compliance (97.2%). The BRB phytochemicals cyanidin-3-rutinoside and cyanidin-3-xylosylrutinoside were detected in all OSCC tissues analyzed, demonstrating that bioactive components were successfully reaching targeted OSCC tissues. We confirmed that hallmark antiapoptotic and proinflammatory molecular biomarkers were overexpressed in OSCCs and that their gene expression was significantly reduced following BRB troche administration. As these molecular biomarkers are fundamental to oral carcinogenesis and are modifiable, they may represent emerging biomarkers of molecular efficacy for BRB-mediated oral cancer chemoprevention. ©2015 American Association for Cancer

  5. Proinflammatory Cytokine Responses in Extra-Respiratory Tissues During Severe Influenza

    NARCIS (Netherlands)

    Short, Kirsty R; Veeris, Rebecca; Leijten, Lonneke M; van den Brand, Judith M; Jong, Victor L; Stittelaar, Koert J; Osterhaus, Ab D M E|info:eu-repo/dai/nl/074960172; Andeweg, Arno C; van Riel, Debby

    2017-01-01

    Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show

  6. Proinflammatory Cytokine Responses in Extra-Respiratory Tissues during Severe Influenza

    NARCIS (Netherlands)

    Short, Kirsty R.; Veeris, Rebecca; Leijten, Lonneke M.; van den Brand, Judith M A; Jong, Victor L.; Stittelaar, Koert; Osterhaus, Ab D.M.E.; Andeweg, Arno C; Van Riel, Debby

    2017-01-01

    Severe influenza is often associated with disease manifestations outside the respiratory tract. While proinflammatory cytokines can be detected in the lungs and blood of infected patients, the role of extra-respiratory organs in the production of proinflammatory cytokines is unknown. Here, we show

  7. Turbulence Dissipation Rates in the Planetary Boundary Layer from Wind Profiling Radars and Mesoscale Numerical Weather Prediction Models during WFIP2

    Science.gov (United States)

    Bianco, L.; McCaffrey, K.; Wilczak, J. M.; Olson, J. B.; Kenyon, J.

    2016-12-01

    When forecasting winds at a wind plant for energy production, the turbulence parameterizations in the forecast models are crucial for understanding wind plant performance. Recent research shows that the turbulence (eddy) dissipation rate in planetary boundary layer (PBL) parameterization schemes introduces significant uncertainty in the Weather Research and Forecasting (WRF) model. Thus, developing the capability to measure dissipation rates in the PBL will allow for identification of weaknesses in, and improvements to the parameterizations. During a preliminary field study at the Boulder Atmospheric Observatory in spring 2015, a 915-MHz wind profiling radar (WPR) measured dissipation rates concurrently with sonic anemometers mounted on a 300-meter tower. WPR set-up parameters (e.g., spectral resolution), post-processing techniques (e.g., filtering for non-atmospheric signals), and spectral averaging were optimized to capture the most accurate Doppler spectra for measuring spectral widths for use in the computation of the eddy dissipation rates. These encouraging results lead to the implementation of the observing strategy on a 915-MHz WPR in Wasco, OR, operating as part of the Wind Forecasting Improvement Project 2 (WFIP2). These observations are compared to dissipation rates calculated from the High-Resolution Rapid Refresh model, a WRF-based mesoscale numerical weather prediction model run for WFIP2 at 3000 m horizontal grid spacing and with a nest, which has 750-meter horizontal grid spacing, in the complex terrain region of the Columbia River Gorge. The observed profiles of dissipation rates are used to evaluate the PBL parameterization schemes used in the HRRR model, which are based on the modeled turbulent kinetic energy and a tunable length scale.

  8. Epithelial cell pro-inflammatory cytokine response differs across dental plaque bacterial species.

    Science.gov (United States)

    Stathopoulou, Panagiota G; Benakanakere, Manjunatha R; Galicia, Johnah C; Kinane, Denis F

    2010-01-01

    The dental plaque is comprised of numerous bacterial species, which may or may not be pathogenic. Human gingival epithelial cells (HGECs) respond to perturbation by various bacteria of the dental plaque by production of different levels of inflammatory cytokines, which is a putative reflection of their virulence. The aim of the current study was to determine responses in terms of interleukin (IL)-1beta, IL-6, IL-8 and IL-10 secretion induced by Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum and Streptococcus gordonii in order to gauge their virulence potential. HGECs were challenged with the four bacterial species, live or heat killed, at various multiplicity of infections and the elicited IL-1beta, IL-6, IL-8 and IL-10 responses were assayed by enzyme-linked immunosorbent assay. Primary HGECs challenged with live P. gingivalis produced high levels of IL-1beta, while challenge with live A. actinomycetemcomitans gave high levels of IL-8. The opportunistic pathogen F. nucleatum induces the highest levels of pro-inflammatory cytokines, while the commensal S. gordonii is the least stimulatory. We conclude that various dental plaque biofilm bacteria induce different cytokine response profiles in primary HGECs that may reflect their individual virulence or commensal status.

  9. Comparison of percentage body fat and body mass index for the prediction of inflammatory and atherogenic lipid risk profiles in elderly women

    Directory of Open Access Journals (Sweden)

    Funghetto SS

    2015-01-01

    Full Text Available Silvana Schwerz Funghetto,1 Alessandro de Oliveira Silva,2 Nuno Manuel Frade de Sousa,3 Marina Morato Stival,1 Ramires Alsamir Tibana,4 Leonardo Costa Pereira,1 Marja Letícia Chaves Antunes,1 Luciano Ramos de Lima,1 Jonato Prestes,4 Ricardo Jacó Oliveira,1 Maurílio Tiradentes Dutra,2 Vinícius Carolino Souza,1,4 Dahan da Cunha Nascimento,4 Margô Gomes de Oliveira Karnikowski1 1University of Brasília (UnB, Brasília, DF, Brazil; 2Center University of Brasilia (UNICEUB, Brasilia, DF, Brazil; 3Laboratory of Exercise Physiology, Faculty Estácio de Sá of Vitória, ES, Brazil; 4Catholic University of Brasília, Brasília, DF, Brazil Objective: To compare the clinical classification of the body mass index (BMI and percentage body fat (PBF for the prediction of inflammatory and atherogenic lipid profile risk in older women.Method: Cross-sectional analytical study with 277 elderly women from a local community in the Federal District, Brazil. PBF and fat-free mass (FFM were determined by dual energy X-ray absorptiometry. The investigated inflammatory parameters were interleukin 6 and C-reactive protein.Results: Twenty-five percent of the elderly women were classified as normal weight, 50% overweight, and 25% obese by the BMI. The obese group had higher levels of triglycerides and very low-density lipoproteins than did the normal weight group (P≤0.05 and lower levels of high-density lipoproteins (HDL than did the overweight group (P≤0.05. According to the PBF, 49% of the elderly women were classified as eutrophic, 28% overweight, and 23% obese. In the binomial logistic regression analyses including age, FFM, and lipid profile, only FFM (odds ratio [OR]=0.809, 95% confidence interval [CI]: 0.739–0.886; P<0.0005 proved to be a predictor of reaching the eutrophic state by the BMI. When the cutoff points of PBF were used for the classification, FFM (OR=0.903, CI=0.884–0.965; P=0.003 and the total cholesterol/HDL ratio (OR=0.113, CI=0.023–0

  10. Improved Metabolic Control in Diabetes, HSP60, and Proinflammatory Mediators

    Directory of Open Access Journals (Sweden)

    Claudio Blasi

    2012-01-01

    Full Text Available The diabetes-atherosclerosis relationship remains to be fully defined. Repeated prolonged hyperglycemia, increased ROS production and endothelial dysfunction are important factors. One theory is that increased blood levels of heat shock protein (HSP60 are proinflammatory, through activation of innate immunity, and contribute to the progression of vascular disease. It was hypothesized that improvement of diabetes control in patients presenting with metabolic syndrome would lower HSP60, and anti-HSP60 antibody levels and decrease inflammatory markers. Paired sera of 17 Italian patients, before and after intensive treatment, were assayed for cytokines, HSP60 and anti-HSP60 antibodies. As expected, intensive treatment was associated with a decrease in HgbA1C (P<0.001 and BMI (P<0.001. After treatment, there was a significant decrease in IL-6 (P<0.05. HSP60 levels were before treatment −6.9+1.9, after treatment −7.1+2.0 ng/mL (P=ns. Overall HSP60 concentrations were lower than published reports. Anti-HSP60 antibody titers were high and did not decrease with treatment. In conclusion, improvement of diabetic control did not alter HSP60 concentrations or antiHSP60 antibody titers, but led to a reduction of IL-6 levels.

  11. The Staphyloccous aureus Eap protein activates expression of proinflammatory cytokines.

    Science.gov (United States)

    Scriba, Thomas J; Sierro, Sophie; Brown, Eric L; Phillips, Rodney E; Sewell, Andrew K; Massey, Ruth C

    2008-05-01

    The extracellular adhesion protein (Eap) secreted by the major human pathogen Staphylococcus aureus is known to have several effects on human immunity. We have recently added to knowledge of these roles by demonstrating that Eap enhances interactions between major histocompatibility complex molecules and human leukocytes. Several studies have indicated that Eap can induce cytokine production by human peripheral blood mononuclear cells (PBMCs). To date, there has been no rigorous attempt to identify the breadth of cytokines produced by Eap stimulation or to identify the cell subsets that respond. Here, we demonstrate that Eap induces the secretion of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) by CD14(+) leukocytes (monocytes and macrophages) within direct ex vivo PBMC populations (note that granulocytes are also CD14(+) but are largely depleted from PBMC preparations). Anti-intercellular adhesion molecule 1 (CD54) antibodies inhibited this induction and implicated a role for this known Eap binding protein in cellular activation. IL-6 and TNF-alpha secretion by murine cells exposed to Eap was also observed. The activation of CD14(+) cells by Eap suggests that it could play a significant role in both septic shock and fever, two of the major pathological features of S. aureus infections.

  12. Immunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase.

    Science.gov (United States)

    Honjo, Kie; Hiraki, Tsubasa; Higashi, Michiyo; Noguchi, Hirotsugu; Nomoto, Mitsuharu; Yoshimura, Takuya; Batra, Surinder K; Yonezawa, Suguru; Semba, Ichiro; Nakamura, Norifumi; Tanimoto, Akihide; Yamada, Sohsuke

    2018-02-01

    In mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6-negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.

  13. Rapid profiling of polymeric phenolic acids in Salvia miltiorrhiza by hybrid data-dependent/targeted multistage mass spectrometry acquisition based on expected compounds prediction and fragment ion searching.

    Science.gov (United States)

    Shen, Yao; Feng, Zijin; Yang, Min; Zhou, Zhe; Han, Sumei; Hou, Jinjun; Li, Zhenwei; Wu, Wanying; Guo, De-An

    2018-04-01

    Phenolic acids are the major water-soluble components in Salvia miltiorrhiza (>5%). According to previous studies, many of them contribute to the cardiovascular effects and antioxidant effects of S. miltiorrhiza. Polymeric phenolic acids can be considered as the tanshinol derived metabolites, e.g., dimmers, trimers, and tetramers. A strategy combined with tanshinol-based expected compounds prediction, total ion chromatogram filtering, fragment ion searching, and parent list-based multistage mass spectrometry acquisition by linear trap quadropole-orbitrap Velos mass spectrometry was proposed to rapid profile polymeric phenolic acids in S. miltiorrhiza. More than 480 potential polymeric phenolic acids could be screened out by this strategy. Based on the fragment information obtained by parent list-activated data dependent multistage mass spectrometry acquisition, 190 polymeric phenolic acids were characterized by comparing their mass information with literature data, and 18 of them were firstly detected from S. miltiorrhiza. Seven potential compounds were tentatively characterized as new polymeric phenolic acids from S. miltiorrhiza. This strategy facilitates identification of polymeric phenolic acids in complex matrix with both selectivity and sensitivity, which could be expanded for rapid discovery and identification of compounds from complex matrix. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Fourier transform infrared spectroscopy for the prediction of fatty acid profiles in Mucor fungi grown in media with different carbon sources.

    Science.gov (United States)

    Shapaval, Volha; Afseth, Nils Kristian; Vogt, Gjermund; Kohler, Achim

    2014-09-11

    Fungal production of polyunsaturated fatty acids (PUFAs) is a highly potential approach in biotechnology. Currently the main focus is directed towards screening of hundreds strains in order to select of few potential ones. Thus, a reliable method for screening a high number of strains within a short period of time is needed. Here, we present a novel method for screening of PUFA-producing fungi by high-throughput microcultivation and FTIR spectroscopy. In the study selected Mucor fungi were grown in media with different carbon sources and fatty acid profiles were predicted on the basis of the obtained spectral data. FTIR spectra were calibrated against fatty acid analysis by GC-FD. The calibration models were cross-validated and correlation coefficients (R2) from 0.71 to 0.78 with RMSECV (root mean squared error) from 2.86% to 6.96% (percentage of total fat) were obtained. The FTIR results show a strong correlation to the results obtained by GC analysis, where high total contents of unsaturated fatty acids (both PUFA and MUFA) were achieved for Mucor plumbeus VI02019 cultivated in canola, olive and sunflower oil and Mucor hiemalis VI01993 cultivated in canola and olive oil.

  15. [The value of fasting plasma glucose and lipid profiles between 7 and 15 gestational weeks in the prediction of gestational diabetes mellitus].

    Science.gov (United States)

    Zhao, M; Li, G H

    2016-11-25

    Objective: To explore the value of using fasting plasma glucose (FPG) and lipid profiles between 7 and 15 gestational weeks to predict gestational diabetes mellitus (GDM). Methods: The medical records of 2 138 pregnant women who had prenatal care in Beijing Obstetrics and Gynecology Hospital from August 2011 to February 2012 were analyzed retrospectively. According to results of the oral glucose tolerance tests, women were devided into the GDM group ( n =240) and the normal group ( n= 1 898). Maternal characteristics, FPG and lipid levels between 7 and 15 gestational weeks were compared between the two groups. Logistic regression analysis and receiver operator characteristics(ROC) curve were used in the analysis. Results: Potential markers for the prediction of GDM included total cholesterol, triglyceride (TG) , low-density lipoprotein cholesterol/high-density lipoprotein cholesterol ratios (LDL-C/HDL-C) , triglyceride to high-density lipoprotein cholesterol ratios (TG/HDL-C) and FPG. After adjustment of confounding factors, age ( OR= 1.046, 95% CI: 1.003-1.090), pre- pregnancy body mass index ( OR= 1.104, 95% CI: 1.049-1.161), gravidity>3 ( OR= 1.768, 95% CI: 1.071-2.920), FPG ( OR= 8.137, 95% CI: 5.412-12.236), TG ( OR= 1.460, 95% CI: 1.148-1.858) were independently associated with the risk of developing GDM. Equation, P GDM =1/{1+exp[-(-16.542+0.045×age+0.103×pre-pregnancy body mass index+0.551×gravidity>3+2.110×FPG+0.372×TG)]}, was constructed by the logistic regression analysis. Sensitivity (67.5%) and specificity (70.5%) were determined by the calculated risk score, with a cut-off value of 0.11 (area under the curve: 0.751, 95% CI: 0.718-0.783, P< 0.001). Conclusions: FPG and TG, together with clinical characteristics may have a better predictive value for the risk of GDM.

  16. The association between maternal cervicovaginal proinflammatory cytokines concentrations during pregnancy and subsequent early-onset neonatal infection.

    Science.gov (United States)

    Kalinka, Jarosław; Krajewski, Paweł; Sobala, Wojciech; Wasiela, Małgorzata; Brzezińska-Błaszczyk, Ewa

    2006-01-01

    The aim of this study was to investigate the relationship between the concentration of selected proinflammatory cytokines (IL-1alpha, IL-1beta, IL-6 and IL-8) in cervicovaginal fluid, as measured in midgestation, and the risk of early-onset neonatal infection (EONI). Cervicovaginal fluids were obtained from a cohort of 114 pregnant women at 22 to 34 weeks' gestation. The samples were analyzed for the concentrations of selected proinflammatory cytokines using standard enzyme-linked immunosorbent assay technique (ELISA). Lower genital tract microbiology was diagnosed using Gram stain method according to Spiegel's criteria and by culture. Mean gestational age at the time of sampling was 29.0 weeks. Mean time between sampling and delivery was 9.3 (SD 4.7) weeks. Bacterial vaginosis (BV) was diagnosed in 27.2% of subjects and M. hominis and U. urealyticum in 22.8% and 26.3%, respectively. Out of 114 women examined, 20 (17.5%) delivered newborns with EONI. Median cervicovaginal concentrations of IL-1alpha, IL-1beta, IL-6 and IL-8 did not differ between women who delivered newborns with EONI as compared to women who delivered newborns without EONI. Women with pathological lower genital tract microflora and low IL-8 concentration (below 25(th) percentile) during pregnancy presented a significant risk of delivering newborns with EONI (OR=4.9; 95% CI, 1.1-22.8). Subjects with pathological lower genital tract microflora and a low concentration of more than one cytokine had the highest risk of delivering a newborn with EONI, OR=16.2, 95% CI, 1.1-234.0. Cytokine measurement in cervicovaginal fluid in early gestation could be useful for predicting subsequent EONI only among pregnant women with lower genital tract infection. Maternal genital tract immune hyporesponsiveness as represented by low concentrations of proinflammatory cytokines may create a permissive environment for ascending infection and may lead to subsequent EONI.

  17. Proinflammatory Cytokines, Enolase and S-100 as Early Biochemical Indicators of Hypoxic-Ischemic Encephalopathy Following Perinatal Asphyxia in Newborns.

    Science.gov (United States)

    Chaparro-Huerta, Verónica; Flores-Soto, Mario Eduardo; Merin Sigala, Mario Ernesto; Barrera de León, Juan Carlos; Lemus-Varela, María de Lourdes; Torres-Mendoza, Blanca Miriam de Guadalupe; Beas-Zárate, Carlos

    2017-02-01

    Estimation of the neurological prognosis of infants suffering from perinatal asphyxia and signs of hypoxic-ischemic encephalopathy is of great clinical importance; however, it remains difficult to satisfactorily assess these signs with current standard medical practices. Prognoses are typically based on data obtained from clinical examinations and neurological tests, such as electroencephalography (EEG) and neuroimaging, but their sensitivities and specificities are far from optimal, and they do not always reliably predict future neurological sequelae. In an attempt to improve prognostic estimates, neurological research envisaged various biochemical markers detectable in the umbilical cord blood of newborns (NB). Few studies examining these biochemical factors in the whole blood of newborns exist. Thus, the aim of this study was to determine the expression and concentrations of proinflammatory cytokines (TNF-α, IL-1β and IL-6) and specific CNS enzymes (S-100 and enolase) in infants with perinatal asphyxia. These data were compared between the affected infants and controls and were related to the degree of HIE to determine their utilities as biochemical markers for early diagnosis and prognosis. The levels of the proinflammatory cytokines and enzymes were measured by enzyme-linked immunosorbent assay (ELISA) and Reverse Transcription polymerase chain reaction (RT-PCR). The expression and serum levels of the proinflammatory cytokines, enolase and S-100 were significantly increased in the children with asphyxia compared with the controls. The role of cytokines after hypoxic-ischemic insult has been determined in studies of transgenic mice that support the use of these molecules as candidate biomarkers. Similarly, S-100 and enolase are considered promising candidates because these markers have been correlated with tissue damage in different experimental models. Copyright © 2016. Published by Elsevier B.V.

  18. Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia.

    Science.gov (United States)

    Mishra, Pooja-Shree; Vijayalakshmi, K; Nalini, A; Sathyaprabha, T N; Kramer, B W; Alladi, Phalguni Anand; Raju, T R

    2017-12-16

    Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated. We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures. We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells. Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory

  19. Development and validation of a gene profile predicting benefit of postmastectomy radiotherapy in patients with high-risk breast cancer: a study of gene expression in the DBCG82bc cohort.

    Science.gov (United States)

    Tramm, Trine; Mohammed, Hayat; Myhre, Simen; Kyndi, Marianne; Alsner, Jan; Børresen-Dale, Anne-Lise; Sørlie, Therese; Frigessi, Arnoldo; Overgaard, Jens

    2014-10-15

    To identify genes predicting benefit of radiotherapy in patients with high-risk breast cancer treated with systemic therapy and randomized to receive or not receive postmastectomy radiotherapy (PMRT). The study was based on the Danish Breast Cancer Cooperative Group (DBCG82bc) cohort. Gene-expression analysis was performed in a training set of frozen tumor tissue from 191 patients. Genes were identified through the Lasso method with the endpoint being locoregional recurrence (LRR). A weighted gene-expression index (DBCG-RT profile) was calculated and transferred to quantitative real-time PCR (qRT-PCR) in corresponding formalin-fixed, paraffin-embedded (FFPE) samples, before validation in FFPE from 112 additional patients. Seven genes were identified, and the derived DBCG-RT profile divided the 191 patients into "high LRR risk" and "low LRR risk" groups. PMRT significantly reduced risk of LRR in "high LRR risk" patients, whereas "low LRR risk" patients showed no additional reduction in LRR rate. Technical transfer of the DBCG-RT profile to FFPE/qRT-PCR was successful, and the predictive impact was successfully validated in another 112 patients. A DBCG-RT gene profile was identified and validated, identifying patients with very low risk of LRR and no benefit from PMRT. The profile may provide a method to individualize treatment with PMRT. ©2014 American Association for Cancer Research.

  20. A comparative analysis of cardiovascular disease risk profiles of five Pacific ethnic groups assessed in New Zealand primary care practice: PREDICT CVD-13.

    Science.gov (United States)

    Grey, Corina; Wells, Sue; Riddell, Tania; Pylypchuk, Romana; Marshall, Roger; Drury, Paul; Elley, Raina; Ameratunga, Shanthi; Gentles, Dudley; Erick-Peletiy, Stephanie; Bell, Fionna; Kerr, Andrew; Jackson, Rod

    2010-11-05

    Data on the cardiovascular disease risk profiles of Pacific peoples in New Zealand is usually aggregated and treated as a single entity. Little is known about the comparability or otherwise of cardiovascular disease (CVD) risk between different Pacific groups. To compare CVD risk profiles for the main Pacific ethnic groups assessed in New Zealand primary care practice to determine if it is reasonable to aggregate these data, or if significant differences exist. A web-based clinical decision support system for CVD risk assessment and management (PREDICT) has been implemented in primary care practices in nine PHOs throughout Auckland and Northland since 2002, covering approximately 65% of the population of these regions. Between 2002 and January 2009, baseline CVD risk assessments were carried out on 11,642 patients aged 35-74 years identifying with one or more Pacific ethnic groups (4933 Samoans, 1724 Tongans, 1366 Cook Island Maori, 880 Niueans, 1341 Fijians and 1398 people identified as Other Pacific or Pacific Not Further Defined). Fijians were subsequently excluded from the analyses because of a probable misclassification error that appears to combine Fijian Indians with ethnic Fijians. Prevalences of smoking, diabetes and prior history of CVD, as well as mean total cholesterol/HDL ratio, systolic and diastolic blood pressures, and Framingham 5-year CVD risk were calculated for each Pacific group. Age-adjusted risk ratios and mean differences stratified by gender were calculated using Samoans as the reference group. Cook Island women were almost 60% more likely to smoke than Samoan women. While Tongan men had the highest proportion of smoking (29%) among Pacific men, Tongan women had the lowest smoking proportion (10%) among Pacific women. Tongan women and Niuean men and women had a higher burden of diabetes than other Pacific ethnic groups, which were 20-30% higher than their Samoan counterparts. Niuean men and women had lower blood pressure levels than all

  1. Pro-inflammatory cytokines derived from West Nile virus (WNV-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death

    Directory of Open Access Journals (Sweden)

    Nerurkar Vivek R

    2010-10-01

    Full Text Available Abstract Background WNV-associated encephalitis (WNVE is characterized by increased production of pro-inflammatory mediators, glial cells activation and eventual loss of neurons. WNV infection of neurons is rapidly progressive and destructive whereas infection of non-neuronal brain cells is limited. However, the role of neurons and pathological consequences of pro-inflammatory cytokines released as a result of WNV infection is unclear. Therefore, the objective of this study was to examine the role of key cytokines secreted by WNV-infected neurons in mediating neuroinflammatory markers and neuronal death. Methods A transformed human neuroblastoma cell line, SK-N-SH, was infected with WNV at multiplicity of infection (MOI-1 and -5, and WNV replication kinetics and expression profile of key pro-inflammatory cytokines were analyzed by plaque assay, qRT-PCR, and ELISA. Cell death was measured in SK-N-SH cell line in the presence and absence of neutralizing antibodies against key pro-inflammatory cytokines using cell viability assay, TUNEL and flow cytometry. Further, naïve primary astrocytes were treated with UV-inactivated supernatant from mock- and WNV-infected SK-N-SH cell line and the activation of astrocytes was measured using flow cytometry and ELISA. Results WNV-infected SK-N-SH cells induced the expression of IL-1β, -6, -8, and TNF-α in a dose- and time-dependent manner, which coincided with increase in virus-induced cell death. Treatment of cells with anti-IL-1β or -TNF-α resulted in significant reduction of the neurotoxic effects of WNV. Furthermore treatment of naïve astrocytes with UV-inactivated supernatant from WNV-infected SK-N-SH cell line increased expression of glial fibrillary acidic protein and key inflammatory cytokines. Conclusion Our results for the first time suggest that neurons are one of the potential sources of pro-inflammatory cytokines in WNV-infected brain and these neuron-derived cytokines contribute to WNV

  2. Expression profiles analysis of long non-coding RNAs identified novel lncRNA biomarkers with predictive value in outcome of cutaneous melanoma.

    Science.gov (United States)

    Ma, Xu; He, Zhijuan; Li, Ling; Yang, Daping; Liu, Guofeng

    2017-09-29

    Recent advancements in cancer biology have identified a large number of lncRNAs that are dysregulated expression in the development and tumorigenesis of cancers, highlighting the importance of lncRNAs as a key player for human cancers. However, the prognostic value of lncRNAs still remains unclear and needs to be further investigated. In the present study, we aim to assess the prognostic value of lncRNAs in cutaneous melanoma by integrated lncRNA expression profiles from TCGA database and matched clinical information from a large cohort of patients with cutaneous melanoma. We finally identified a set of six lncRNAs that are significantly associated with survival of patients with cutaneous melanoma. A linear combination of six lncRNAs ( LINC01260, HCP5, PIGBOS1, RP11-247L20.4, CTA-292E10.6 and CTB-113P19.5 ) was constructed as a six-lncRNA signature which classified patients of training cohort into the high-risk group and low-risk group with significantly different survival time. The prognostic value of the six-lncRNA signature was validated in both the validation cohort and entire TCGA cohort. Moreover, the six-lncRNA signature is independent of known clinic-pathological factors by multivariate Cox regression analysis and demonstrated good performance for predicting three- and five-year overall survival by time-dependent receiver operating characteristic (ROC) analysis. Our study provides novel insights into the molecular heterogeneity of cutaneous melanoma and also shows potentially important implications of lncRNAs for prognosis and therapy for cutaneous melanoma.

  3. A pro-inflammatory effect of foot and mouth disease vírus on immune and non immune guinea pigs

    Directory of Open Access Journals (Sweden)

    Helio José Montassier

    1992-12-01

    Full Text Available The O1Campos strain of foot and mouth disease virus (FMDV used as inducing agent in the pleurisy model was able to trigger a pro-inflammatory effect on normal and immune guinea pigs. The proinflammatory activity which was detected at two times of the pleurisy (24 and 48 hours on normal guinea pigs was characterized only by mononuclear (MN cell influx, during the first interval of the reaction and by edematogenic effect, MN and polimorphonuclcar (PMN leucocyte migration, at the last time of the reaction. The inflammatory reaction profiles recorded on immune guinea pigs (vaccinated with anti-O1Campos oil adjuvanted vaccine, both after 7 and 30 days post vaccination (pv have showed, in both interval, lower intensities than that observed in normal guinea pigs, although in the 7 days PV guinea pigs the accumulations of total leucocytes and PMN were similar to that displayed by normal animals, after 48 hours of the reaction. Besides, on thirty days PV guinea pigs the FMDV induced a significant increase in volume of exudate and MN cell infiltration, after 24 hours, and all of the inflammatory parameters values dropped to normal levels, during the second interval of the reaction. It was found a negative association between the increase in serum neutralizing antibody titer, from 7 to 30 days PV and the intensities of pleural inflammatory parameters on the immune guinea pigs. The pleurisy test revealed itself feasible to evaluate the pro-inflammatory activity of FMDV.

  4. Iodinated contrast media alter immune responses in pro-inflammatory states.

    LENUS (Irish Health Repository)

    O'Donnell, David H

    2010-07-01

    Hypertonic saline causes a transient elevation of blood osmolality and has been shown to alter cellular inflammatory responses in pro-inflammatory states. Intravascular administration of iodine contrast media also causes a transient elevation of blood osmolarity.

  5. Pro-inflammatory cytokine single nucleotide polymorphisms in Kawasaki disease.

    Science.gov (United States)

    Assari, Raheleh; Aghighi, Yahya; Ziaee, Vahid; Sadr, Maryam; Rahmani, Farzaneh; Rezaei, Arezou; Sadr, Zeinab; Moradinejad, Mohammad Hassan; Raeeskarami, Seyed Reza; Rezaei, Nima

    2016-07-25

    Kawasaki disease (KD) is a systemic vasculitis of children associated with cardiovascular sequelae. Proinflammatory cytokines play a major role in KD pathogenesis. However, their role is both influenced and modified by regulatory T-cells. IL-1 gene cluster, IL-6 and TNF-α polymorphisms have shown significant associations with some vasculitides. Herein we investigated their role in KD. Fifty-five patients with KD who were randomly selected from referrals to the main pediatric hospital were enrolled in this case-control study. Single nucleotide polymorphisms (SNPs) of the following genes were assessed in patients and 140 healthy subjects as control group: IL-1α at -889 (rs1800587), IL-1β at -511 (rs16944), IL-1β at +3962 (rs1143634), IL-1R at Pst-I 1970 (rs2234650), IL-1RN/A at Mspa-I 11100 (rs315952), TNF-α at -308 (rs1800629), TNF-α at -238, IL-6 at -174 (rs1800795) and IL-6 at +565. Twenty-one percent of the control group had A allele at TNF-α -238 while only 8% of KD patients had A allele at this position (P = 0.003, OR [95%CI] = 0.32 [0.14-0.71]). Consistently, TNF-α genotype GG at -238 had significant association with KD (OR [95% CI] = 4.31 [1.79-10.73]). Most controls carried the CG genotype at IL-6 -174 (n = 93 [66.9%]) while GG genotype was the most common genotype (n = 27 [49%]) among patients. Carriers of the GG haplotype at TNF-α (-308, -238) were significantly more prevalent among the KD group. No association was found between IL-1 gene cluster, allelic or haplotypic variants and KD. TNF-α GG genotype at -238 and GG haplotype at positions -308 and -238 were associated with KD in an Iranian population. © 2016 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.

  6. Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

    OpenAIRE

    Hye Joo Kim; Seong Hwan Kim; Jung-Mi Yun

    2012-01-01

    Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria), and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-?B signaling pathway. In this...

  7. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index

    OpenAIRE

    Hernandez, Maria E; Becerril, Enrique; Perez, Mayra; Leff, Philippe; Anton, Benito; Estrada, Sergio; Estrada, Iris; Sarasa, Manuel; Serrano, Enrique; Pavon, Lenin

    2010-01-01

    Abstract Background Fibromyalgia (FM) is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6) may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure ...

  8. Progression of symptomatic intracranial large artery atherosclerosis is associated with a proinflammatory state and impaired fibrinolysis.

    Science.gov (United States)

    Arenillas, Juan F; Alvarez-Sabín, José; Molina, Carlos A; Chacón, Pilar; Fernández-Cadenas, Israel; Ribó, Marc; Delgado, Pilar; Rubiera, Marta; Penalba, Anna; Rovira, Alex; Montaner, Joan

    2008-05-01

    The molecular pathways involved in the progression of intracranial large artery atherosclerosis (ILA) are largely unknown. Our objective was to prospectively study the relationship between circulating levels of inflammatory markers and fibrinolysis inhibitors, and the risk of progression of symptomatic ILA. Seventy-five consecutive patients with first-ever symptomatic intracranial atherostenosis were studied. Blood levels of C-reactive protein (CRP), E-selectin, monocyte chemoattractant protein-1, intercellular adhesion molecule-1, matrix metalloproteinases 1, 2, 3, 8, 9, 10, and 13, plasminogen activator inhibitor-1 (PAI-1), and lipoprotein(a) were measured 3 months after the qualifying stroke or transient ischemic attack. Thereafter, patients underwent long-term transcranial Doppler follow-up to detect progression of ILA. During a median follow-up time of 23 months, 25 (33%) patients showed ILA progression. Multivariable adjusted Cox regression models and Kaplan-Meier curves showed that high baseline level of CRP, E-selectin, intercellular adhesion molecule-1, matrix metalloproteinase 9, PAI-1, and lipoprotein(a) predicted ILA progression independently of vascular risk factors. Of them, only CRP (CRP>5.5 mg/L; HR, 5.4 [2.3 to 12.7]; P=0.0001) and PAI-1 (PAI-1>23.1 ng/mL; HR, 2.4 [1.0 to 5.8]; P=0.05) predicted ILA progression also independently of the other studied molecules. Progression of symptomatic ILA is associated with a proinflammatory state, as reflected by high levels of inflammatory markers, and with defective fibrinolysis, as indicated by raised concentrations of endogenous fibrinolysis inhibitors.

  9. HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats.

    Directory of Open Access Journals (Sweden)

    Osiris Marroquin Belaunzaran

    Full Text Available HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA. HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272 and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS patients and HLA-B27 transgenic rats. We characterized a novel B272-specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders.The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry.HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM. HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules.HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders.

  10. HLA-B27-Homodimer-Specific Antibody Modulates the Expansion of Pro-Inflammatory T-Cells in HLA-B27 Transgenic Rats

    Science.gov (United States)

    Marroquin Belaunzaran, Osiris; Kleber, Sascha; Schauer, Stefan; Hausmann, Martin; Nicholls, Flora; Van den Broek, Maries; Payeli, Sravan; Ciurea, Adrian; Milling, Simon; Stenner, Frank; Shaw, Jackie; Kollnberger, Simon; Bowness, Paul; Petrausch, Ulf; Renner, Christoph

    2015-01-01

    Objectives HLA-B27 is a common genetic risk factor for the development of Spondyloarthritides (SpA). HLA-B27 can misfold to form cell-surface heavy chain homodimers (B272) and induce pro-inflammatory responses that may lead to SpA pathogenesis. The presence of B272 can be detected on leukocytes of HLA-B27+ Ankylosing spondylitis (AS) patients and HLA-B27 transgenic rats. We characterized a novel B272–specific monoclonal antibody to study its therapeutic use in HLA-B27 associated disorders. Methods The monoclonal HD5 antibody was selected from a phage library to target cell-surface B272 homodimers and characterized for affinity, specificity and ligand binding. The immune modulating effect of HD5 was tested in HLA-B27 transgenic rats. Onset and progression of disease profiles were monitored during therapy. Cell-surface B272 and expansion of pro-inflammatory cells from blood, spleen and draining lymph nodes were assessed by flow cytometry. Results HD5 bound B272 with high specificity and affinity (Kd = 0.32 nM). HD5 blocked cell-surface interaction of B272 with immune regulatory receptors KIR3DL2, LILRB2 and Pirb. In addition, HD5 modulated the production of TNF from CD4+ T-cells by limiting B272 interactions in vitro. In an HLA-B27 transgenic rat model repetitive dosing of HD5 reduced the expansion of pro-inflammatory CD4+ T-cells, and decreased the levels of soluble TNF and number of cell-surface B272 molecules. Conclusion HD5 predominantly inhibits early TNF production and expansion of pro-inflammatory CD4+ T-cells in HLA-B27 transgenic rats. Monoclonal antibodies targeting cell-surface B272 propose a new concept for the modulation of inflammatory responses in HLA-B27 related disorders. PMID:26125554

  11. PhosphoLipid transfer protein (PLTP) exerts a direct pro-inflammatory effect on rheumatoid arthritis (RA) fibroblasts-like-synoviocytes (FLS) independently of its lipid transfer activity

    Science.gov (United States)

    Deckert, Valérie; Daien, Claire I.; Che, Hélène; Elhmioui, Jamila; Lemaire, Stéphanie; Pais de Barros, Jean-Paul; Desrumaux, Catherine; Combe, Bernard; Hahne, Michael; Lagrost, Laurent; Morel, Jacques

    2018-01-01

    Rheumatoid arthritis (RA) is a chronic inflammatory rheumatic disease with modification of lipids profile and an increased risk of cardiovascular events related to inflammation. Plasma phospholipid transfer protein (PLTP) exerts a lipid transfer activity through its active form. PLTP can also bind to receptors such as ATP-binding cassette transporter A1 (ABCA1). In addition to its role in lipoprotein metabolism and atherosclerosis, the latest advances came in support of a complex role of PLTP in the regulation of the inflammatory response, both with pro-inflammatory or anti-inflammatory properties. The aim of the present study was to decipher the role of PLTP in joint inflammation and to assess its relevance in the context of RA. PLTP expression was examined by western-blot and by immunochemistry. ABCA1 expression was analyzed by flow cytometry. Lipid transfer activity of PLTP and pro-inflammatory cytokines were measured in sera and synovial fluid (SF) from RA patients and controls (healthy subjects or osteoarthritis patients [OA]). FLS were treated with both lipid-transfer active form and inactive form of recombinant human PLTP. IL-8, IL-6, VEGF and MMP3 produced by FLS were assessed by ELISA, and proliferation by measuring 3H-Thymidine incorporation. RA synovial tissues showed higher PLTP staining than OA and PLTP protein levels were also significantly higher in RA-FLS. In addition, RA, unlike OA patients, displayed elevated levels of PLTP activity in SF, which correlated with pro-inflammatory cytokines. Both lipid-transfer active and inactive forms of PLTP significantly increased the production of cytokines and proliferation of FLS. ABCA1 was expressed on RAFLS and PLTP activated STAT3 pathway. To conclude, PLTP is highly expressed in the joints of RA patients and may directly trigger inflammation and FLS proliferation, independently of its lipid transfer activity. These results suggest a pro-inflammatory role for PLTP in RA. PMID:29565987

  12. Osteoarthritis and rheumatoid arthritis pannus have similar qualitative metabolic characteristics and pro-inflammatory cytokine response.

    Science.gov (United States)

    Furuzawa-Carballeda, J; Macip-Rodríguez, P M; Cabral, A R

    2008-01-01

    Pannus in osteoarthritis (OA) has only recently been characterized. Little is known, however, regarding the behavior of OA pannus in vitro compared to rheumatoid arthritis (RA) pannus. The purpose of our study was to compare OA with RA pannus. Pannus and synovial tissue co-cultures from 5 patients with OA and 5 patients with RA obtained during arthroplasty were studied. Pannus was defined as the microscopic invasive granulation tissue covering the articular surface. Tissues were cultured for 7 days and stained with Alcian Blue technique. Interleukin-1beta (IL-1beta), IL-8, IL-10, IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon gamma (IFN-gamma) were also determined in supernatants by ELISA. Cartilage oligomeric matrix protein (COMP), type II collagen, TNF-alpha, IL-10 and Ki-67 expression were also detected by immunohistochemistry. All patients had vascular or fibrous pannus. Synovial proliferation, inflammatory infiltrates and a decrease of extracellular matrix proteins were observed in all tissue samples. Chondrocyte proliferation was lower in OA than RA cartilage. OA synovial tissue expressed lower levels of proteoglycans than RA synoyium. Type II collagen levels were lower in OA than in RA cartilage. Significantly higher levels of IL-1beta were found in the supernatants of RA pannus compared to OA pannus (ppannus supernatants. IL-10, IL-12 and IFN-gamma were undetectable. RA and OA pannus had similar pro-inflammatory and anti-inflammatory cytokine profile expression. OA cartilage, synovial tissue and pannus had lower production of proteoglycans, type II collagen and IL-1beta. It remains to be elucidated why OA pannus invades the cartilage surface but does not cause the marginal erosions typically seen in RA.

  13. Proinflammatory and anti-inflammatory cytokine balance in gasoline exhaust induced pulmonary injury in mice.

    Science.gov (United States)

    Sureshkumar, Veerapandian; Paul, Bholanath; Uthirappan, Mani; Pandey, Renu; Sahu, Anand Prakash; Lal, Kewal; Prasad, Arun Kumar; Srivastava, Suresh; Saxena, Ashok; Mathur, Neeraj; Gupta, Yogendra Kumar

    2005-03-01

    Proinflammatory and anti-inflammatory cytokine balance and associated changes in pulmonary bronchoalveolar lavage fluid (BALF) of unleaded gasoline exhaust (GE) exposed mice were investigated. Animals were exposed to GE (1 L/min of GE mixed with 14 L/min of compressed air) using a flow-past, nose-only, dynamic inhalation exposure chamber for different durations (7, 14, and 21 days). The particulate content of the GE was found to be 0.635, +/-0.10 mg PM/m3. Elevated levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were observed in BALF of GE-exposed mice, but interleukin 1beta(IL-1beta) and the anti-inflammatory cytokine interleukin-10 (IL-10) remained unaffected. GE induced higher activities of alkaline phosphatase (ALP), gamma-glutamyl transferase (gammaGT), and lactate dehydrogenase (LDH) in the BALF, indicating Type II alveolar epithelial cell injury, Clara-cell injury, and general toxicity, respectively. Total protein in the BALF increased after 14 and 21 days of exposure, indicating enhanced alveolar-capillary permeability. However, the difference in the mean was found statistically insignificant in comparison to the compressed air control. Total cell count in the BALF of GE-exposed mice ranged between 0.898 and 0.813x10(6) cells/ml, whereas the compressed air control showed 0.65x10(6) cells/mL. The histopathological changes in GE-exposed lung includes perivascular, and peribronchiolar cuffing of mononuclear cells, migration of polymorphonuclear cells in the alveolar septa, alveolar thickening, and mild alveolar edematous changes indicating inflammation. The shift in pro- and anti-inflammatory cytokine balance and elevation of the pulmonary marker enzymes indicate toxic insult of GE. This study will help in our understanding of the mechanism of pulmonary injury by GE in the light of cytokine profiles, pulmonary marker enzymes, and lung architecture.

  14. Gene expression profile of blood cells for the prediction of delayed cerebral ischemia after intracranial aneurysm rupture: a pilot study in humans.

    Science.gov (United States)

    Baumann, Antoine; Devaux, Yvan; Audibert, Gérard; Zhang, Lu; Bracard, Serge; Colnat-Coulbois, Sophie; Klein, Olivier; Zannad, Faiez; Charpentier, Claire; Longrois, Dan; Mertes, Paul-Michel

    2013-01-01

    Delayed cerebral ischemia (DCI) is a potentially devastating complication after intracranial aneurysm rupture and its mechanisms remain poorly elucidated. Early identification of the patients prone to developing DCI after rupture may represent a major breakthrough in its prevention and treatment. The single gene approach of DCI has demonstrated interest in humans. We hypothesized that whole genome expression profile of blood cells may be useful for better comprehension and prediction of aneurysmal DCI. Over a 35-month period, 218 patients with aneurysm rupture were included in this study. DCI was defined as the occurrence of a new delayed neurological deficit occurring within 2 weeks after aneurysm rupture with evidence of ischemia either on perfusion-diffusion MRI, CT angiography or CT perfusion imaging, or with cerebral angiography. DCI patients were matched against controls based on 4 out of 5 criteria (age, sex, Fisher grade, aneurysm location and smoking status). Genome-wide expression analysis of blood cells obtained at admission was performed by microarrays. Transcriptomic analysis was performed using long oligonucleotide microarrays representing 25,000 genes. Quantitative PCR: 1 µg of total RNA extracted was reverse-transcribed, and the resulting cDNA was diluted 10-fold before performing quantitative PCR. Microarray data were first analyzed by 'Significance Analysis of Microarrays' software which includes the Benjamini correction for multiple testing. In a second step, microarray data fold change was compared using a two-tailed, paired t test. Analysis of receiver-operating characteristic (ROC) curves and the area under the ROC curves were used for prediction analysis. Logistic regression models were used to investigate the additive value of multiple biomarkers. A total of 16 patients demonstrated DCI. Significance Analysis of Microarrays software failed to retrieve significant genes, most probably because of the heterogeneity of the patients included in

  15. Sexual victimization and family violence among urban African American adolescent women: do violence cluster profiles predict partner violence victimization and sex trade exposure?

    Science.gov (United States)

    Kennedy, Angie C; Bybee, Deborah; Kulkarni, Shanti J; Archer, Gretchen

    2012-11-01

    Guided by an intersectional feminist perspective, we examined sexual victimization, witnessing intimate partner violence (IPV) in the family, and familial physical abuse among a sample of 180 urban African American adolescent women. We used cluster analysis to better understand the profiles of cumulative victimization, and the relationships between profiles and IPV victimization and personal exposure to the sex trade. Just under one third of the sample reported sexual victimization, with cooccurrence with both forms of family violence common. The cluster profile with high levels of severe family violence was associated with the highest rate of IPV victimization and sex trade exposure.

  16. Temperature profiles from XBT casts from the OLEANDER as part of the Marine Resources Monitoring, Assessment and Prediction (MARMAP) project from 1982-06-11 (NODC Accession 8200127)

    Data.gov (United States)

    National Oceanic and Atmospheric Administration, Department of Commerce — Temperature profiles were collected from XBT casts from the OLEANDER from 11 June 1982. Data were collected by the National Marine Fisheries Service (NMFS) as part...

  17. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    Energy Technology Data Exchange (ETDEWEB)

    Erez, Neta, E-mail: netaerez@post.tau.ac.il [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Glanz, Sarah [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Raz, Yael [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Obstetrics and Gynecology, LIS Maternity Hospital, Tel Aviv Sourasky Medical Center, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Avivi, Camilla [Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel); Barshack, Iris [Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel-Aviv 69978 (Israel); Department of Pathology, Sheba Medical Center, Tel Hashomer, affiliated with Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv (Israel)

    2013-08-02

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics.

  18. Cancer Associated Fibroblasts express pro-inflammatory factors in human breast and ovarian tumors

    International Nuclear Information System (INIS)

    Erez, Neta; Glanz, Sarah; Raz, Yael; Avivi, Camilla; Barshack, Iris

    2013-01-01

    Highlights: •CAFs in human breast and ovarian tumors express pro-inflammatory factors. •Expression of pro-inflammatory factors correlates with tumor invasiveness. •Expression of pro-inflammatory factors is associated with NF-κb activation in CAFs. -- Abstract: Inflammation has been established in recent years as a hallmark of cancer. Cancer Associated Fibroblasts (CAFs) support tumorigenesis by stimulating angiogenesis, cancer cell proliferation and invasion. We previously demonstrated that CAFs also mediate tumor-enhancing inflammation in a mouse model of skin carcinoma. Breast and ovarian carcinomas are amongst the leading causes of cancer-related mortality in women and cancer-related inflammation is linked with both these tumor types. However, the role of CAFs in mediating inflammation in these malignancies remains obscure. Here we show that CAFs in human breast and ovarian tumors express high levels of the pro-inflammatory factors IL-6, COX-2 and CXCL1, previously identified to be part of a CAF pro-inflammatory gene signature. Moreover, we show that both pro-inflammatory signaling by CAFs and leukocyte infiltration of tumors are enhanced in invasive ductal carcinoma as compared with ductal carcinoma in situ. The pro-inflammatory genes expressed by CAFs are known NF-κB targets and we show that NF-κB is up-regulated in breast and ovarian CAFs. Our data imply that CAFs mediate tumor-promoting inflammation in human breast and ovarian tumors and thus may be an attractive target for stromal-directed therapeutics

  19. Plasma Free Amino Acid Profiles Predict Four-Year Risk of Developing Diabetes, Metabolic Syndrome, Dyslipidemia, and Hypertension in Japanese Population

    OpenAIRE

    Yamakado, Minoru; Nagao, Kenji; Imaizumi, Akira; Tani, Mizuki; Toda, Akiko; Tanaka, Takayuki; Jinzu, Hiroko; Miyano, Hiroshi; Yamamoto, Hiroshi; Daimon, Takashi; Horimoto, Katsuhisa; Ishizaka, Yuko

    2015-01-01

    Plasma free amino acid (PFAA) profile is highlighted in its association with visceral obesity and hyperinsulinemia, and future diabetes. Indeed PFAA profiling potentially can evaluate individuals? future risks of developing lifestyle-related diseases, in addition to diabetes. However, few studies have been performed especially in Asian populations, about the optimal combination of PFAAs for evaluating health risks. We quantified PFAA levels in 3,701 Japanese subjects, and determined visceral ...

  20. Proinflammatory Cytokines in Prostate Cancer Development and Progression Promoted by High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Hua Xu

    2015-01-01

    Full Text Available Background. We aimed to examine whether proinflammatory cytokines participated in prostate cancer (PCa development and progression promoted by high-fat diet (HFD. Methods. TRAMP (transgenic adenocarcinoma mouse prostate mice were randomly divided into two groups: normal diet group and HFD group. Mortality rate and tumor formation rate were examined. TRAMP mice were sacrificed and sampled on the 20th, 24th, and 28th week, respectively. Levels of proinflammatory cytokines, including IL-1α, IL-1β, IL-6, and TNF-α, were tested by FlowCytomix. Prostate tissue of TRAMP mice was used for histology study. Results. A total of 13 deaths of TRAMP mice were observed, among which 3 (8.33% were from the normal diet group and 10 (27.78% from the HFD group. The mortality rate of TRAMP mice from HFD group was significantly higher than that of normal diet group (P=0.032. Tumor formation rate at 20th week of age of HFD group was significantly higher than that of normal diet group (P=0.045. Proinflammatory cytokines levels, including IL-1α, IL-1β, IL-6, and TNF-α, were significantly higher in HFD TRAMP mice. Conclusions. HFD could promote TRAMP mouse PCa development and progression with elevated proinflammatory cytokines levels. Proinflammatory cytokines could contribute to PCa development and progression promoted by HFD.

  1. Effects of transcutaneous electrical nerve stimulation (TENS) on proinflammatory cytokines: protocol for systematic review.

    Science.gov (United States)

    Almeida, Tábata Cristina do Carmo; Figueiredo, Francisco Winter Dos Santos; Barbosa Filho, Valter Cordeiro; de Abreu, Luiz Carlos; Fonseca, Fernando Luiz Affonso; Adami, Fernando

    2017-07-11

    Pain reduction can be achieved by lowering proinflammatory cytokine levels in the blood. Transcutaneous electrical nerve stimulation (TENS) is a non-invasive physiotherapeutic resource for pain management, but evidence on the effectiveness of this device at reducing proinflammatory cytokines in the blood is unclear. This study systematically reviews the literature on the effect of TENS on proinflammatory cytokines. A systematic review protocol was developed based on searches of articles in six electronic databases and references of retrieved articles, contact with authors, and repositories of clinical trials. Eligibility criteria: publication in peer-reviewed journals, randomized clinical trials, use of TENS in the experimental group, and pre- and post-measurements of proinflammatory cytokines in the blood. Selection of the studies and extraction of the data will be carried out by two reviewers independently. Characteristics of the study, participants, interventions and outcomes were extracted and described. Assessments were performed on the risk of bias, level of evidence and the size of the intervention effect in the studies, according to GRADE guidelines and the Cochrane Handbook for Systematic Reviews. Clinical and statistical assessments compared the effects of the interventions (meta-analysis), taking into consideration any influencing characteristics of the studies (e.g., methods and application sites). We anticipate that this review will strengthen evidence-based knowledge of the effect of TENS on proinflammatory cytokines and, as a result, direct new studies to benefit patients with specific pathologies. PROSPERO, CRD42017060379 .

  2. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index

    Directory of Open Access Journals (Sweden)

    Estrada Iris

    2010-06-01

    Full Text Available Abstract Background Fibromyalgia (FM is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1β, TNF-α, and IL-6 may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure the circulatory levels of proinflammatory cytokines to determine the influence of BMI on these levels in FM patients and healthy volunteers (HVs. In Spanish FM patients (n = 64 and HVs (n = 25, we measured BMI and serum concentrations of proinflammatory cytokines by capture ELISA. Findings There were significant differences in BMI levels between FM patients (26.40 ± 4.46 and HVs (23.64 ± 3.45 and significant increase in IL-6 in FM patients (16.28 ± 8.13 vs 0.92 ± 0.32 pg/ml (P Conclusions Our analysis in FM patients of BMI as a covariate of proinflammatory cytokines levels showed that serum TNF-α and IL-6 levels are independent of BMI. Further studies are necessary to dissect these findings and their implication in future therapeutic approaches for FM patients.

  3. Proinflammatory cytokine levels in fibromyalgia patients are independent of body mass index.

    Science.gov (United States)

    Hernandez, Maria E; Becerril, Enrique; Perez, Mayra; Leff, Philippe; Anton, Benito; Estrada, Sergio; Estrada, Iris; Sarasa, Manuel; Serrano, Enrique; Pavon, Lenin

    2010-06-03

    Fibromyalgia (FM) is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1beta, TNF-alpha, and IL-6) may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure the circulatory levels of proinflammatory cytokines to determine the influence of BMI on these levels in FM patients and healthy volunteers (HVs). In Spanish FM patients (n = 64) and HVs (n = 25), we measured BMI and serum concentrations of proinflammatory cytokines by capture ELISA. There were significant differences in BMI levels between FM patients (26.40 +/- 4.46) and HVs (23.64 +/- 3.45) and significant increase in IL-6 in FM patients (16.28 +/- 8.13 vs 0.92 +/- 0.32 pg/ml) (P BMI and TNF-alpha (F = 0.098, p = 0.75) or IL-6 (F = 0.221, p = 0.63) levels in FM patients. Our analysis in FM patients of BMI as a covariate of proinflammatory cytokines levels showed that serum TNF-alpha and IL-6 levels are independent of BMI. Further studies are necessary to dissect these findings and their implication in future therapeutic approaches for FM patients.

  4. The importance of balanced pro-inflammatory and anti-inflammatory mechanisms in diffuse lung disease

    Directory of Open Access Journals (Sweden)

    Strieter Robert

    2002-01-01

    Full Text Available Abstract The lung responds to a variety of insults in a remarkably consistent fashion but with inconsistent outcomes that vary from complete resolution and return to normal to the destruction of normal architecture and progressive fibrosis. Increasing evidence indicates that diffuse lung disease results from an imbalance between the pro-inflammatory and anti-inflammatory mechanisms, with a persistent imbalance that favors pro-inflammatory mediators dictating the development of chronic diffuse lung disease. This review focuses on the mediators that influence this imbalance.

  5. Brief Report: Predicting Inner Speech Use amongst Children with Autism Spectrum Disorder (ASD)--The Roles of Verbal Ability and Cognitive Profile

    Science.gov (United States)

    Williams, David M.; Jarrold, Christopher

    2010-01-01

    Studies of inner speech use in ASD have produced conflicting results. Lidstone et al., J "Autism Dev Disord" (2009) hypothesised that Cognitive Profile (i.e., "discrepancy" between non-verbal and verbal abilities) is a predictor of inner speech use amongst children with ASD. They suggested other, contradictory results might be explained in terms…

  6. Moving Toward Integrating Gene Expression Profiling into High-throughput Testing:A Gene Expression Biomarker Accurately Predicts Estrogen Receptor α Modulation in a Microarray Compendium

    Science.gov (United States)

    Microarray profiling of chemical-induced effects is being increasingly used in medium and high-throughput formats. In this study, we describe computational methods to identify molecular targets from whole-genome microarray data using as an example the estrogen receptor α (ERα), ...

  7. Terbinafine stimulates the pro-inflammatory responses in human monocytic THP-1 cells through an ERK signaling pathway.

    Science.gov (United States)

    Mizuno, Katsuhiko; Fukami, Tatsuki; Toyoda, Yasuyuki; Nakajima, Miki; Yokoi, Tsuyoshi

    2010-10-23

    Oral antifungal terbinafine has been reported to cause liver injury with inflammatory responses in a small percentage of patients. However the underlying mechanism remains unknown. To examine the inflammatory reactions, we investigated whether terbinafine and other antifungal drugs increase the release of pro-inflammatory cytokines using human monocytic cells. Dose- and time-dependent changes in the mRNA expression levels and the release of interleukin (IL)-8 and tumor necrosis factor (TNF)α from human monocytic THP-1 and HL-60 cells with antifungal drugs were measured. Effects of terbinafine on the phosphorylation of extracellular signal-regulated kinase (ERK)1/2, p38 mitogen-activated protein (MAP) kinase and c-Jun N-terminal kinase (JNK)1/2 were investigated. The release of IL-8 and TNFα from THP-1 and HL-60 cells was significantly increased by treatment with terbinafine but not by fluconazole, suggesting that terbinafine can stimulate monocytes and increase the pro-inflammatory cytokine release. Terbinafine also significantly increased the phosphorylation of ERK1/2 and p38 MAP kinase in THP-1 cells. Pretreatment with a MAP kinase/ERK kinase (MEK)1/2 inhibitor U0126 significantly suppressed the increase of IL-8 and TNFα levels by terbinafine treatment in THP-1 cells, but p38 MAPK inhibitor SB203580 did not. These results suggested that an ERK1/2 pathway plays an important role in the release of IL-8 and TNFα in THP-1 cells treated with terbinafine. The release of inflammatory mediators by terbinafine might be one of the mechanisms underlying immune-mediated liver injury. This in vitro method may be useful to predict adverse inflammatory reactions that lead to drug-induced liver injury. Copyright © 2010 Elsevier Inc. All rights reserved.

  8. Acute Zika Virus Infection in an Endemic Area Shows Modest Proinflammatory Systemic Immunoactivation and Cytokine-Symptom Associations

    Directory of Open Access Journals (Sweden)

    Jéssica Barletto de Sousa Barros

    2018-05-01

    Full Text Available An early immune response to Zika virus (ZIKV infection may determine its clinical manifestation and outcome, including neurological effects. However, low-grade and transient viremia limits the prompt diagnosis of acute ZIKV infection. We have investigated the plasma cytokine, chemokine, and growth factor profiles of 36 individuals from an endemic area displaying different symptoms such as exanthema, headache, myalgia, arthralgia, fever, hyperemia, swelling, itching, and nausea during early-phase infection. These profiles were then associated with symptoms, revealing important aspects of the immunopathophysiology of ZIKV infection. The levels of some cytokines/chemokines were significantly higher in acute ZIKV-infected individuals compared to healthy donors, including interferon (IFN gamma-induced protein 10 (IP-10, regulated on activation, normal T cell expressed and secreted (RANTES, IFN-γ, interleukin (IL-9, IL-7, IL-5, and IL-1ra, including some with predominantly immunoregulatory activity. Of note, we found that higher levels of IP-10 and IL-5 in ZIKV-infected individuals were strongly associated with exanthema and headache, respectively. Also, higher levels of IL-1ra were associated with subjects with arthralgia, whereas those with fever showed lower levels of granulocyte-colony stimulating factor (G-CSF. No correlation was observed between the number of symptoms and ZIKV viral load. Interestingly, only IP-10 showed significantly decreased levels in the recovery phase. In conclusion, our results indicate that acute ZIKV infection in a larger cohort resident to an endemic area displays a modest systemic immune activation profile, involving both proinflammatory and immunoregulatory cytokines and chemokines that could participate of virus control. In addition, we showed that differential cytokine/chemokine levels are related to specific clinical symptoms, suggesting their participation in underlying mechanisms.

  9. Persistent Microvascular Obstruction After Myocardial Infarction Culminates in the Confluence of Ferric Iron Oxide Crystals, Proinflammatory Burden, and Adverse RemodelingCLINICAL PERSPECTIVE

    Energy Technology Data Exchange (ETDEWEB)

    Kali, Avinash; Cokic, Ivan; Tang, Richard; Dohnalkova, Alice; Kovarik, Libor; Yang, Hsin-Jung; Kumar, Andreas; Prato, Frank S.; Wood, John C.; Underhill, David; Marban, Eduardo; Dharmakumar, Rohan

    2016-11-01

    Emerging evidence now supports the notion that persistent microvascular obstruction (PMO) may be more predictive of major adverse cardiovascular events than MI size itself. But, how PMO, a phenomenon limited to the acute/sub-acute period of MI, imparts adverse remodeling throughout the post MI period, particularly after its resolution, is incompletely understood. We hypothesized that PMOs resolve into chronic iron crystals within MI territories and actively impart a proinflammatory burden and adverse remodeling of infarction and LV in the chronic phase of MI. Canine models reperfused (n=20) and non-reperfused (n=20) with and without PMO were studied with serial cardiac MRI to characterize the spatiotemporal relationships between PMO, iron deposition, and infarct and LV remodeling indices between acute (day 7, post MI) and chronic (week 8, post MI). Histopathology and immunohistochemistry were used to validate the iron deposition, microscopically map and quantify the relationship between iron-rich chronic MI regions against pro-inflammatory macrophages, proinflammatory cytokines and matrix metalloproteinase. Atomic resolution transmission electron microscopy (TEM) was used to determine the crystallinity of iron and assess the physical effects of iron on lysosomes within macrophages, and energy-dispersive X-ray spectroscopy (EDS) to identify the chemical composition of the iron composite. Results showed that PMOs lead to iron deposition within chronic MI and that the extent of chronic iron deposition is strongly related to PMO Volume (r>0.6, p<0.001). TEM and EDS analysis showed that iron within chronic MI is found within macrophages as aggregates of nanocrystals of ~2.5 nm diameter in ferric state. Correlative histological studies showed that iron content, proinflammatory burden and collagen degrading enzyme were highly correlated (r >0.7, p<0.001). Iron within chronic MI was significantly associated with infarct resorption (r>0.5, p<0.001) and adverse structural (r

  10. Mining a database of single amplified genomes from Red Sea brine pool extremophiles—improving reliability of gene function prediction using a profile and pattern matching algorithm (PPMA)

    Science.gov (United States)

    Grötzinger, Stefan W.; Alam, Intikhab; Ba Alawi, Wail; Bajic, Vladimir B.; Stingl, Ulrich; Eppinger, Jörg

    2014-01-01

    Reliable functional annotation of genomic data is the key-step in the discovery of novel enzymes. Intrinsic sequencing data quality problems of single amplified genomes (SAGs) and poor homology of novel extremophile's genomes pose significant challenges for the attribution of functions to the coding sequences identified. The anoxic deep-sea brine pools of the Red Sea are a promising source of novel enzymes with unique evolutionary adaptation. Sequencing data from Red Sea brine pool cultures and SAGs are annotated and stored in the Integrated Data Warehouse of Microbial Genomes (INDIGO) data warehouse. Low sequence homology of annotated genes (no similarity for 35% of these genes) may translate into false positives when searching for specific functions. The Profile and Pattern Matching (PPM) strategy described here was developed to eliminate false positive annotations of enzyme function before progressing to labor-intensive hyper-saline gene expression and characterization. It utilizes InterPro-derived Gene Ontology (GO)-terms (which represent enzyme function profiles) and annotated relevant PROSITE IDs (which are linked to an amino acid consensus pattern). The PPM algorithm was tested on 15 protein families, which were selected based on scientific and commercial potential. An initial list of 2577 enzyme commission (E.C.) numbers was translated into 171 GO-terms and 49 consensus patterns. A subset of INDIGO-sequences consisting of 58 SAGs from six different taxons of bacteria and archaea were selected from six different brine pool environments. Those SAGs code for 74,516 genes, which were independently scanned for the GO-terms (profile filter) and PROSITE IDs (pattern filter). Following stringent reliability filtering, the non-redundant hits (106 profile hits and 147 pattern hits) are classified as reliable, if at least two relevant descriptors (GO-terms and/or consensus patterns) are present. Scripts for annotation, as well as for the PPM algorithm, are available

  11. Mining a database of single amplified genomes from Red Sea brine pool extremophiles – Improving reliability of gene function prediction using a profile and pattern matching algorithm (PPMA

    Directory of Open Access Journals (Sweden)

    Stefan Wolfgang Grötzinger

    2014-04-01

    Full Text Available Reliable functional annotation of genomic data is the key-step in the discovery of novel enzymes. Intrinsic sequencing data quality problems of single amplified genomes (SAGs and poor homology of novel extremophile’s genomes pose significant challenges for the attribution of functions to the coding sequences identified. The anoxic deep-sea brine pools of the Red Sea are a promising source of novel enzymes with unique evolutionary adaptation. Sequencing data from Red Sea brine pool cultures and SAGs are annotated and stored in the INDIGO data warehouse. Low sequence homology of annotated genes (no similarity for 35% of these genes may translate into false positives when searching for specific functions. The Profile & Pattern Matching (PPM strategy described here was developed to eliminate false positive annotations of enzyme function before progressing to labor-intensive hyper-saline gene expression and characterization. It utilizes InterPro-derived Gene Ontology (GO-terms (which represent enzyme function profiles and annotated relevant PROSITE IDs (which are linked to an amino acid consensus pattern. The PPM algorithm was tested on 15 protein families, which were selected based on scientific and commercial potential. An initial list of 2,577 E.C. numbers was translated into 171 GO-terms and 49 consensus patterns. A subset of INDIGO-sequences consisting of 58 SAGs from six different taxons of bacteria and archaea were selected from 6 different brine pool environments. Those SAGs code for 74,516 genes, which were independently scanned for the GO-terms (profile filter and PROSITE IDs (pattern filter. Following stringent reliability filtering, the non-redundant hits (106 profile hits and 147 pattern hits are classified as reliable, if at least two relevant descriptors (GO-terms and/or consensus patterns are present. Scripts for annotation, as well as for the PPM algorithm, are available through the INDIGO website.

  12. Mining a database of single amplified genomes from Red Sea brine pool extremophiles-improving reliability of gene function prediction using a profile and pattern matching algorithm (PPMA).

    KAUST Repository

    Grötzinger, Stefan W.

    2014-04-07

    Reliable functional annotation of genomic data is the key-step in the discovery of novel enzymes. Intrinsic sequencing data quality problems of single amplified genomes (SAGs) and poor homology of novel extremophile\\'s genomes pose significant challenges for the attribution of functions to the coding sequences identified. The anoxic deep-sea brine pools of the Red Sea are a promising source of novel enzymes with unique evolutionary adaptation. Sequencing data from Red Sea brine pool cultures and SAGs are annotated and stored in the Integrated Data Warehouse of Microbial Genomes (INDIGO) data warehouse. Low sequence homology of annotated genes (no similarity for 35% of these genes) may translate into false positives when searching for specific functions. The Profile and Pattern Matching (PPM) strategy described here was developed to eliminate false positive annotations of enzyme function before progressing to labor-intensive hyper-saline gene expression and characterization. It utilizes InterPro-derived Gene Ontology (GO)-terms (which represent enzyme function profiles) and annotated relevant PROSITE IDs (which are linked to an amino acid consensus pattern). The PPM algorithm was tested on 15 protein families, which were selected based on scientific and commercial potential. An initial list of 2577 enzyme commission (E.C.) numbers was translated into 171 GO-terms and 49 consensus patterns. A subset of INDIGO-sequences consisting of 58 SAGs from six different taxons of bacteria and archaea were selected from six different brine pool environments. Those SAGs code for 74,516 genes, which were independently scanned for the GO-terms (profile filter) and PROSITE IDs (pattern filter). Following stringent reliability filtering, the non-redundant hits (106 profile hits and 147 pattern hits) are classified as reliable, if at least two relevant descriptors (GO-terms and/or consensus patterns) are present. Scripts for annotation, as well as for the PPM algorithm, are available

  13. Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines

    DEFF Research Database (Denmark)

    Jehs, Tina; Faber, Carsten; Udsen, Maja S.

    2016-01-01

    of 10 HCM donors induced a high initial level of monocyte migration, which decreased upon stimulation with either TCM or IFN-γ and TNF-α. The supernatants from three HCM donors initially showed a low level of monocyte attraction, which increased after exposure to proinflammatory cytokines. Direct...

  14. Retracted: Effects of pro-inflammatory cytokines on mineralization potential of rat dental pulp stem cells

    NARCIS (Netherlands)

    Yang, X.; Walboomers, X.F.; Bian, Z.; Jansen, J.A.; Fan, M.

    2011-01-01

    The following article from the Journal of Tissue Engineering and Regenerative Medicine, 'Effects of Pro-inflammatory Cytokines on Mineralization Potential of Rat Dental Pulp Stem Cells' by Yang X, Walboomers XF, Bian Z, Jansen JA, Fan M, published online on 11 July 2011 in Wiley Online Library

  15. Pro-inflammatory delipidizing cytokines reduce adiponectin secretion from human adipocytes without affecting adiponectin oligomerization

    NARCIS (Netherlands)

    Simons, Peter J.; van den Pangaart, Petra S.; Aerts, Johannes M. F. G.; Boon, Louis

    2007-01-01

    Adiponectin and, especially, its oligomeric complex composition have been suggested to be critical in determining insulin sensitivity. Pro-inflammatory cytokines play an important role in the development of insulin resistance in obesity and associated diseases. Therefore, we investigated the effect

  16. Chronic disruptions of circadian sleep regulation induce specific proinflammatory responses in the rat colon

    Czech Academy of Sciences Publication Activity Database

    Polidarová, Lenka; Houdek, Pavel; Sumová, Alena

    2017-01-01

    Roč. 34, č. 9 (2017), s. 1273-1287 ISSN 0742-0528 R&D Projects: GA ČR(CZ) GA14-07711S Institutional support: RVO:67985823 Keywords : aging * colon * constant light * melatonin * proinflammatory cytokine * Rgs16 * sleep disruption Subject RIV: ED - Physiology OBOR OECD: Physiology (including cytology) Impact factor: 2.562, year: 2016

  17. Efficient Maturation and Cytokine Production of Neonatal DCs Requires Combined Proinflammatory Signals

    Directory of Open Access Journals (Sweden)

    Doreen Krumbiegel

    2005-01-01

    Full Text Available Specific functional properties of dendritic cells (DCs have been suspected as being responsible for the impaired specific immune responses observed in human neonates. To analyze stimulatory requirements for the critical transition from immature, antigen-processing DCs to mature, antigen-presenting DCs, we investigated the effect of different proinflammatory mediators and antigens on phenotype and cytokine secretion of human neonatal DCs derived from hematopoietic progenitor cells (HPCs. Whereas single proinflammatory mediators were unable to induce the maturation of neonatal DCs, various combinations of IFNγ, CD40L, TNFα, LPS and antigens, induced the maturation of neonatal DCs documented by up-regulation of HLA-DR, CD83 and CD86. Combinations of proinflammatory mediators also increased cytokine secretion by neonatal DCs. Especially combined stimulation with LPS and IFNγ proved to be very efficient in inducing maturation and cytokine synthesis of neonatal DCs. In conclusion, neonatal DCs can be stimulated to express maturation as well as costimulatory surface molecules. However, induction of maturation requires combined stimulation with multiple proinflammatory signals.

  18. Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells.

    Science.gov (United States)

    Park, Hyo-Hyun; Lee, Soyoung; Son, Hee-Young; Park, Seung-Bin; Kim, Mi-Sun; Choi, Eun-Ju; Singh, Thoudam S K; Ha, Jeoung-Hee; Lee, Maan-Gee; Kim, Jung-Eun; Hyun, Myung Chul; Kwon, Taeg Kyu; Kim, Yeo Hyang; Kim, Sang-Hyun

    2008-10-01

    Mast cells participate in allergy and inflammation by secreting inflammatory mediators such as histamine and proinflammatory cytokines. Flavonoids are naturally occurring molecules with antioxidant, cytoprotective, and antiinflammatory actions. However, effect of flavonoids on the release of histamine and proinflammatory mediator, and their comparative mechanism of action in mast cells were not well defined. Here, we compared the effect of six flavonoids (astragalin, fisetin, kaempferol, myricetin, quercetin, and rutin) on the mast cell-mediated allergic inflammation. Fisetin, kaempferol, myricetin, quercetin, and rutin inhibited IgE or phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-mediated histamine release in RBL-2H3 cells. These five flavonoids also inhibited elevation of intracellular calcium. Gene expressions and secretion of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, and IL-8 were assessed in PMACI-stimulated human mast cells (HMC-1). Fisetin, quercetin, and rutin decreased gene expression and production of all the proinflammatory cytokines after PMACI stimulation. Myricetin attenuated TNF-alpha and IL-6 but not IL-1beta and IL-8. Fisetin, myricetin, and rutin suppressed activation of NF-kappaB indicated by inhibition of nuclear translocation of NF-kappaB, NF-kappaB/DNA binding, and NF-kappaB-dependent gene reporter assay. The pharmacological actions of these flavonoids suggest their potential activity for treatment of allergic inflammatory diseases through the down-regulation of mast cell activation.

  19. Involvement of Pro-Inflammatory Macrophages in Liver Pathology of Pirital Virus-Infected Syrian Hamsters

    Directory of Open Access Journals (Sweden)

    Corey L. Campbell

    2018-05-01

    Full Text Available New World arenaviruses cause fatal hemorrhagic disease in South America. Pirital virus (PIRV, a mammarenavirus hosted by Alston’s cotton rat (Sigmodon alstoni, causes a disease in Syrian golden hamsters (Mesocricetus auratus (biosafety level-3, BSL-3 that has many pathologic similarities to the South American hemorrhagic fevers (BSL-4 and, thus, is considered among the best small-animal models for human arenavirus disease. Here, we extend in greater detail previously described clinical and pathological findings in Syrian hamsters and provide evidence for a pro-inflammatory macrophage response during PIRV infection. The liver was the principal target organ of the disease, and signs of Kupffer cell involvement were identified in mortally infected hamster histopathology data. Differential expression analysis of liver mRNA revealed signatures of the pro-inflammatory response, hematologic dysregulation, interferon pathway and other host response pathways, including 17 key transcripts that were also reported in two non-human primate (NHP arenavirus liver-infection models, representing both Old and New World mammarenavirus infections. Although antigen presentation may differ among rodent and NHP species, key hemostatic and innate immune-response components showed expression parallels. Signatures of pro-inflammatory macrophage involvement in PIRV-infected livers included enrichment of Ifng, Nfkb2, Stat1, Irf1, Klf6, Il1b, Cxcl10, and Cxcl11 transcripts. Together, these data indicate that pro-inflammatory macrophage M1 responses likely contribute to the pathogenesis of acute PIRV infection.

  20. Suppression of pro-inflammatory and pro-survival biomarkers in oral cancer patients consuming a black raspberry phytochemical-rich troche

    Science.gov (United States)

    Knobloch, Thomas J.; Uhrig, Lana K.; Pearl, Dennis K.; Casto, Bruce C.; Warner, Blake M.; Clinton, Steven K.; Sardo-Molmenti, Christine L.; Ferguson, Jeanette M.; Daly, Brett T.; Riedl, Kenneth; Schwartz, Steven J.; Vodovotz, Yael; Buchta, Anthony J.; Schuller, David E.; Ozer, Enver; Agrawal, Amit; Weghorst, Christopher M.

    2016-01-01

    Black raspberries (BRBs) demonstrate potent inhibition of aerodigestive tract carcinogenesis in animal models. However, translational clinical trials evaluating the ability of BRB phytochemicals to impact molecular biomarkers in the oral mucosa remain limited. The present phase 0 study addresses a fundamental question for oral cancer food-based prevention: Do BRB phytochemicals successfully reach the targeted oral tissues and reduce pro-inflammatory and anti-apoptotic gene expression profiles? Patients with biopsy-confirmed oral squamous cell carcinomas (OSCCs) administered oral troches containing freeze-dried BRB powder from the time of enrollment to the date of curative intent surgery (13.9 ± 1.27 days). Transcriptional biomarkers were evaluated in patient-matched OSCCs and non-involved high at-risk mucosa (HARM) for BRB-associated changes. Significant expression differences between baseline OSCC and HARM tissues were confirmed using a panel of genes commonly deregulated during oral carcinogenesis. Following BRB troche administration, the expression of pro-survival genes (AURKA, BIRC5, EGFR) and pro-inflammatory genes (NFKB1, PTGS2) were significantly reduced. There were no BRB-associated Grade 3–4 toxicities or adverse events and 79.2% (N = 30) of patients successfully completed the study with high levels of compliance (97.2%). The BRB phytochemicals cyanidin-3-rutinoside and cyanidin-3-xylosylrutinoside were detected in all OSCC tissues analyzed, demonstrating that bioactive components were successfully reaching targeted OSCC tissues. We confirmed that hallmark anti-apoptotic and pro-inflammatory molecular biomarkers were over-expressed in OSCCs and that their gene expression was significantly reduced following BRB troche administration. Since these molecular biomarkers are fundamental to oral carcinogenesis and are modifiable, they may represent emerging biomarkers of molecular efficacy for BRB-mediated oral cancer chemoprevention. PMID:26701664

  1. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

    International Nuclear Information System (INIS)

    Sárvári, Anitta K.; Veréb, Zoltán; Uray, Iván P.; Fésüs, László; Balajthy, Zoltán

    2014-01-01

    Highlights: • Antipsychotics modulate the expression of adipogenic genes in human adipocytes. • Secretion of proinflammatory cytokine IL8 and MCP-1 is induced by antipsychotics. • Adipocyte-dependent inflammatory abnormality could develop during chronic treatment. • Infiltrated macrophages would further enhance proinflammatory cytokine production. - Abstract: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin

  2. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Sárvári, Anitta K., E-mail: anittasarvari@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); Veréb, Zoltán, E-mail: jzvereb@gmail.com [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); Uray, Iván P., E-mail: ipuray@mdanderson.org [Clinical Cancer Prevention Department, The University of Texas, MD Anderson Cancer Center, Houston, TX (United States); Fésüs, László, E-mail: fesus@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary); MTA DE Apoptosis, Genomics and Stem Cell Research Group of the Hungarian Academy of Sciences (Hungary); Balajthy, Zoltán, E-mail: balajthy@med.unideb.hu [Department of Biochemistry and Molecular Biology, Medical and Health Science Center, University of Debrecen, Debrecen (Hungary)

    2014-08-08

    Highlights: • Antipsychotics modulate the expression of adipogenic genes in human adipocytes. • Secretion of proinflammatory cytokine IL8 and MCP-1 is induced by antipsychotics. • Adipocyte-dependent inflammatory abnormality could develop during chronic treatment. • Infiltrated macrophages would further enhance proinflammatory cytokine production. - Abstract: Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin

  3. Pro-inflammatory cytokines upregulate sympathoexcitatory mechanisms in the subfornical organ of the rat

    Science.gov (United States)

    Wei, Shun-Guang; Yu, Yang; Zhang, Zhi-Hua; Felder, Robert B.

    2015-01-01

    Our previous work indicated that the subfornical organ (SFO) is an important brain sensor of blood-borne pro-inflammatory cytokines, mediating their central effects on autonomic and cardiovascular function. However, the mechanisms by which SFO mediates the central effects of circulating pro-inflammatory cytokines remain unclear. We hypothesized that pro-inflammatory cytokines act within the SFO to upregulate the expression of excitatory and inflammatory mediators that drive sympathetic nerve activity. In urethane-anesthetized Sprague-Dawley rats, direct microinjection of TNF-α (25 ng) or IL-1β (25 ng) into SFO increased mean blood pressure, heart rate and renal sympathetic nerve activity within 15–20 minutes, mimicking the response to systemically administered pro-inflammatory cytokines. Pretreatment of SFO with microinjections of the angiotensin II type 1 receptor (AT1R) blocker losartan (1 µg), angiotensin-converting enzyme (ACE) inhibitor captopril (1 µg) or cyclooxygenase (COX)-2 inhibitor NS-398 (2 µg) attenuated those responses. Four hours after the SFO microinjection of TNF-α (25 ng) or IL-1β (25 ng), mRNA for ACE, AT1R, TNF-α and the p55 TNF-α receptor TNFR1, IL-1β and the IL-1R receptor, and COX-2 had increased in SFO, and mRNA for ACE, AT1R and COX-2 had increased downstream in the hypothalamic paraventricular nucleus. Confocal immunofluorescent images revealed that immunoreactivity for TNFR1 and the IL-1 receptor accessory protein, a subunit of the IL-1 receptor, co-localized with ACE, AT1R-like, COX-2 and prostaglandin E2 EP3 receptor immunoreactivity in SFO neurons. These data suggest that pro-inflammatory cytokines act within the SFO to upregulate the expression of inflammatory and excitatory mediators that drive sympathetic excitation. PMID:25776070

  4. Data Profiling

    OpenAIRE

    Hladíková, Radka

    2010-01-01

    Title: Data Profiling Author: Radka Hladíková Department: Department of Software Engineering Supervisor: Ing. Vladimír Kyjonka Supervisor's e-mail address: Abstract: This thesis puts mind on problems with data quality and data profiling. This Work analyses and summarizes problems of data quality, data defects, process of data quality, data quality assessment and data profiling. The main topic is data profiling as a process of researching data available in existing...

  5. Predicting enteric methane emission of dairy cows with milk Fourier-transform infrared spectra and gas chromatography-based milk fatty acid profiles.

    Science.gov (United States)

    van Gastelen, S; Mollenhorst, H; Antunes-Fernandes, E C; Hettinga, K A; van Burgsteden, G G; Dijkstra, J; Rademaker, J L W

    2018-06-01

    The objective of the present study was to compare the prediction potential of milk Fourier-transform infrared spectroscopy (FTIR) for CH 4 emissions of dairy cows with that of gas chromatography (GC)-based milk fatty acids (MFA). Data from 9 experiments with lactating Holstein-Friesian cows, with a total of 30 dietary treatments and 218 observations, were used. Methane emissions were measured for 3 consecutive days in climate respiration chambers and expressed as production (g/d), yield (g/kg of dry matter intake; DMI), and intensity (g/kg of fat- and protein-corrected milk; FPCM). Dry matter intake was 16.3 ± 2.18 kg/d (mean ± standard deviation), FPCM yield was 25.9 ± 5.06 kg/d, CH 4 production was 366 ± 53.9 g/d, CH 4 yield was 22.5 ± 2.10 g/kg of DMI, and CH 4 intensity was 14.4 ± 2.58 g/kg of FPCM. Milk was sampled during the same days and analyzed by GC and by FTIR. Multivariate GC-determined MFA-based and FTIR-based CH 4 prediction models were developed, and subsequently, the final CH 4 prediction models were evaluated with root mean squared error of prediction and concordance correlation coefficient analysis. Further, we performed a random 10-fold cross validation to calculate the performance parameters of the models (e.g., the coefficient of determination of cross validation). The final GC-determined MFA-based CH 4 prediction models estimate CH 4 production, yield, and intensity with a root mean squared error of prediction of 35.7 g/d, 1.6 g/kg of DMI, and 1.6 g/kg of FPCM and with a concordance correlation coefficient of 0.72, 0.59, and 0.77, respectively. The final FTIR-based CH 4 prediction models estimate CH 4 production, yield, and intensity with a root mean squared error of prediction of 43.2 g/d, 1.9 g/kg of DMI, and 1.7 g/kg of FPCM and with a concordance correlation coefficient of 0.52, 0.40, and 0.72, respectively. The GC-determined MFA-based prediction models described a greater part of the observed variation in CH 4 emission than did the

  6. DI/LC-MS/MS-Based Metabolic Profiling for Identification of Early Predictive Serum Biomarkers of Metritis in Transition Dairy Cows.

    Science.gov (United States)

    Zhang, Guanshi; Deng, Qilan; Mandal, Rupasri; Wishart, David S; Ametaj, Burim N

    2017-09-27

    The objectives of this study were to evaluate alterations of metabolites in the blood of dairy cows before, during, and after diagnosis of metritis and identify predictive serum metabolite biomarkers for metritis. DI/LC-MS/MS was used to analyze serum samples collected from both healthy and metritic cows during -8, -4, disease diagnosis, +4, and +8 wks relative to parturition. Results indicated that cows with metritis experienced altered concentrations of serum amino acids, glycerophospholipids, sphingolipids, acylcarnitines, and biogenic amines during the entire experimental period. Moreover, two sets of predictive biomarker models and one set of diagnostic biomarker models for metritis were developed, and all of them showed high sensitivity and specificity (e.g., high AUC values by the ROC curve evaluation), which indicate that serum metabolites identified have pretty accurate predictive, diagnostic, and prognostic abilities for metritis in transition dairy cows.

  7. Histone modification profiles are predictive for tissue/cell-type specific expression of both protein-coding and microRNA genes

    Directory of Open Access Journals (Sweden)

    Zhang Michael Q

    2011-05-01

    Full Text Available Abstract Background Gene expression is regulated at both the DNA sequence level and through modification of chromatin. However, the effect of chromatin on tissue/cell-type specific gene regulation (TCSR is largely unknown. In this paper, we present a method to elucidate the relationship between histone modification/variation (HMV and TCSR. Results A classifier for differentiating CD4+ T cell-specific genes from housekeeping genes using HMV data was built. We found HMV in both promoter and gene body regions to be predictive of genes which are targets of TCSR. For example, the histone modification types H3K4me3 and H3K27ac were identified as the most predictive for CpG-related promoters, whereas H3K4me3 and H3K79me3 were the most predictive for nonCpG-related promoters. However, genes targeted by TCSR can be predicted using other type of HMVs as well. Such redundancy implies that multiple type of underlying regulatory elements, such as enhancers or intragenic alternative promoters, which can regulate gene expression in a tissue/cell-type specific fashion, may be marked by the HMVs. Finally, we show that the predictive power of HMV for TCSR is not limited to protein-coding genes in CD4+ T cells, as we successfully predicted TCSR targeted genes in muscle cells, as well as microRNA genes with expression specific to CD4+ T cells, by the same classifier which was trained on HMV data of protein-coding genes in CD4+ T cells. Conclusion We have begun to understand the HMV patterns that guide gene expression in both tissue/cell-type specific and ubiquitous manner.

  8. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    Science.gov (United States)

    Alnek, Kristi; Kisand, Kalle; Heilman, Kaire; Peet, Aleksandr; Varik, Karin; Uibo, Raivo

    2015-01-01

    The production of several cytokines could be dysregulated in type 1 diabetes (T1D). In particular, the activation of T helper (Th) type 1 (Th1) cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α), Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8), but not human leukocyte antigen (HLA) genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  9. Transgenic Mouse Model Harboring the Transcriptional Fusion Ccl20-Luciferase as a Novel Reporter of Pro-Inflammatory Response

    Science.gov (United States)

    Crispo, Martina; Van Maele, Laurye; Tabareau, Julien; Cayet, Delphine; Errea, Agustina; Ferreira, Ana María; Rumbo, Martin; Sirard, Jean Claude

    2013-01-01

    The chemokine CCL20, the unique ligand of CCR6 functions as an attractant of immune cells. Expression of CCL20 is induced by Toll-like Receptor (TLR) signaling or proinflammatory cytokine stimulation. However CCL20 is also constitutively produced at specific epithelial sites of mucosa. This expression profile is achieved by transcriptional regulation. In the present work we characterized regulatory features of mouse Ccl20 gene. Transcriptional fusions between the mouse Ccl20 promoter and the firefly luciferase (luc) encoding gene were constructed and assessed in in vitro and in vivo assays. We found that liver CCL20 expression and luciferase activity were upregulated by systemic administration of the TLR5 agonist flagellin. Using shRNA and dominant negative form specific for mouse TLR5, we showed that this expression was controlled by TLR5. To address in situ the regulation of gene activity, a transgenic mouse line harboring a functional Ccl20-luc fusion was generated. The luciferase expression was highly concordant with Ccl20 expression in different tissues. Our data indicate that the transgenic mouse model can be used to monitor activation of innate response in vivo. PMID:24265691

  10. Soil-covered strategy for ecological restoration alters the bacterial community structure and predictive energy metabolic functions in mine tailings profiles.

    Science.gov (United States)

    Li, Yang; Sun, Qingye; Zhan, Jing; Yang, Yang; Wang, Dan

    2017-03-01

    Native soil amendment has been widely used to stabilize mine tailings and speed up the development of soil biogeochemical functions before revegetation; however, it remains poorly understood about the response of microbial communities to ecological restoration of mine tailings with soil-covered strategy. In this study, microbial communities along a 60-cm profile were investigated in mine tailings during ecological restoration of two revegetation strategies (directly revegetation and native soil covered) with different plant species. The mine tailings were covered by native soils as thick as 40 cm for more than 10 years, and the total nitrogen, total organic carbon, water content, and heavy metal (Fe, Cu, and Zn) contents in the 0-40 cm intervals of profiles were changed. In addition, increased microbial diversity and changed microbial community structure were also found in the 10-40 cm intervals of profiles in soil-covered area. Soil-covered strategy rather than plant species and soil depth was the main factor influencing the bacterial community, which explained the largest portion (29.96%) of the observed variation. Compared directly to revegetation, soil-covered strategy exhibited the higher relative abundance of Acidobacteria and Deltaproteobacteria and the lower relative abundance of Bacteroidetes, Gemmatimonadetes, Betaproteobacteria, and Gammaproteobacteria. PICRUSt analysis further demonstrated that soil-covered caused energy metabolic functional changes in carbon, nitrogen, and sulfur metabolism. Given all these, the soil-covered strategy may be used to fast-track the establishment of native microbial communities and is conducive to the rehabilitation of biogeochemical processes for establishing native plant species.

  11. Predictive value of glucose-insulin ratio in PCOS and profile of women who will benefit from metformin therapy: obese, lean, hyper or normoinsulinemic?

    Science.gov (United States)

    Onalan, Gogsen; Goktolga, Umit; Ceyhan, Temel; Bagis, Tayfun; Onalan, Reside; Pabuçcu, Recai

    2005-12-01

    The aim of the present study is to evaluate sub-groups of PCOS patients who will benefit from metformin therapy and to find out any predictors of ovulation in PCOS sub-groups. In the current prospective-randomized, placebo-controlled, double-blind study, PCOS patients (n = 116) were divided into six main groups according to glucose to insulin ratio (G-I ratio mg/10(-4) U) and body mass index (BMI kg/m2) as: Group 1: normoinsulinemic (G-I ratio > or = 4.5 mg/10(-4) U), lean (BMI or = 30) (n = 18); Group 4: hyperinsulinemic (G-I ratio lean (n = 28); Group 5: hyperinsulinemic, overweight (n = 17); Group 6: hyperinsulinemic, obese (n = 20). Patients in each group were randomized onto placebo or metformin treatments (850 mg two to three times per day according to BMI). The rate of ovulation, biochemical profile, hormonal profile and clinical symptoms of hyperandrogenism were evaluated before and after 6 months of metformin and placebo treatments. We observed a significant decrease in WHR following metformin therapy in the normoinsulinemic overweight sub-group (P lean women (P lean hyperinsulinemic and normoinsulinemic groups (P lean hyperinsulinemic women (P PCOS patients.

  12.  DNA microarray-based gene expression profiling in diagnosis, assessing prognosis and predicting response to therapy in colorectal cancer

    Directory of Open Access Journals (Sweden)

    Przemysław Kwiatkowski

    2012-06-01

    Full Text Available  Colorectal cancer is the most common cancer of the gastrointestinal tract. It is considered as a biological model of a certain type of cancerogenesis process in which progression from an early to late stage adenoma and cancer is accompanied by distinct genetic alterations.Clinical and pathological parameters commonly used in clinical practice are often insufficient to determine groups of patients suitable for personalized treatment. Moreover, reliable molecular markers with high prognostic value have not yet been determined. Molecular studies using DNA-based microarrays have identified numerous genes involved in cell proliferation and differentiation during the process of cancerogenesis. Assessment of the genetic profile of colorectal cancer using the microarray technique might be a useful tool in determining the groups of patients with different clinical outcomes who would benefit from additional personalized treatment.The main objective of this study was to present the current state of knowledge on the practical application of gene profiling techniques using microarrays for determining diagnosis, prognosis and response to treatment in colorectal cancer.

  13. Easy to use program “Simkine3” for simulating kinetic profiles of multi-step chemical Systems and optimisation of predictable rate coefficients therein

    Directory of Open Access Journals (Sweden)

    S.B. Jonnalagadda

    2012-08-01

    Full Text Available ‘Simkine3’, a Delphi based software is developed to simulate the kinetic schemes of complex reaction mechanisms involving multiple sequential and competitive elementary steps for homogeneous and heterogeneous chemical reactions. Simkine3 is designed to translate the user specified mechanism into chemical first-order differential equations (ODEs and optimise the estimated rate constants in such a way that simulated curves match the experimental kinetic profiles. TLSoda which uses backward differentiation method is utilised to solve resulting ODEs and Downhill Simplex method is used to optimise the estimated rate constants in a robotic way. An online help file is developed using HelpScrible Demo to guide the users of Simkine3. The versatility of the software is demonstrated by simulating the complex reaction between methylene violet and acidic bromate, a reaction which exhibits complex nonlinear kinetics. The new software is validated after testing it on a 19-step intricate mechanism involving 15 different species. The kinetic profiles of multiple simulated curves, illustrating the effect of initial concentrations of bromate, and bromide were matched with the corresponding experimental curves.DOI: http://dx.doi.org/10.4314/bcse.v26i2.10

  14. Predicting workload profiles of brain-robot interface and electromygraphic neurofeedback with cortical resting-state networks: personal trait or task-specific challenge?

    Science.gov (United States)

    Fels, Meike; Bauer, Robert; Gharabaghi, Alireza

    2015-08-01

    Objective. Novel rehabilitation strategies apply robot-assisted exercises and neurofeedback tasks to facilitate intensive motor training. We aimed to disentangle task-specific and subject-related contributions to the perceived workload of these interventions and the related cortical activation patterns. Approach. We assessed the perceived workload with the NASA Task Load Index in twenty-one subjects who were exposed to two different feedback tasks in a cross-over design: (i) brain-robot interface (BRI) with haptic/proprioceptive feedback of sensorimotor oscillations related to motor imagery, and (ii) control of neuromuscular activity with feedback of the electromyography (EMG) of the same hand. We also used electroencephalography to examine the cortical activation patterns beforehand in resting state and during the training session of each task. Main results. The workload profile of BRI feedback differed from EMG feedback and was particularly characterized by the experience of frustration. The frustration level was highly correlated across tasks, suggesting subject-related relevance of this workload component. Those subjects who were specifically challenged by the respective tasks could be detected by an interhemispheric alpha-band network in resting state before the training and by their sensorimotor theta-band activation pattern during the exercise. Significance. Neurophysiological profiles in resting state and during the exercise may provide task-independent workload markers for monitoring and matching participants’ ability and task difficulty of neurofeedback interventions.

  15. Karolinske psychodynamic profile (KAPP)

    DEFF Research Database (Denmark)

    Mathiesen, Birgit Bork; Søgaard, Ulf

    2006-01-01

    psykologiske testmetoder, assesment, Karolinska psychodynamic profile (KAPP), psykodynamisk profil......psykologiske testmetoder, assesment, Karolinska psychodynamic profile (KAPP), psykodynamisk profil...

  16. Blood profile of proteins and steroid hormones predicts weight change after weight loss with interactions of dietary protein level and glycemic index.

    Directory of Open Access Journals (Sweden)

    Ping Wang

    2011-02-01

    Full Text Available Weight regain after weight loss is common. In the Diogenes dietary intervention study, high protein and low glycemic index (GI diet improved weight maintenance.To identify blood predictors for weight change after weight loss following the dietary intervention within the Diogenes study.Blood samples were collected at baseline and after 8-week low caloric diet-induced weight loss from 48 women who continued to lose weight and 48 women who regained weight during subsequent 6-month dietary intervention period with 4 diets varying in protein and GI levels. Thirty-one proteins and 3 steroid hormones were measured.Angiotensin I converting enzyme (ACE was the most important predictor. Its greater reduction during the 8-week weight loss was related to continued weight loss during the subsequent 6 months, identified by both Logistic Regression and Random Forests analyses. The prediction power of ACE was influenced by immunoproteins, particularly fibrinogen. Leptin, luteinizing hormone and some immunoproteins showed interactions with dietary protein level, while interleukin 8 showed interaction with GI level on the prediction of weight maintenance. A predictor panel of 15 variables enabled an optimal classification by Random Forests with an error rate of 24±1%. A logistic regression model with independent variables from 9 blood analytes had a prediction accuracy of 92%.A selected panel of blood proteins/steroids can predict the weight change after weight loss. ACE may play an important role in weight maintenance. The interactions of blood factors with dietary components are important for personalized dietary advice after weight loss.ClinicalTrials.gov NCT00390637.

  17. Artemisia umbelliformis Lam. and Génépi Liqueur: Volatile Profile as Diagnostic Marker for Geographic Origin and To Predict Liqueur Safety.

    Science.gov (United States)

    Boggia, Lorenzo; Pignata, Giuseppe; Sgorbini, Barbara; Colombo, Maria Laura; Marengo, Arianna; Casale, Manuela; Nicola, Silvana; Bicchi, Carlo; Rubiolo, Patrizia

    2017-04-05

    Artemisia umbelliformis, commonly known as "white génépi", is characterized by a volatile fraction rich in α- and β-thujones, two monoterpenoids; under European Union (EU) regulations these are limited to 35 mg/L in Artemisia-based beverages because of their recognized activity on the human central nervous system. This study reports the results of an investigation to define the geographical origin and thujone content of individual plants of A. umbelliformis from different geographical sites, cultivated experimentally at a single site, and to predict the thujone content in the resulting liqueurs through their volatile fraction. Headspace solid phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS) and non-separative HS-SPME-MS were used as analytical platforms to create a database suitable for chemometric description and prediction through linear discriminant analysis (LDA). HS-SPME-MS was applied to shorten analysis time. With both approaches, a diagnostic prediction of (i) plant geographical origin and (ii) thujone content of plant-related liqueurs could be made.

  18. A Danish Profiling System

    DEFF Research Database (Denmark)

    Rosholm, Michael; Staghøj, Jonas; Svarer, Michael

    2006-01-01

    This paper describes the statistical model used for profiling new unemployed workers in Denmark. When a worker – during his or her first six months in unemployment – enters the employment office for the first time, this model predicts whether or not he or she will be unemployed for more than six ...

  19. Evaluation of Machine Learning and Rules-Based Approaches for Predicting Antimicrobial Resistance Profiles in Gram-negative Bacilli from Whole Genome Sequence Data.

    Science.gov (United States)

    Pesesky, Mitchell W; Hussain, Tahir; Wallace, Meghan; Patel, Sanket; Andleeb, Saadia; Burnham, Carey-Ann D; Dantas, Gautam

    2016-01-01

    The time-to-result for culture-based microorganism recovery and phenotypic antimicrobial susceptibility testing necessitates initial use of empiric (frequently broad-spectrum) antimicrobial therapy. If the empiric therapy is not optimal, this can lead to adverse patient outcomes and contribute to increasing antibiotic resistance in pathogens. New, more rapid technologies are emerging to meet this need. Many of these are based on identifying resistance genes, rather than directly assaying resistance phenotypes, and thus require interpretation to translate the genotype into treatment recommendations. These interpretations, like other parts of clinical diagnostic workflows, are likely to be increasingly automated in the future. We set out to evaluate the two major approaches that could be amenable to automation pipelines: rules-based methods and machine learning methods. The rules-based algorithm makes predictions based upon current, curated knowledge of Enterobacteriaceae resistance genes. The machine-learning algorithm predicts resistance and susceptibility based on a model built from a training set of variably resistant isolates. As our test set, we used whole genome sequence data from 78 clinical Enterobacteriaceae isolates, previously identified to represent a variety of phenotypes, from fully-susceptible to pan-resistant strains for the antibiotics tested. We tested three antibiotic resistance determinant databases for their utility in identifying the complete resistome for each isolate. The predictions of the rules-based and machine learning algorithms for these isolates were compared to results of phenotype-based diagnostics. The rules based and machine-learning predictions achieved agreement with standard-of-care phenotypic diagnostics of 89.0 and 90.3%, respectively, across twelve antibiotic agents from six major antibiotic classes. Several sources of disagreement between the algorithms were identified. Novel variants of known resistance factors and

  20. Evaluation of Machine Learning and Rules-Based Approaches for Predicting Antimicrobial Resistance Profiles in Gram-negative Bacilli from Whole Genome Sequence Data

    Directory of Open Access Journals (Sweden)

    Mitchell Pesesky

    2016-11-01

    Full Text Available The time-to-result for culture-based microorganism recovery and phenotypic antimicrobial susceptibility testing necessitate initial use of empiric (frequently broad-spectrum antimicrobial therapy. If the empiric therapy is not optimal, this can lead to adverse patient outcomes and contribute to increasing antibiotic resistance in pathogens. New, more rapid technologies are emerging to meet this need. Many of these are based on identifying resistance genes, rather than directly assaying resistance phenotypes, and thus require interpretation to translate the genotype into treatment recommendations. These interpretations, like other parts of clinical diagnostic workflows, are likely to be increasingly automated in the future. We set out to evaluate the two major approaches that could be amenable to automation pipelines: rules-based methods and machine learning methods. The rules-based algorithm makes predictions based upon current, curated knowledge of Enterobacteriaceae resistance genes. The machine-learning algorithm predicts resistance and susceptibility based on a model built from a training set of variably resistant isolates. As our test set, we used whole genome sequence data from 78 clinical Enterobacteriaceae isolates, previously identified to represent a variety of phenotypes, from fully-susceptible to pan-resistant strains for the antibiotics tested. We tested three antibiotic resistance determinant databases for their utility in identifying the complete resistome for each isolate. The predictions of the rules-based and machine learning algorithms for these isolates were compared to results of phenotype-based diagnostics. The rules based and machine-learning predictions achieved agreement with standard-of-care phenotypic diagnostics of 89.0% and 90.3%, respectively, across twelve antibiotic agents from six major antibiotic classes. Several sources of disagreement between the algorithms were identified. Novel variants of known resistance

  1. MiR-155 induction by F. novicida but not the virulent F. tularensis results in SHIP down-regulation and enhanced pro-inflammatory cytokine response.

    Directory of Open Access Journals (Sweden)

    Thomas J Cremer

    2009-12-01

    Full Text Available The intracellular gram-negative bacterium Francisella tularensis causes the disease tularemia and is known for its ability to subvert host immune responses. Previous work from our laboratory identified the PI3K/Akt pathway and SHIP as critical modulators of host resistance to Francisella. Here, we show that SHIP expression is strongly down-regulated in monocytes and macrophages following infection with F. tularensis novicida (F.n.. To account for this negative regulation we explored the possibility that microRNAs (miRs that target SHIP may be induced during infection. There is one miR that is predicted to target SHIP, miR-155. We tested for induction and found that F.n. induced miR-155 both in primary monocytes/macrophages and in vivo. Using luciferase reporter assays we confirmed that miR-155 led to down-regulation of SHIP, showing that it specifically targets the SHIP 3'UTR. Further experiments showed that miR-155 and BIC, the gene that encodes miR-155, were induced as early as four hours post-infection in primary human monocytes. This expression was dependent on TLR2/MyD88 and did not require inflammasome activation. Importantly, miR-155 positively regulated pro-inflammatory cytokine release in human monocytes infected with Francisella. In sharp contrast, we found that the highly virulent type A SCHU S4 strain of Francisella tularensis (F.t. led to a significantly lower miR-155 response than the less virulent F.n. Hence, F.n. induces miR-155 expression and leads to down-regulation of SHIP, resulting in enhanced pro-inflammatory responses. However, impaired miR-155 induction by SCHU S4 may help explain the lack of both SHIP down-regulation and pro-inflammatory response and may account for the virulence of Type A Francisella.

  2. Kruppel-like factor 2 (KLF2) regulates proinflammatory activation of monocytes

    Science.gov (United States)

    Das, Hiranmoy; Kumar, Ajay; Lin, Zhiyong; Patino, Willmar D.; Hwang, Paul M.; Feinberg, Mark W.; Majumder, Pradip K.; Jain, Mukesh K.

    2006-01-01

    The mechanisms regulating activation of monocytes remain incompletely understood. Herein we provide evidence that Kruppel-like factor 2 (KLF2) inhibits proinflammatory activation of monocytes. In vitro, KLF2 expression in monocytes is reduced by cytokine activation or differentiation. Consistent with this observation, KLF2 expression in circulating monocytes is reduced in patients with chronic inflammatory conditions such as coronary artery disease. Adenoviral overexpression of KLF2 inhibits the LPS-mediated induction of proinflammatory factors, cytokines, and chemokines and reduces phagocytosis. Conversely, short interfering RNA-mediated reduction in KLF2 increased inflammatory gene expression. Reconstitution of immunodeficient mice with KLF2-overexpressing monocytes significantly reduced carrageenan-induced acute paw edema formation. Mechanistically, KLF2 inhibits the transcriptional activity of both NF-κB and activator protein 1, in part by means of recruitment of transcriptional coactivator p300/CBP-associated factor. These observations identify KLF2 as a novel negative regulator of monocytic activation. PMID:16617118

  3. Prediabetes and prehypertension in disease free obese adults correlate with an exacerbated systemic proinflammatory milieu

    Directory of Open Access Journals (Sweden)

    Johnson William D

    2010-07-01

    Full Text Available Abstract Background Obesity is a pro-inflammatory state frequently associated with widespread metabolic alterations that include insulin resistance and deregulation of blood pressure (BP. This cascade of events in some measure explains the susceptibility of obese adults for co-morbid conditions like diabetes mellitus and hypertension. Hypothesis We hypothesized that an elevated systemic proinflammatory burden correlates with dysglycemia and deregulated blood pressure. Methods We analyzed the screening anthropometric and laboratory measures from healthy disease free obese adults (n = 35; women (W 27, men (M 8 in a weight loss study. Results Healthy obese normoglycemic (fasting serum glucose: FSG Conclusions In otherwise healthy disease free obese adults, a higher degree of systemic inflammation is associated with prediabetes and prehypertension.

  4. Tumour-Derived Interleukin-1 Beta Induces Pro-inflammatory Response in Human Mesenchymal Stem Cells

    DEFF Research Database (Denmark)

    Alajez, Nehad M; Al-toub, Mashael; Almusa, Abdulaziz

    ’ secreted factors as represented by a panel of human cancer cell lines (breast (MCF7 and MDA-MB-231); prostate (PC-3); lung (NCI-H522); colon (HT-29) and head & neck (FaDu)) on the biological characteristics of MSCs. Background Over the past several years, significant amount of research has emerged......, the goal of this study was to assess the cellular and molecular changes in MSCs in response to secreted factors present in conditioned media (CM) from a panel of human tumor cell lines covering a spectrum of human cancers (Breast, Prostate, Lung, colon, and head and neck). Research Morphological changes...... with bipolar processes. In association with phenotypic changes, genome-wide gene expression and bioinformatics analysis revealed an enhanced pro-inflammatory response of those MSCs. Pharmacological inhibitions of FAK and MAPKK severely impaired the pro-inflammatory response of MSCs to tumor CM (~80-99%, and 55...

  5. Polybrominated diphenyl ethers enhance the production of proinflammatory cytokines by the placenta.

    Science.gov (United States)

    Peltier, M R; Klimova, N G; Arita, Y; Gurzenda, E M; Murthy, A; Chawala, K; Lerner, V; Richardson, J; Hanna, N

    2012-09-01

    Polybrominated diphenyl ether(s) (PBDE) are ubiquitous environmental contaminants that bind and cross the placenta but their effects on pregnancy outcome are unclear. It is possible that environmental contaminants increase the risk of inflammation-mediated pregnancy complications such as preterm birth by promoting a proinflammatory environment at the maternal-fetal interface. We hypothesized that PBDE would reduce IL-10 production and enhance the production of proinflammatory cytokines associated with preterm labor/birth by placental explants. Second-trimester placental explants were cultured in either vehicle (control) or 2 μM PBDE mixture of congers 47, 99 and 100 for 72 h. Cultures were then stimulated with 10(6) CFU/ml heat-killed Escherichia coli for a final 24 h incubation and conditioned medium was harvested for quantification of cytokines and PGE(2). COX-2 content and viability of the treated tissues were then quantified by tissue ELISA and MTT reduction activity, respectively. PBDE pre-treatment reduced E. coli-stimulated IL-10 production and significantly increased E. coli-stimulated IL-1β secretion. PBDE exposure also increased basal and bacteria-stimulated COX-2 expression. Basal, but not bacteria-stimulated PGE(2), was also enhanced by PBDE exposure. No effect of PBDE on viability of the explants cultures was detected. In summary, pre-exposure of placental explants to congers 47, 99, and 100 enhanced the placental proinflammatory response to infection. This may increase the risk of infection-mediated preterm birth by lowering the threshold for bacteria to stimulate a proinflammatory response(s). Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

    International Nuclear Information System (INIS)

    Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana; Klegeris, Andis; Little, Jonathan P.

    2014-01-01

    Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes

  7. A pro-inflammatory role for Th22 cells in Helicobacter pylori-associated gastritis.

    Science.gov (United States)

    Zhuang, Yuan; Cheng, Ping; Liu, Xiao-fei; Peng, Liu-sheng; Li, Bo-sheng; Wang, Ting-ting; Chen, Na; Li, Wen-hua; Shi, Yun; Chen, Weisan; Pang, Ken C; Zeng, Ming; Mao, Xu-hu; Yang, Shi-ming; Guo, Hong; Guo, Gang; Liu, Tao; Zuo, Qian-fei; Yang, Hui-jie; Yang, Liu-yang; Mao, Fang-yuan; Lv, Yi-pin; Zou, Quan-ming

    2015-09-01

    Helper T (Th) cell responses are critical for the pathogenesis of Helicobacter pylori-induced gastritis. Th22 cells represent a newly discovered Th cell subset, but their relevance to H. pylori-induced gastritis is unknown. Flow cytometry, real-time PCR and ELISA analyses were performed to examine cell, protein and transcript levels in gastric samples from patients and mice infected with H. pylori. Gastric tissues from interleukin (IL)-22-deficient and wild-type (control) mice were also examined. Tissue inflammation was determined for pro-inflammatory cell infiltration and pro-inflammatory protein production. Gastric epithelial cells and myeloid-derived suppressor cells (MDSC) were isolated, stimulated and/or cultured for Th22 cell function assays. Th22 cells accumulated in gastric mucosa of both patients and mice infected with H. pylori. Th22 cell polarisation was promoted via the production of IL-23 by dendritic cells (DC) during H. pylori infection, and resulted in increased inflammation within the gastric mucosa. This inflammation was characterised by the CXCR2-dependent influx of MDSCs, whose migration was induced via the IL-22-dependent production of CXCL2 by gastric epithelial cells. Under the influence of IL-22, MDSCs, in turn, produced pro-inflammatory proteins, such as S100A8 and S100A9, and suppressed Th1 cell responses, thereby contributing to the development of H. pylori-associated gastritis. This study, therefore, identifies a novel regulatory network involving H. pylori, DCs, Th22 cells, gastric epithelial cells and MDSCs, which collectively exert a pro-inflammatory effect within the gastric microenvironment. Efforts to inhibit this Th22-dependent pathway may therefore prove a valuable strategy in the therapy of H. pylori-associated gastritis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  8. Proinflammatory effects of exogenously administered IL-10 in experimental autoimmune orchitis

    DEFF Research Database (Denmark)

    Kaneko, Tetsushi; Itoh, Masahiro; Nakamura, Yoichi

    2003-01-01

    We studied the effects of exogenously administered recombinant murine interleukin (IL)-10 on the development of experimental autoimmune orchitis (EAO) in C3H/He mice. IL-10 significantly augments histological signs of EAO when administered for 6 consecutive days from days 15 to 20 after primary...... immunisations with testicular germ cells. These data demonstrate that IL-10, in addition to its well-known antiinflammatory property, also has proinflammatory functions capable of up-regulating testicular immunoinflammatory processes in vivo....

  9. Globular adiponectin induces a pro-inflammatory response in human astrocytic cells

    Energy Technology Data Exchange (ETDEWEB)

    Wan, Zhongxiao; Mah, Dorrian; Simtchouk, Svetlana [School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC (Canada); Klegeris, Andis [Department of Biology, University of British Columbia Okanagan, Kelowna, BC (Canada); Little, Jonathan P., E-mail: jonathan.little@ubc.ca [School of Health and Exercise Sciences, University of British Columbia Okanagan, Kelowna, BC (Canada)

    2014-03-28

    Highlights: • Adiponectin receptors are expressed in human astrocytes. • Globular adiponectin induces secretion of IL-6 and MCP-1 from cultured astrocytes. • Adiponectin may play a pro-inflammatory role in astrocytes. - Abstract: Neuroinflammation, mediated in part by activated brain astrocytes, plays a critical role in the development of neurodegenerative disorders, including Alzheimer’s disease (AD). Adiponectin is the most abundant adipokine secreted from adipose tissue and has been reported to exert both anti- and pro-inflammatory effects in peripheral tissues; however, the effects of adiponectin on astrocytes remain unknown. Shifts in peripheral concentrations of adipokines, including adiponectin, could contribute to the observed link between midlife adiposity and increased AD risk. The aim of the present study was to characterize the effects of globular adiponectin (gAd) on pro-inflammatory cytokine mRNA expression and secretion in human U373 MG astrocytic cells and to explore the potential involvement of nuclear factor (NF)-κB, p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, c-Jun N-terminal kinase (JNK) and phosphatidylinositide 3-kinases (PI3 K) signaling pathways in these processes. We demonstrated expression of adiponectin receptor 1 (adipoR1) and adipoR2 in U373 MG cells and primary human astrocytes. gAd induced secretion of interleukin (IL)-6 and monocyte chemoattractant protein (MCP)-1, and gene expression of IL-6, MCP-1, IL-1β and IL-8 in U373 MG cells. Using specific inhibitors, we found that NF-κB, p38MAPK and ERK1/2 pathways are involved in gAd-induced induction of cytokines with ERK1/2 contributing the most. These findings provide evidence that gAd may induce a pro-inflammatory phenotype in human astrocytes.

  10. Hemocyanins Stimulate Innate Immunity by Inducing Different Temporal Patterns of Proinflammatory Cytokine Expression in Macrophages.

    Science.gov (United States)

    Zhong, Ta-Ying; Arancibia, Sergio; Born, Raimundo; Tampe, Ricardo; Villar, Javiera; Del Campo, Miguel; Manubens, Augusto; Becker, María Inés

    2016-06-01

    Hemocyanins induce a potent Th1-dominant immune response with beneficial clinical outcomes when used as a carrier/adjuvant in vaccines and nonspecific immunostimulant in cancer. However, the mechanisms by which hemocyanins trigger innate immune responses, leading to beneficial adaptive immune responses, are unknown. This response is triggered by a proinflammatory signal from various components, of which macrophages are an essential part. To understand how these proteins influence macrophage response, we investigated the effects of mollusks hemocyanins with varying structural and immunological properties, including hemocyanins from Concholepas concholepas, Fissurella latimarginata, and Megathura crenulata (keyhole limpet hemocyanin), on cultures of peritoneal macrophages. Hemocyanins were phagocytosed and slowly processed. Analysis of this process showed differential gene expression along with protein levels of proinflammatory markers, including IL-1β, IL-6, IL-12p40, and TNF-α. An extended expression analysis of 84 cytokines during a 24-h period showed a robust proinflammatory response for F. latimarginata hemocyanin in comparison with keyhole limpet hemocyanin and C. concholepas hemocyanin, which was characterized by an increase in the transcript levels of M1 cytokines involved in leukocyte recruitment. These cytokine genes included chemokines (Cxcl1, Cxcl3, Cxcl5, Ccl2, and Ccl3), ILs (Il1b and Ifng), growth factors (Csf2 and Csf3), and TNF family members (Cd40lg). The protein levels of certain cytokines were increased. However, every hemocyanin maintains downregulated key M2 cytokine genes, including Il4 and Il5 Collectively, our data demonstrate that hemocyanins are able to trigger the release of proinflammatory factors with different patterns of cytokine expression, suggesting differential signaling pathways and transcriptional network mechanisms that lead to the activation of M1-polarized macrophages. Copyright © 2016 by The American Association of

  11. Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye patients

    OpenAIRE

    Na, Kyung-Sun; Mok, Jee-Won; Kim, Ja Yeon; Joo, Choun-Ki

    2011-01-01

    Purpose To determine whether proinflammatory cytokine genes were potential susceptibility candidate genes for Korean patients with non-Sjogren dry eye, we investigated the association of the interleukin 1 beta (IL1B), interleukin 6 (IL6), and interleukin 6 receptor (IL6R) variations with this disease in Korean patients. Methods Genomic DNA was extracted from blood samples of unrelated non-Sjogren dry eye patients and healthy control individuals who visited the Eye Center and Health Promotion ...

  12. Fisetin Inhibits Hyperglycemia-Induced Proinflammatory Cytokine Production by Epigenetic Mechanisms

    Directory of Open Access Journals (Sweden)

    Hye Joo Kim

    2012-01-01

    Full Text Available Diabetes is characterized by a proinflammatory state, and several inflammatory processes have been associated with both type 1 and type 2 diabetes and the resulting complications. High glucose levels induce the release of proinflammatory cytokines. Fisetin, a flavonoid dietary ingredient found in the smoke tree (Cotinus coggygria, and is also widely distributed in fruits and vegetables. Fisetin is known to exert anti-inflammatory effects via inhibition of the NF-κB signaling pathway. In this study, we analyzed the effects of fisetin on proinflammatory cytokine secretion and epigenetic regulation, in human monocytes cultured under hyperglycemic conditions. Human monocytic (THP-1 cells were cultured under control (14.5 mmol/L mannitol, normoglycemic (NG, 5.5 mmol/L glucose, or hyperglycemic (HG, 20 mmol/L glucose conditions, in the absence or presence of fisetin. Fisetin was added (3–10 μM for 48 h. While the HG condition significantly induced histone acetylation, NF-κB activation, and proinflammatory cytokine (IL-6 and TNF-α release from THP-1 cells, fisetin suppressed NF-κB activity and cytokine release. Fisetin treatment also significantly reduced CBP/p300 gene expression, as well as the levels of acetylation and HAT activity of the CBP/p300 protein, which is a known NF-κB coactivator. These results suggest that fisetin inhibits HG-induced cytokine production in monocytes, through epigenetic changes involving NF-κB. We therefore propose that fisetin supplementation be considered for diabetes prevention.

  13. Histamine mediates the pro-inflammatory effect of latex of Calotropis procera in rats

    Directory of Open Access Journals (Sweden)

    Yatin M. Shivkar

    2003-01-01

    Full Text Available Introduction: Calotropis procera is known to produce contact dermatitis and the latex of this plant produces intense inflammation when injected locally. However, the precise mode of its pro-inflammatory effect is not known. In present study we have pharmacologically characterized the inflammation induced by latex of C. procera in a rat paw edema model and determined the role of histamine in latex-induced inflammation.

  14. Chitosan drives anti-inflammatory macrophage polarisation and pro-inflammatory dendritic cell stimulation

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    MI Oliveira

    2012-07-01

    Full Text Available Macrophages and dendritic cells (DC share the same precursor and play key roles in immunity. Modulation of their behaviour to achieve an optimal host response towards an implanted device is still a challenge. Here we compare the differentiation process and polarisation of these related cell populations and show that they exhibit different responses to chitosan (Ch, with human monocyte-derived macrophages polarising towards an anti-inflammatory phenotype while their DC counterparts display pro-inflammatory features. Macrophages and DC, whose interactions with biomaterials are frequently analysed using fully differentiated cells, were cultured directly on Ch films, rather than exposed to the polymer after complete differentiation. Ch was the sole stimulating factor and activated both macrophages and DC, without leading to significant T cell proliferation. After 10 d on Ch, macrophages significantly down-regulated expression of pro-inflammatory markers, CD86 and MHCII. Production of pro-inflammatory cytokines, particularly TNF-α, decreased with time for cells cultured on Ch, while anti-inflammatory IL-10 and TGF-β1, significantly increased. Altogether, these results suggest an M2c polarisation. Also, macrophage matrix metalloproteinase activity was augmented and cell motility was stimulated by Ch. Conversely, DC significantly enhanced CD86 expression, reduced IL-10 secretion and increased TNF-α and IL-1β levels. Our findings indicate that cells with a common precursor may display different responses, when challenged by the same biomaterial. Moreover, they help to further comprehend macrophage/DC interactions with Ch and the balance between pro- and anti-inflammatory signals associated with implant biomaterials. We propose that an overall pro-inflammatory reaction may hide the expression of anti-inflammatory cytokines, likely relevant for tissue repair/regeneration.

  15. Supplementation of xanthophylls decreased proinflammatory and increased anti-inflammatory cytokines in hens and chicks.

    Science.gov (United States)

    Gao, Yu-Yun; Xie, Qing-Mei; Jin, Ling; Sun, Bao-Li; Ji, Jun; Chen, Feng; Ma, Jing-Yun; Bi, Ying-Zuo

    2012-11-28

    The present study investigated the effects of xanthophylls (containing 40 % of lutein and 60 % of zeaxanthin) on proinflammatory cytokine (IL-1β, IL-6, interferon (IFN)-γ and lipopolysaccharide-induced TNF-α factor (LITAF)) and anti-inflammatory cytokine (IL-4 and IL-10) expression of breeding hens and chicks. In Expt 1, a total of 432 hens were fed diets supplemented with 0 (as the control group), 20 or 40 mg/kg xanthophylls (six replicates per treatment). The liver, duodenum, jejunum and ileum were sampled at 35 d of the trial. The results showed that both levels of xanthophyll addition decreased IL-1β mRNA in the liver and jejunum, IL-6 mRNA in the liver, IFN-γ mRNA in the jejunum and LITAF mRNA in the liver compared to the control group. Expt 2 was a 2 × 2 factorial design. Male chicks hatched from 0 or 40 mg/kg xanthophyll diet of hens were fed a diet containing either 0 or 40 mg/kg xanthophylls. The liver, duodenum, jejunum and ileum were collected at 0, 7, 14 and 21 d after hatching. The results showed that in ovo xanthophylls decreased proinflammatory cytokine expression (IL-1β, IL-6, IFN-γ and LITAF) in the liver, duodenum, jejunum and ileum and increased anti-inflammatory cytokine expression (IL-4 and IL-10) in the liver, jejunum and ileum mainly at 0-7 d after hatching. In ovo effects gradually vanished and dietary effects began to work during 1-2 weeks after hatching. Dietary xanthophylls modulated proinflammatory cytokines (IL-1β, IL-6 and IFN-γ) in the liver, duodenum, jejunum and ileum and anti-inflammatory cytokine (IL-10) in the liver and jejunum mainly from 2 weeks onwards. In conclusion, xanthophylls could regulate proinflammatory and anti-inflammatory cytokine expression in different tissues of hens and chicks.

  16. Murine Neonates Infected with Yersinia enterocolitica Develop Rapid and Robust Proinflammatory Responses in Intestinal Lymphoid Tissues

    Science.gov (United States)

    Siefker, David T.; Echeverry, Andrea; Brambilla, Roberta; Fukata, Masayuki; Schesser, Kurt

    2014-01-01

    Neonatal animals are generally very susceptible to infection with bacterial pathogens. However, we recently reported that neonatal mice are highly resistant to orogastric infection with Yersinia enterocolitica. Here, we show that proinflammatory responses greatly exceeding those in adults arise very rapidly in the mesenteric lymph nodes (MLN) of neonates. High-level induction of proinflammatory gene expression occurred in the neonatal MLN as early as 18 h postinfection. Marked innate phagocyte recruitment was subsequently detected at 24 h postinfection. Enzyme-linked immunosorbent spot assay (ELISPOT) analyses indicated that enhanced inflammation in neonatal MLN is contributed to, in part, by an increased frequency of proinflammatory cytokine-secreting cells. Moreover, both CD11b+ and CD11b− cell populations appeared to play a role in proinflammatory gene expression. The level of inflammation in neonatal MLN was also dependent on key bacterial components. Y. enterocolitica lacking the virulence plasmid failed to induce innate phagocyte recruitment. In contrast, tumor necrosis factor alpha (TNF-α) protein expression and neutrophil recruitment were strikingly higher in neonatal MLN after infection with a yopP-deficient strain than with wild-type Y. enterocolitica, whereas only modest increases occurred in adults. This hyperinflammatory response was associated with greater colonization of the spleen and higher mortality in neonates, while there was no difference in mortality among adults. This model highlights the dynamic levels of inflammation in the intestinal lymphoid tissues and reveals the protective (wild-type strain) versus harmful (yopP-deficient strain) consequences of inflammation in neonates. Moreover, these results reveal that the neonatal intestinal lymphoid tissues have great potential to rapidly mobilize innate components in response to infection with bacterial enteropathogens. PMID:24478090

  17. Understanding the independent influence of duty and achievement striving when predicting the relationship between conscientiousness and organizational cultural profiles and helping behaviors.

    Science.gov (United States)

    Moon, Henry; Livne, Ephrat; Marinova, Sophia

    2013-01-01

    The theory that 2 facets of the factor conscientiousness, duty and achievement striving, are related to self- or other-centered motives, is supported in 2 studies. In Study 1 (N = 204 undergraduates), the self-centered facet of achievement striving was found to be the most important predictor of attraction toward organizational cultures that were outcome-based, aggressive, and emphasized rewards. Achievement strivers were less attracted to supportive and decisive organizations. In Study 2 (N = 189 part-time MBA students) the other-centered facet of duty was found to be predictive of helping behaviors. Theoretical and practical implications are discussed.

  18. Anthocyanin prevents CD40-activated proinflammatory signaling in endothelial cells by regulating cholesterol distribution.

    Science.gov (United States)

    Xia, Min; Ling, Wenhua; Zhu, Huilian; Wang, Qing; Ma, Jing; Hou, Mengjun; Tang, Zhihong; Li, Lan; Ye, Qinyuan

    2007-03-01

    Intracellular tumor necrosis factor receptor-associated factors (TRAFs) translocation to lipid rafts is a key element in CD40-induced signaling. The purpose of this study was to investigate the influence of anthocyanin on CD40-mediated proinflammatory events in human endothelial cells and the underlying possible molecular mechanism. Treatment of endothelial cells with anthocyanin prevented from CD40-induced proinflammatory status, measured by production of IL-6, IL-8, and monocyte chemoattractant protein-1 through inhibiting CD40-induced nuclear factor-kappaB (NF-kappaB) activation. TRAF-2 played pivotal role in CD40-NF-kappaB pathway as TRAF-2 small interference RNA (siRNA) diminished CD40-induced NF-kappaB activation and inflammation. TRAF-2 overexpression increased CD40-mediated NF-kappaB activation. Moreover, TRAF-2 almost totally recruited to lipid rafts after stimulation by CD40 ligand and depletion of cholesterol diminished CD40-mediated NF-kappaB activation. Exposure to anthocyanin not only interrupted TRAF-2 recruitment to lipid rafts but also decreased cholesterol content in Triton X-100 insoluble lipid rafts. However, anthocyanin did not influence the interaction between CD40 ligand and CD40 receptor. Our findings suggest that anthocyanin protects from CD40-induced proinflammatory signaling by preventing TRAF-2 translocation to lipid rafts through regulation of cholesterol distribution, which thereby may represent a mechanism that would explain the anti-inflammatory response of anthocyanin.

  19. Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

    Directory of Open Access Journals (Sweden)

    Stephanie H. Shirley

    2012-01-01

    Full Text Available Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy.

  20. Irradiation of existing atherosclerotic lesions increased inflammation by favoring pro-inflammatory macrophages

    International Nuclear Information System (INIS)

    Gabriels, Karen; Hoving, Saske; Gijbels, Marion J.; Pol, Jeffrey F.; Poele, Johannes A. te; Biessen, Erik A.; Daemen, Mat J.; Stewart, Fiona A.; Heeneman, Sylvia

    2014-01-01

    Background and purpose: Recent studies have shown an increased incidence of localized atherosclerosis and subsequent cardiovascular events in cancer patients treated with thoracic radiotherapy. We previously demonstrated that irradiation accelerated the development of atherosclerosis and predisposed to an inflammatory plaque phenotype in young hypercholesterolemic ApoE −/− mice. However, as older cancer patients already have early or advanced stages of atherosclerosis at the time of radiotherapy, we investigated the effects of irradiation on the progression of existing atherosclerotic lesions in vivo. Material and methods: ApoE −/− mice (28 weeks old) received local irradiation with 14 or 0 Gy (sham-treated) at the aortic arch and were examined after 4 and 12 weeks for atherosclerotic lesions, plaque size and phenotype. Moreover, we investigated the impact of irradiation on macrophage phenotype (pro- or anti-inflammatory) and function (efferocytotic capacity, i.e. clearance of apoptotic cells) in vitro. Results: Irradiation of existing lesions in the aortic arch resulted in smaller, macrophage-rich plaques with intraplaque hemorrhage and increased apoptosis. In keeping with the latter, in vitro studies revealed augmented polarization toward pro-inflammatory macrophages after irradiation and reduced efferocytosis by anti-inflammatory macrophages. In addition, considerably more lesions in irradiated mice were enriched in pro-inflammatory macrophages. Conclusions: Irradiation of existing atherosclerotic lesions led to smaller but more inflamed plaques, with increased numbers of apoptotic cells, most likely due to a shift toward pro-inflammatory macrophages in the plaque

  1. Changes in proinflammatory cytokines and white matter in chronically stressed rats

    Directory of Open Access Journals (Sweden)

    Yang P

    2015-03-01

    Full Text Available Ping Yang,1 Zhenyong Gao,1 Handi Zhang,1 Zeman Fang,1 Cairu Wu,1 Haiyun Xu,1,2 Qing-Jun Huang1 1Mental Health Center, 2Department of Anatomy, Shantou University Medical College, Shantou, Guangdong, People’s Republic of China Abstract: Although the pathogenesis of depression, an incapacitating psychiatric ailment, remains largely unknown, previous human and animal studies have suggested that both proinflammatory cytokines and altered oligodendrocytes play important roles in the condition. This study examined these two factors in the brains of rats following unpredictable chronic mild stress for 4 weeks, with the hypothesis that chronic stress may affect oligodendrocytes and elevate proinflammatory cytokines in the brain. After suffering unpredictable stressors for 4 weeks, the rats showed depression-like behaviors, including decreased locomotion in the open field, increased immobility time in the forced swim test, and decreased sucrose consumption and less sucrose preference when compared with controls. Immunohistochemical staining of brain sections showed higher immunoreactivity of proinflammatory cytokines in certain brain regions of stressed rats compared with controls; lower immunoreactivity of myelin basic protein and fewer mature oligodendrocytes were seen in the prefrontal cortex, but no demyelination was detected. These results are interpreted and discussed in the context of recent findings from human and animal studies. Keywords: cytokines, depression, myelination, oligodendrocytes, stress 

  2. A Proinflammatory Effect of the β-Glucan from Pleurotus cornucopiae Mushroom on Macrophage Action

    Directory of Open Access Journals (Sweden)

    Ken-ichiro Minato

    2017-01-01

    Full Text Available PCPS from P. citrinopileatus mushroom extract is a β-1,6-glucan possessing a proinflammatory effect on innate immune cells. The PCPS stimulated THP-1 macrophages to secrete significant levels of TNF. Moreover, the mRNA expressions of TNF and IL-1β were significantly enhanced by PCPS treatment. However, the PCPS did not induce to express both IL-12 and IL-10 mRNA in the macrophages. Next, the P. cornucopiae extract (containing mainly PCPS treatment against mice showed significant increases in TNF and IL-1β mRNA expressions in the peritoneal macrophages of them. In this study, the expression levels of IFNγ mRNA in the spleen were almost the same between the extract- (PCPS- treated group and control group. However, the expression of IL-4 mRNA showed a lower level in the extract-treated group than that in the control. Our results suggested that the PCPS could induce proinflammatory action in the immune response. In addition, the proinflammatory effect of the PCPS on THP-1 was enhanced by 5′-GMP-Na, while it was reduced by vitamin D2. These two compounds are majorly contained in the P. citrinopileatus mushroom. Therefore, these results suggested that the P. citrinopileatus mushroom might contain other immune regulative compounds, such as vitamin D2, as well as PCPS.

  3. Herpesviruses viral loads and levels of proinflammatory cytokines in apical periodontitis.

    Science.gov (United States)

    Jakovljevic, A; Knezevic, A; Nikolic, N; Soldatovic, I; Jovanovic, T; Milasin, J; Andric, M

    2018-07-01

    This study aimed to analyse Epstein-Barr virus (EBV) and human cytomegalovirus (HCMV) viral loads in symptomatic and asymptomatic apical periodontitis lesions, to determine levels of TNF-α, IL-1β and IL-6 in these lesions and to investigate a possible correlation between herpesviral copy numbers and levels of proinflammatory cytokines. A total of 100 samples of apical periodontitis were subjected to HCMV and EBV copy numbers analysis by nested polymerase chain reaction (PCR) and TaqMan real-time PCR. The concentrations of TNF-α, IL-1β and IL-6 were determined by ELISA method. SPSS software was used for statistical analysis. There were no significant differences in the occurrence of EBV and HCMV between symptomatic and asymptomatic periapical lesions (p = .686, p = .879, respectively). Only 12 of 74 EBV (16.2%) and four of 54 HCMV (13.5%) nested PCR-positive samples showed increased viral copy numbers above the limit of 125 copies/ml. There was no significant correlation between the levels of analysed proinflammatory cytokines and herpesviral copy numbers in our sample. The observed low viral loads point to a relatively rare occurrence of active EBV and HCMV infection in our sample. Latent herpesviral infection does not enhance the production of investigated proinflammatory cytokines. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.

  4. Transferrin-derived synthetic peptide induces highly conserved pro-inflammatory responses of macrophages.

    Science.gov (United States)

    Haddad, George; Belosevic, Miodrag

    2009-02-01

    We examined the induction of macrophage pro-inflammatory responses by transferrin-derived synthetic peptide originally identified following digestion of transferrin from different species (murine, bovine, human N-lobe and goldfish) using elastase. The mass spectrometry analysis of elastase-digested murine transferrin identified a 31 amino acid peptide located in the N2 sub-domain of the transferrin N-lobe, that we named TMAP. TMAP was synthetically produced and shown to induce a number of pro-inflammatory genes by quantitative PCR. TMAP induced chemotaxis, a potent nitric oxide response, and TNF-alpha secretion in different macrophage populations; P338D1 macrophage-like cells, mouse peritoneal macrophages, mouse bone marrow-derived macrophages (BMDM) and goldfish macrophages. The treatment of BMDM cultures with TMAP stimulated the production of nine cytokines and chemokines (IL-6, MCP-5, MIP-1 alpha, MIP-1 gamma, MIP-2, GCSF, KC, VEGF, and RANTES) that was measured using cytokine antibody array and confirmed by Western blot. Our results indicate that transferrin-derived peptide, TMAP, is an immunomodulating molecule capable of inducing pro-inflammatory responses in lower and higher vertebrates.

  5. Intermittent fasting during Ramadan attenuates proinflammatory cytokines and immune cells in healthy subjects.

    Science.gov (United States)

    Faris, Mo'ez Al-Islam E; Kacimi, Safia; Al-Kurd, Ref'at A; Fararjeh, Mohammad A; Bustanji, Yasser K; Mohammad, Mohammad K; Salem, Mohammad L

    2012-12-01

    Intermittent fasting and caloric restriction have been shown to extend life expectancy and reduce inflammation and cancer promotion in animal models. It was hypothesized that intermittent prolonged fasting practiced during the month of Ramadan (RIF) could positively affect the inflammatory state. To investigate this hypothesis, a cross-sectional study was designed to investigate the impact of RIF on selected inflammatory cytokines and immune biomarkers in healthy subjects. Fifty (21 men and 29 women) healthy volunteers who practiced Ramadan fasting were recruited for the investigation of circulating proinflammatory cytokines (interleukin [IL]-1β, IL-6, and tumor necrosis factor α), immune cells (total leukocytes, monocytes, granulocytes, and lymphocytes), and anthropometric and dietary assessments. The investigations were conducted 1 week before Ramadan fasting, at the end of the third week of Ramadan, and 1 month after the cessation of Ramadan month. The proinflammatory cytokines IL-1β, IL-6, and tumor necrosis factor α; systolic and diastolic blood pressures; body weight; and body fat percentage were significantly lower (P fasting. Immune cells significantly decreased during Ramadan but still remained within the reference ranges. These results indicate that RIF attenuates inflammatory status of the body by suppressing proinflammatory cytokine expression and decreasing body fat and circulating levels of leukocytes. Copyright © 2012 Elsevier Inc. All rights reserved.

  6. Proinflammatory Soluble Interleukin-15 Receptor Alpha Is Increased in Rheumatoid Arthritis

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    Ana Cecilia Machado Diaz

    2012-01-01

    Full Text Available Rheumatoid arthritis (RA is an autoimmune and inflammatory disease in which many cytokines have been implicated. In particular, IL-15 is a cytokine involved in the inflammatory processes and bone loss. The aim of this study was to investigate the existence in synovial fluid of soluble IL-15Rα, a private receptor subunit for IL-15 which may act as an enhancer of IL-15-induced proinflammatory cytokines. Soluble IL-15Rα was quantified by a newly developed enzyme-linked immunosorbent assay (ELISA in samples of synovial fluid from patients with RA and osteoarthritis (OA. The levels of IL-15Rα were significantly increased in RA patients compared to OA patients. Also, we studied the presence of membrane-bound IL-15 in cells from synovial fluids, another element necessary to induce pro-inflammatory cytokines through reverse signaling. Interestingly, we found high levels of IL-6 related to high levels of IL-15Rα in RA but not in OA. Thus, our results evidenced presence of IL-15Rα in synovial fluids and suggested that its pro-inflammatory effect could be related to induction of IL-6.

  7. Loss of function mutations in the progranulin gene are related to pro-inflammatory cytokine dysregulation in frontotemporal lobar degeneration patients

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    Spalletta Gianfranco

    2011-06-01

    Full Text Available Abstract The progranulin gene (PGRN encodes a pleiotropic molecule with anti-inflammatory actions and neuronal protective effects. Accordingly, PGRN-deficient mice have been demonstrated to develop enhanced inflammation and progressive neurodegeneration. Loss of function mutations of the PGRN gene have been also reported to cause frontotemporal lobar degeneration (FTLD, a neurodegenerative disease leading to dementia generally in the presenium. Since neurodegeneration might be negatively impacted by chronic inflammation, the possible influence of PGRN defects on inflammatory pathways appears to be of great relevance for the understanding of neurodegeneration pathogenic processes in those patients. However, no data about the inflammatory profile of PGRN-defective subjects have been so far provided. In this study, we analyzed serum levels of the pro-inflammatory mediators IL-6, TNF-α and IL-18 in FTLD patients with or without PGRN mutations, at both pre-symptomatic and symptomatic stages. We provide evidence that circulating IL-6 is increased in PGRN-mutated FTLD patients, as compared to both PGRN non-mutated FTLD patients and controls. In contrast, levels of IL-6 were not altered in asymptomatic subjects carrying the PGRN mutations. Finally, TNF-α and IL-18 serum levels did not differ among all groups of included subjects. We conclude that the profile of circulating pro-inflammatory cytokines is altered in PGRN-related symptomatic FTLD. Thus, our findings point to IL-6 as a possible specific mediator and a potential therapeutic target in this monogenic disease, suggesting that an enhanced inflammatory response might be indeed involved in its progression.

  8. PRECIPITATING FACTORS, CLINICAL PROFILE AND METABOLIC ABNORMALITIES OF DIABETIC KETOACIDOSIS IN CHILDREN WITH TYPE 1 DIABETES AND THEIR ROLE IN PREDICTING THE OUTCOME

    Directory of Open Access Journals (Sweden)

    Madhava Vijaya Kumar

    2017-01-01

    Full Text Available BACKGROUND The aim of the study is to study the clinical profile of diabetic ketoacidosis in children with type 1 diabetes to identify the precipitating factors, to assess the metabolic alterations due to this illness and to correlate these parameters with the outcome. MATERIALS AND METHODS This was a prospective observational study and 33 children admitted in PICU during the study period were recruited for the study. RESULTS 24 children were newly-diagnosed cases and 9 children were already established cases of type 1 diabetes. Mean age group was 10.7 years. Major precipitating causes of DKA in established cases were intercurrent respiratory infections and omission of insulin. Nausea, vomiting, thirst and polyuria were the most common symptoms. Mean duration of symptoms before diagnosing DKA were 20 days in newly-diagnosed cases and 4 days in established cases. ¾ of children had dehydration at the time of admission. Severity was more in younger children. Commonest biochemical abnormality was hypokalaemia. Late diagnosis and delay in the initiation of treatment were the commonest predisposing factors for the development of cerebral oedema. CONCLUSION DKA is a life-threatening complication of type 1 diabetes and the red flag signs of bad outcome were young age, late diagnosis, late referral and late initiation of treatment. Hence, a high index of suspicion is necessary to diagnose DKA in first presentation of diabetes as well as in established cases.

  9. The association between school exclusion, delinquency and subtypes of cyber- and F2F-victimizations: identifying and predicting risk profiles and subtypes using latent class analysis.

    Science.gov (United States)

    Barboza, Gia Elise

    2015-01-01

    This purpose of this paper is to identify risk profiles of youth who are victimized by on- and offline harassment and to explore the consequences of victimization on school outcomes. Latent class analysis is used to explore the overlap and co-occurrence of different clusters of victims and to examine the relationship between class membership and school exclusion and delinquency. Participants were a random sample of youth between the ages of 12 and 18 selected for inclusion to participate in the 2011 National Crime Victimization Survey: School Supplement. The latent class analysis resulted in four categories of victims: approximately 3.1% of students were highly victimized by both bullying and cyberbullying behaviors; 11.6% of youth were classified as being victims of relational bullying, verbal bullying and cyberbullying; a third class of students were victims of relational bullying, verbal bullying and physical bullying but were not cyberbullied (8%); the fourth and final class, characteristic of the majority of students (77.3%), was comprised of non-victims. The inclusion of covariates to the latent class model indicated that gender, grade and race were significant predictors of at least one of the four victim classes. School delinquency measures were included as distal outcomes to test for both overall and pairwise associations between classes. With one exception, the results were indicative of a significant relationship between school delinquency and the victim subtypes. Implications for these findings are discussed. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Policy-Led Comparative Environmental Risk Assessment of Genetically Modified Crops: Testing for Increased Risk Rather Than Profiling Phenotypes Leads to Predictable and Transparent Decision-Making

    Directory of Open Access Journals (Sweden)

    Alan Raybould

    2018-04-01

    Full Text Available We describe two contrasting methods of comparative environmental risk assessment for genetically modified (GM crops. Both are science-based, in the sense that they use science to help make decisions, but they differ in the relationship between science and policy. Policy-led comparative risk assessment begins by defining what would be regarded as unacceptable changes when the use a particular GM crop replaces an accepted use of another crop. Hypotheses that these changes will not occur are tested using existing or new data, and corroboration or falsification of the hypotheses is used to inform decision-making. Science-led comparative risk assessment, on the other hand, tends to test null hypotheses of no difference between a GM crop and a comparator. The variables that are compared may have little or no relevance to any previously stated policy objective and hence decision-making tends to be ad hoc in response to possibly spurious statistical significance. We argue that policy-led comparative risk assessment is the far more effective method. With this in mind, we caution that phenotypic profiling of GM crops, particularly with omics methods, is potentially detrimental to risk assessment.

  11. Alteration in peripheral blood concentration of certain pro-inflammatory cytokines in cows developing retention of fetal membranes.

    Science.gov (United States)

    Boro, Prasanta; Kumaresan, A; Pathak, Rupal; Patbandha, T K; Kumari, Susavi; Yadav, Asha; Manimaran, A; Baithalu, R K; Attupuram, Nitin M; Mohanty, T K

    2015-06-01

    Retention of fetal membranes (RFM) adversely affects the production and reproduction potential of the affected cows leading to huge economic loss. Physiological separation of fetal membranes is reported to be an inflammatory process. The present study compared the concentrations of certain pro inflammatory cytokines [Interleukin 1β (IL-1), Interleukin 6 (IL-6), Interleukin 8 (IL-8) and Tumor necrosis factor α (TNF-α) between the cows that developed RFM (n=10) and the cows that expelled fetal membranes normally (n=10) to find out if they could serve as a predictive tool for RFM. Blood samples were collected from the cows from 30 days before expected parturition through day -21, day -14, day -7, day -5, day -3, day -1, on the day of parturition (day 0), day 1 postpartum and the pro-inflammatory cytokines were estimated in blood plasma by ELISA method. The IL-1β concentration was significantly lower (Pmembranes normally from 3 days before calving till the day of calving. The plasma concentrations of IL-6 and IL-8 were also lower (Pmembranes normally. It may be inferred that the concentrations of IL-1, IL-6, IL-8 and TNF-α around parturition were altered in cows developing RFM compared to those expelled fetal membranes normally. Copyright © 2015. Published by Elsevier B.V.

  12. LYATK1 potently inhibits LPS-mediated pro-inflammatory response

    International Nuclear Information System (INIS)

    Xi, Feng; Liu, Yuan; Wang, Xiujuan; Kong, Wei; Zhao, Feng

    2016-01-01

    Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.

  13. LYATK1 potently inhibits LPS-mediated pro-inflammatory response

    Energy Technology Data Exchange (ETDEWEB)

    Xi, Feng [Department of Intensive Care Unit, Taixing People" ' s Hospital, Taixing, Jiangsu Province, 225400 (China); Liu, Yuan [Department of Ophthalmology, Nanjing First Hospital, Nanjing Medical University, Nanjing (China); Wang, Xiujuan; Kong, Wei [Department of Intensive Care Unit, Taixing People" ' s Hospital, Taixing, Jiangsu Province, 225400 (China); Zhao, Feng, E-mail: taixingzhaofeng163@163.com [Department of Intensive Care Unit, Taixing People" ' s Hospital, Taixing, Jiangsu Province, 225400 (China)

    2016-01-29

    Lipopolysaccharide (LPS)-primed monocytes/macrophages produce pro-inflammatory cytokines, which could lead to endotoxin shock. TGF-β-activated kinase1 (TAK1) activation is involved in the process. In the current study, we studied the potential effect of a selective TAK1 inhibitor, LYTAK1, on LPS-stimulated response both in vitro and in vivo. We demonstrated that LYTAK1 inhibited LPS-induced mRNA expression and production of several pro-inflammatory cytokines [interleukin 1β (IL-1β), tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6)] in RAW 264.7 macrophages. LYTAK1's activity was almost nullified with TAK1 shRNA-knockdown. Meanwhile, in both primary mouse bone marrow derived macrophages (BMDMs) and human peripheral blood mononuclear cells (PBMCs), LPS-induced pro-inflammatory cytokine production was again attenuated with LYTAK1 co-treatment. Molecularly, LYTAK1 dramatically inhibited LPS-induced TAK1-nuclear factor kappa B (NFκB) and mitogen-activated protein kinase (Erk, Jnk and p38) activation in RAW 264.7 cells, mouse BMDMs and human PBMCs. In vivo, oral administration of LYTAK1 inhibited LPS-induced activation of TAK1-NFκB-p38 in ex-vivo cultured PBMCs, and cytokine production and endotoxin shock in mice. Together, these results demonstrate that LYTAK1 inhibits LPS-induced production of several pro-inflammatory cytokines and endotoxin shock probably through blocking TAK1-regulated signalings. - Highlights: • LYTAK1 inhibits LPS-induced pro-inflammatory cytokine production in RAW 264.7 cells. • The effect by LYTAK1 is more potent than other known TAK1 inhibitors. • LYTAK1 inhibits LPS-induced cytokine production in primary macrophages/monocytes. • LYTAK1 inhibits LPS-induced TAK1-NFκB and MAPK activation in macrophages/monocytes. • LYTAK1 gavage inhibits LPS-induced endotoxin shock and cytokine production in mice.

  14. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer.

    Science.gov (United States)

    Gianni, Luca; Zambetti, Milvia; Clark, Kim; Baker, Joffre; Cronin, Maureen; Wu, Jenny; Mariani, Gabriella; Rodriguez, Jaime; Carcangiu, Marialuisa; Watson, Drew; Valagussa, Pinuccia; Rouzier, Roman; Symmans, W Fraser; Ross, Jeffrey S; Hortobagyi, Gabriel N; Pusztai, Lajos; Shak, Steven

    2005-10-10

    We sought to identify gene expression markers that predict the likelihood of chemotherapy response. We also tested whether chemotherapy response is correlated with the 21-gene Recurrence Score assay that quantifies recurrence risk. Patients with locally advanced breast cancer received neoadjuvant paclitaxel and doxorubicin. RNA was extracted from the pretreatment formalin-fixed paraffin-embedded core biopsies. The expression of 384 genes was quantified using reverse transcriptase polymerase chain reaction and correlated with pathologic complete response (pCR). The performance of genes predicting for pCR was tested in patients from an independent neoadjuvant study where gene expression was obtained using DNA microarrays. Of 89 assessable patients (mean age, 49.9 years; mean tumor size, 6.4 cm), 11 (12%) had a pCR. Eighty-six genes correlated with pCR (unadjusted P < .05); pCR was more likely with higher expression of proliferation-related genes and immune-related genes, and with lower expression of estrogen receptor (ER) -related genes. In 82 independent patients treated with neoadjuvant paclitaxel and doxorubicin, DNA microarray data were available for 79 of the 86 genes. In univariate analysis, 24 genes correlated with pCR with P < .05 (false discovery, four genes) and 32 genes showed correlation with P < .1 (false discovery, eight genes). The Recurrence Score was positively associated with the likelihood of pCR (P = .005), suggesting that the patients who are at greatest recurrence risk are more likely to have chemotherapy benefit. Quantitative expression of ER-related genes, proliferation genes, and immune-related genes are strong predictors of pCR in women with locally advanced breast cancer receiving neoadjuvant anthracyclines and paclitaxel.

  15. How well does wind speed predict air-sea gas transfer in the sea ice zone? A synthesis of radon deficit profiles in the upper water column of the Arctic Ocean

    Science.gov (United States)

    Loose, B.; Kelly, R. P.; Bigdeli, A.; Williams, W.; Krishfield, R.; Rutgers van der Loeff, M.; Moran, S. B.

    2017-05-01

    We present 34 profiles of radon-deficit from the ice-ocean boundary layer of the Beaufort Sea. Including these 34, there are presently 58 published radon-deficit estimates of air-sea gas transfer velocity (k) in the Arctic Ocean; 52 of these estimates were derived from water covered by 10% sea ice or more. The average value of k collected since 2011 is 4.0 ± 1.2 m d-1. This exceeds the quadratic wind speed prediction of weighted kws = 2.85 m d-1 with mean-weighted wind speed of 6.4 m s-1. We show how ice cover changes the mixed-layer radon budget, and yields an "effective gas transfer velocity." We use these 58 estimates to statistically evaluate the suitability of a wind speed parameterization for k, when the ocean surface is ice covered. Whereas the six profiles taken from the open ocean indicate a statistically good fit to wind speed parameterizations, the same parameterizations could not reproduce k from the sea ice zone. We conclude that techniques for estimating k in the open ocean cannot be similarly applied to determine k in the presence of sea ice. The magnitude of k through gaps in the ice may reach high values as ice cover increases, possibly as a result of focused turbulence dissipation at openings in the free surface. These 58 profiles are presently the most complete set of estimates of k across seasons and variable ice cover; as dissolved tracer budgets they reflect air-sea gas exchange with no impact from air-ice gas exchange.

  16. Ethnic influences on the relations between abdominal subcutaneous and visceral adiposity, liver fat, and cardiometabolic risk profile: the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity.

    Science.gov (United States)

    Nazare, Julie-Anne; Smith, Jessica D; Borel, Anne-Laure; Haffner, Steven M; Balkau, Beverley; Ross, Robert; Massien, Christine; Alméras, Natalie; Després, Jean-Pierre

    2012-10-01

    Ethnic differences in cardiometabolic risk (CMR) may be related to patterns of ethnic-specific body fat distribution. We aimed to identify differences across ethnic groups in interrelations between BMI, abdominal adiposity, liver fat, and CMR profile. In the International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship With Cardiometabolic Risk/Intra-Abdominal Adiposity, 297 physicians recruited 4504 patients (from 29 countries). In the current cross-sectional analyses, 2011 whites, 166 African Caribbean blacks, 381 Hispanics, 1192 East Asians, and 347 Southeast Asians were included. Computed tomography was used to assess abdominal fat distribution and to estimate liver fat content. Anthropometric variables and CMR profile were measured. Higher ranges of BMI were associated with higher levels of visceral [visceral adipose tissue (VAT)] and deep subcutaneous [deep subcutaneous adipose tissue (DSAT)] adiposity, with significant ethnic differences regarding the slope of these relations. Despite lower absolute BMI values, East Asians presented the largest accumulation of VAT but the lowest accumulation of DSAT with increasing adiposity. The association of BMI with liver fat did not differ between ethnic groups. Liver fat and DSAT were positively correlated with VAT with no ethnic variation. All ethnic groups had a similar association between a 1-SD increase in VAT, DSAT, or liver fat with hypertension, type 2 diabetes, hypertriglyceridemia, low HDL-cholesterol concentration, or high C-reactive protein concentration. Ethnicity significantly affects abdominal adiposity and liver fat partitioning, and East Asians have the most deleterious abdominal fat distribution. Irrespective of ethnicity, abdominal and hepatic fat depots are strongly interrelated and increased with obesity. Higher amounts of VAT or liver fat are associated with a more deteriorated CMR profile in all ethnic groups.

  17. The influence of a subanaesthetic dose of ketamine on circulating pro-inflammatory cytokines and serotonin in brain reply

    Czech Academy of Sciences Publication Activity Database

    Horáček, J.; Tejkalová, H.; Novák, T.; Bubeníková-Valešová, V.; Páleníček, T.; Rambousek, L.; Růžičková, Šárka; Vaculín, Š.; Hoeschl, C.

    2011-01-01

    Roč. 41, č. 8 (2011), s. 1787-1789 ISSN 0033-2917 Institutional research plan: CEZ:AV0Z50520701 Keywords : serotonin * proinflammatory * cytokines Subject RIV: AN - Psychology Impact factor: 6.159, year: 2011

  18. Fusobacterium nucleatum-Induced Impairment of Autophagic Flux Enhances the Expression of Proinflammatory Cytokines via ROS in Caco-2 Cells.

    Directory of Open Access Journals (Sweden)

    Bin Tang

    Full Text Available Fusobacterium nucleatum (F. nucleatum plays a critical role in gastrointestinal inflammation. However, the exact mechanism by which F. nucleatum contributes to inflammation is unclear. In the present study, it was revealed that F. nucleatum could induce the production of proinflammatory cytokines (IL-8, IL-1β and TNF-α and reactive oxygen species (ROS in Caco-2 colorectal adenocarcinoma cells. Furthermore, ROS scavengers (NAC or Tiron could decrease the production of proinflammatory cytokines during F. nucleatum infection. In addition, we observed that autophagy is impaired in Caco-2 cells after F. nucleatum infection. The production of proinflammatory cytokines and ROS induced by F. nucleatum was enhanced with either autophagy pharmacologic inhibitors (3-methyladenine, bafilomycin A1 or RNA interference in essential autophagy genes (ATG5 or ATG12 in Caco-2 cells. Taken together, these results indicate that F. nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 Cells.

  19. Impact of Work Task-Related Acute Occupational Smoke Exposures on Select Proinflammatory Immune Parameters in Wildland Firefighters

    Science.gov (United States)

    Objective: A repeated measures study was used to assess the effect of work tasks on select proinflammatory biomarkers in firefighters working at prescribed burns. Methods: Ten firefighters and two volunteers were monitored for particulate matter and carbon monoxide on workdays, ...

  20. Equilibrium shoreface profiles

    DEFF Research Database (Denmark)

    Aagaard, Troels; Hughes, Michael G

    2017-01-01

    Large-scale coastal behaviour models use the shoreface profile of equilibrium as a fundamental morphological unit that is translated in space to simulate coastal response to, for example, sea level oscillations and variability in sediment supply. Despite a longstanding focus on the shoreface...... profile and its relevance to predicting coastal response to changing environmental conditions, the processes and dynamics involved in shoreface equilibrium are still not fully understood. Here, we apply a process-based empirical sediment transport model, combined with morphodynamic principles to provide......; there is no tuning or calibration and computation times are short. It is therefore easily implemented with repeated iterations to manage uncertainty....

  1. Increased Blood Levels of Growth Factors, Proinflammatory Cytokines, and Th17 Cytokines in Patients with Newly Diagnosed Type 1 Diabetes.

    Directory of Open Access Journals (Sweden)

    Kristi Alnek

    Full Text Available The production of several cytokines could be dysregulated in type 1 diabetes (T1D. In particular, the activation of T helper (Th type 1 (Th1 cells has been proposed to underlie the autoimmune pathogenesis of the disease, although roles for inflammatory processes and the Th17 pathway have also been shown. Nevertheless, despite evidence for the role of cytokines before and at the onset of T1D, the corresponding findings are inconsistent across studies. Moreover, conflicting data exist regarding the blood cytokine levels in T1D patients. The current study was performed to investigate genetic and autoantibody markers in association with the peripheral blood cytokine profiles by xMap multiplex technology in newly diagnosed young T1D patients and age-matched healthy controls. The onset of young-age T1D was characterized by the upregulation of growth factors, including granulocyte macrophage-colony stimulating factor (GM-CSF and interleukin (IL-7, the proinflammatory cytokine IL-1β (but not IL-6 or tumor necrosis factor [TNF]-α, Th17 cytokines, and the regulatory cytokines IL-10 and IL-27. Ketoacidosis and autoantibodies (anti-IA-2 and -ZnT8, but not human leukocyte antigen (HLA genotype, influenced the blood cytokine levels. These findings broaden the current understanding of the dysregulation of systemic levels of several key cytokines at the young-age onset of T1D and provide a further basis for the development of novel immunoregulatory treatments in this disease.

  2. A legume-based hypocaloric diet reduces proinflammatory status and improves metabolic features in overweight/obese subjects.

    Science.gov (United States)

    Hermsdorff, Helen Hermana M; Zulet, M Ángeles; Abete, Itziar; Martínez, J Alfredo

    2011-02-01

    The nutritional composition of the dietary intake could produce specific effects on metabolic variables and inflammatory marker concentrations. This study assessed the effects of two hypocaloric diets (legume-restricted- vs. legume-based diet) on metabolic and inflammatory changes, accompanying weight loss. Thirty obese subjects (17 M/13F; BMI: 32.5 ± 4.5 kg/m(2); 36 ± 8 years) were randomly assigned to one of the following hypocaloric treatments (8 weeks): Calorie-restricted legume-free diet (Control: C-diet) or calorie-restricted legume-based diet (L-diet), prescribing 4 weekly different cooked-servings (160-235 g) of lentils, chickpeas, peas or beans. Body composition, blood pressure (BP), blood biochemical and inflammatory marker concentrations as well as dietary intake were measured at baseline and after the nutritional intervention. The L-diet achieved a greater body weight loss, when compared to the C-diet (-7.8 ± 2.9% vs. -5.3 ± 2.7%; p = 0.024). Total and LDL cholesterol levels and systolic BP were improved only when consuming the L-diet (p diet also resulted in a significant higher reduction in C-reactive protein (CRP) and complement C3 (C3) concentrations (p diet values. Interestingly, the reduction in the concentrations of CRP and C3 remained significantly higher to L-diet group, after adjusting by weight loss (p diet group, independent from weight loss (p hypocaloric diet resulted in a specific reduction in proinflammatory markers, such as CRP and C3 and a clinically significant improvement of some metabolic features (lipid profile and BP) in overweight/ obese subjects, which were in some cases independent from weight loss.

  3. RNA-seq methods for identifying differentially expressed gene in human pancreatic islet cells treated with pro-inflammatory cytokines.

    Science.gov (United States)

    Li, Bo; Bi, Chang Long; Lang, Ning; Li, Yu Ze; Xu, Chao; Zhang, Ying Qi; Zhai, Ai Xia; Cheng, Zhi Feng

    2014-01-01

    Type 1 diabetes is a chronic autoimmune disease in which pancreatic beta cells are killed by the infiltrating immune cells as well as the cytokines released by these cells. Many studies indicate that inflammatory mediators have an essential role in this disease. In the present study, we profiled the transcriptome in human islets of langerhans under control conditions or following exposure to the pro-inflammatory cytokines based on the RNA sequencing dataset downloaded from SRA database. After filtered the low-quality ones, the RNA readers was aligned to human genome hg19 by TopHat and then assembled by Cufflinks. The expression value of each transcript was calculated and consequently differentially expressed genes were screened out. Finally, a total of 63 differentially expressed genes were identified including 60 up-regulated and three down-regulated genes. GBP5 and CXCL9 stood out as the top two most up-regulated genes in cytokines treated samples with the log2 fold change of 12.208 and 10.901, respectively. Meanwhile, PTF1A and REG3G were identified as the top two most down-regulated genes with the log2 fold change of -3.759 and -3.606, respectively. Of note, we also found 262 lncRNAs (long non-coding RNA), 177 of which were inferred as novel lncRNAs. Further in-depth follow-up analysis of the transcriptional regulation reported in this study may shed light on the specific function of these lncRNA.

  4. Poly-substance use and antisocial personality traits at admission predict cumulative retention in a buprenorphine programme with mandatory work and high compliance profile.

    Science.gov (United States)

    Öhlin, Leif; Hesse, Morten; Fridell, Mats; Tätting, Per

    2011-05-12

    Continuous abstinence and retention in treatment for alcohol and drug use disorders are central challenges for the treatment providers. The literature has failed to show consistent, strong predictors of retention. Predictors and treatment structure may differ across treatment modalities. In this study the structure was reinforced by the addition of supervised urine samples three times a week and mandatory daily work/structured education activities as a prerequisite of inclusion in the program. Of 128 patients consecutively admitted to buprenorphine maintenance treatment five patients dropped out within the first week. Of the remaining 123 demographic data and psychiatric assessment were used to predict involuntary discharge from treatment and corresponding cumulative abstinence probability. All subjects were administered the Structured Clinical Interview for DSM-IV-TR, and the Symptom Checklist 90 (SCL-90), the Alcohol Use Disorder Identification Test (AUDIT), the Swedish universities Scales of Personality (SSP) and the Sense of Coherence Scale (SOC), all self-report measures. Some measures were repeated every third month in addition to interviews. Of 123 patients admitted, 86 (70%) remained in treatment after six months and 61 (50%) remained in treatment after 12 months. Of those discharged involuntarily, 34/62 individuals were readmitted after a suspension period of three months. Younger age at intake, poly-substance abuse at intake (number of drugs in urine), and number of conduct disorder criteria on the SCID Screen were independently associated with an increased risk of involuntary discharge. There were no significant differences between dropouts and completers on SCL-90, SSP, SOC or AUDIT. Of the patients admitted to the programme 50% stayed for the first 12 months with continuous abstinence and daily work. Poly-substance use before intake into treatment, high levels of conduct disorder on SCID screen and younger age at intake had a negative impact on

  5. Theoretical prediction and experimental determination of the effect of mold characteristics on temperature and monomer conversion fraction profiles during polymerization of a PMMA-based bone cement.

    Science.gov (United States)

    Vallo, Claudia I

    2002-01-01

    The present work is concerned with applications of a kinetic model for free-radical polymerization of a polymethylmethacrylate-based bone cement. Autocatalytic behavior at the first part of the reaction as well as a diffusion control phenomenon near vitrification are described by the model. Comparison of theoretical computations with experimental measurements for the temperature evolution during batch casting demonstrated the capacity of the proposed model to represent the kinetic behavior of the polymerization reaction. Temperature evolution and monomer conversion were simulated for the cure of the cement in molds made of different materials. The maximum monomer conversion fraction was markedly influenced by the physical properties of the mold material. The unreacted monomer acts as a plasticizer that influences the mechanical behavior of the cement. Hence, the same cement formulation cured in molds of different materials may result in different mechanical response because of the differences in the amounts of residual monomer. Standardization of the mold type to prepare specimens for the mechanical characterization of bone cements is recommended. Theoretical prediction of temperature evolution during hip replacement indicated that for cement thickness lower than 6 mm the peak temperature at the bone-cement interface was below the limit stated for thermal injury (50 degrees C for more than 1 min). The use of thin cement layers is recommended to diminish the risk of thermal injury; however, it is accompanied by an increase in the amount of unreacted monomer present in the cured material. Copyright 2002 Wiley Periodicals, Inc. J Biomed Mater Res (Appl Biomater) 63: 627-642, 2002

  6. More adaptive versus less maladaptive coping: What is more predictive of symptom severity? Development of a new scale to investigate coping profiles across different psychopathological syndromes.

    Science.gov (United States)

    Moritz, Steffen; Jahns, Anna Katharina; Schröder, Johanna; Berger, Thomas; Lincoln, Tania M; Klein, Jan Philipp; Göritz, Anja S

    2016-02-01

    Lack of adaptive and enhanced maladaptive coping with stress and negative emotions are implicated in many psychopathological disorders. We describe the development of a new scale to investigate the relative contribution of different coping styles to psychopathology in a large population sample. We hypothesized that the magnitude of the supposed positive correlation between maladaptive coping and psychopathology would be stronger than the supposed negative correlation between adaptive coping and psychopathology. We also examined whether distinct coping style patterns emerge for different psychopathological syndromes. A total of 2200 individuals from the general population participated in an online survey. The Patient Health Questionnaire-9 (PHQ-9), the Obsessive-Compulsive Inventory revised (OCI-R) and the Paranoia Checklist were administered along with a novel instrument called Maladaptive and Adaptive Coping Styles (MAX) questionnaire. Participants were reassessed six months later. MAX consists of three dimensions representing adaptive coping, maladaptive coping and avoidance. Across all psychopathological syndromes, similar response patterns emerged. Maladaptive coping was more strongly related to psychopathology than adaptive coping both cross-sectionally and longitudinally. The overall number of coping styles adopted by an individual predicted greater psychopathology. Mediation analysis suggests that a mild positive relationship between adaptive and certain maladaptive styles (emotional suppression) partially accounts for the attenuated relationship between adaptive coping and depressive symptoms. Results should be replicated in a clinical population. Results suggest that maladaptive and adaptive coping styles are not reciprocal. Reducing maladaptive coping seems to be more important for outcome than enhancing adaptive coping. The study supports transdiagnostic approaches advocating that maladaptive coping is a common factor across different psychopathologies

  7. Poly-substance use and antisocial personality traits at admission predict cumulative retention in a buprenorphine programme with mandatory work and high compliance profile

    Directory of Open Access Journals (Sweden)

    Fridell Mats

    2011-05-01

    Full Text Available Abstract Background Continuous abstinence and retention in treatment for alcohol and drug use disorders are central challenges for the treatment providers. The literature has failed to show consistent, strong predictors of retention. Predictors and treatment structure may differ across treatment modalities. In this study the structure was reinforced by the addition of supervised urine samples three times a week and mandatory daily work/structured education activities as a prerequisite of inclusion in the program. Methods Of 128 patients consecutively admitted to buprenorphine maintenance treatment five patients dropped out within the first week. Of the remaining 123 demographic data and psychiatric assessment were used to predict involuntary discharge from treatment and corresponding cumulative abstinence probability. All subjects were administered the Structured Clinical Interview for DSM-IV-TR, and the Symptom Checklist 90 (SCL-90, the Alcohol Use Disorder Identification Test (AUDIT, the Swedish universities Scales of Personality (SSP and the Sense of Coherence Scale (SOC, all self-report measures. Some measures were repeated every third month in addition to interviews. Results Of 123 patients admitted, 86 (70% remained in treatment after six months and 61 (50% remained in treatment after 12 months. Of those discharged involuntarily, 34/62 individuals were readmitted after a suspension period of three months. Younger age at intake, poly-substance abuse at intake (number of drugs in urine, and number of conduct disorder criteria on the SCID Screen were independently associated with an increased risk of involuntary discharge. There were no significant differences between dropouts and completers on SCL-90, SSP, SOC or AUDIT. Conclusion Of the patients admitted to the programme 50% stayed for the first 12 months with continuous abstinence and daily work. Poly-substance use before intake into treatment, high levels of conduct disorder on SCID

  8. Identification of high-risk cutaneous melanoma tumors is improved when combining the online American Joint Committee on Cancer Individualized Melanoma Patient Outcome Prediction Tool with a 31-gene expression profile-based classification.

    Science.gov (United States)

    Ferris, Laura K; Farberg, Aaron S; Middlebrook, Brooke; Johnson, Clare E; Lassen, Natalie; Oelschlager, Kristen M; Maetzold, Derek J; Cook, Robert W; Rigel, Darrell S; Gerami, Pedram

    2017-05-01

    A significant proportion of patients with American Joint Committee on Cancer (AJCC)-defined early-stage cutaneous melanoma have disease recurrence and die. A 31-gene expression profile (GEP) that accurately assesses metastatic risk associated with primary cutaneous melanomas has been described. We sought to compare accuracy of the GEP in combination with risk determined using the web-based AJCC Individualized Melanoma Patient Outcome Prediction Tool. GEP results from 205 stage I/II cutaneous melanomas with sufficient clinical data for prognostication using the AJCC tool were classified as low (class 1) or high (class 2) risk. Two 5-year overall survival cutoffs (AJCC 79% and 68%), reflecting survival for patients with stage IIA or IIB disease, respectively, were assigned for binary AJCC risk. Cox univariate analysis revealed significant risk classification of distant metastasis-free and overall survival (hazard ratio range 3.2-9.4, P risk by GEP but low risk by AJCC. Specimens reflect tertiary care center referrals; more effective therapies have been approved for clinical use after accrual. The GEP provides valuable prognostic information and improves identification of high-risk melanomas when used together with the AJCC online prediction tool. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  9. Galectin-2 induces a proinflammatory, anti-arteriogenic phenotype in monocytes and macrophages.

    Directory of Open Access Journals (Sweden)

    Cansu Yıldırım

    Full Text Available Galectin-2 is a monocyte-expressed carbohydrate-binding lectin, for which increased expression is genetically determined and associated with decreased collateral arteriogenesis in obstructive coronary artery disease patients. The inhibiting effect of galectin-2 on arteriogenesis was confirmed in vivo, but the mechanism is largely unknown. In this study we aimed to explore the effects of galectin-2 on monocyte/macrophage phenotype in vitro and vivo, and to identify the receptor by which galectin-2 exerts these effects. We now show that the binding of galectin-2 to different circulating human monocyte subsets is dependent on monocyte surface expression levels of CD14. The high affinity binding is blocked by an anti-CD14 antibody but not by carbohydrates, indicating a specific protein-protein interaction. Galectin-2 binding to human monocytes modulated their transcriptome by inducing proinflammatory cytokines and inhibiting pro-arteriogenic factors, while attenuating monocyte migration. Using specific knock-out mice, we show that galectin-2 acts through the CD14/toll-like receptor (TLR-4 pathway. Furthermore, galectin-2 skews human macrophages to a M1-like proinflammatory phenotype, characterized by a reduced motility and expression of an anti-arteriogenic cytokine/growth factor repertoire. This is accompanied by a switch in surface protein expression to CD40-high and CD206-low (M1. In a murine model we show that galectin-2 administration, known to attenuate arteriogenesis, leads to increased numbers of CD40-positive (M1 and reduced numbers of CD206-positive (M2 macrophages surrounding actively remodeling collateral arteries. In conclusion galectin-2 is the first endogenous CD14/TLR4 ligand that induces a proinflammatory, non-arteriogenic phenotype in monocytes/macrophages. Interference with CD14-Galectin-2 interaction may provide a new intervention strategy to stimulate growth of collateral arteries in genetically compromised cardiovascular

  10. Atypical antipsychotics induce both proinflammatory and adipogenic gene expression in human adipocytes in vitro.

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    Sárvári, Anitta K; Veréb, Zoltán; Uray, Iván P; Fésüs, László; Balajthy, Zoltán

    2014-08-08

    Schizophrenia requires lifelong treatment, potentially causing systemic changes in metabolic homeostasis. In the clinical setting, antipsychotic treatment may differentially lead to weight gain among individual patients, although the molecular determinants of such adverse effects are currently unknown. In this study, we investigated changes in the expression levels of critical regulatory genes of adipogenesis, lipid metabolism and proinflammatory genes during the differentiation of primary human adipose-derived stem cells (ADSCs). These cells were isolated from patients with body mass indices <25 and treated with the second-generation antipsychotics olanzapine, ziprasidone, clozapine, quetiapine, aripiprazole and risperidone and the first-generation antipsychotic haloperidol. We found that antipsychotics exhibited a marked effect on key genes involved in the regulation of cell cycle, signal transduction, transcription factors, nuclear receptors, differentiation markers and metabolic enzymes. In particular, we observed an induction of the transcription factor NF-KB1 and NF-KB1 target genes in adipocytes in response to these drugs, including the proinflammatory cytokines TNF-α, IL-1β, IL-8 and MCP-1. In addition, enhanced secretion of both IL8 and MCP-1 was observed in the supernatant of these cell cultures. In addition to their remarkable stimulatory effects on proinflammatory gene transcription, three of the most frequently prescribed antipsychotic drugs, clozapine, quetiapine and aripiprazole, also induced the expression of essential adipocyte differentiation genes and the adipocyte hormones leptin and adiponectin, suggesting that both glucose and fat metabolism may be affected by these drugs. These data further suggest that antipsychotic treatments in patients alter the gene expression patterns in adipocytes in a coordinated fashion and priming them for a low-level inflammatory state. Copyright © 2014 Elsevier Inc. All rights reserved.

  11. Host transcription factors in the immediate pro-inflammatory response to the parasitic mite Psoroptes ovis.

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    Stewart T G Burgess

    Full Text Available BACKGROUND: Sheep scab, caused by infestation with the ectoparasitic mite Psoroptes ovis, results in the rapid development of cutaneous inflammation and leads to the crusted skin lesions characteristic of the disease. We described previously the global host transcriptional response to infestation with P. ovis, elucidating elements of the inflammatory processes which lead to the development of a rapid and profound immune response. However, the mechanisms by which this response is instigated remain unclear. To identify novel methods of intervention a better understanding of the early events involved in triggering the immune response is essential. The objective of this study was to gain a clearer understanding of the mechanisms and signaling pathways involved in the instigation of the immediate pro-inflammatory response. RESULTS: Through a combination of transcription factor binding site enrichment and pathway analysis we identified key roles for a number of transcription factors in the instigation of cutaneous inflammation. In particular, defined roles were elucidated for the transcription factors NF-kB and AP-1 in the orchestration of the early pro-inflammatory response, with these factors being implicated in the activation of a suite of inflammatory mediators. CONCLUSIONS: Interrogation of the host temporal response to P. ovis infestation has enabled the further identification of the mechanisms underlying the development of the immediate host pro-inflammatory response. This response involves key regulatory roles for the transcription factors NF-kB and AP-1. Pathway analysis demonstrated that the activation of these transcription factors may be triggered following a host LPS-type response, potentially involving TLR4-signalling and also lead to the intriguing possibility that this could be triggered by a P. ovis allergen.

  12. Induction of intestinal pro-inflammatory immune responses by lipoteichoic acid

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    Zadeh Mojgan

    2012-03-01

    Full Text Available Abstract Background The cellular and molecular mechanisms of inflammatory bowel disease are not fully understood; however, data indicate that uncontrolled chronic inflammation induced by bacterial gene products, including lipoteichoic acid (LTA, may trigger colonic inflammation resulting in disease pathogenesis. LTA is a constituent glycolipid of Gram-positive bacteria that shares many inflammatory properties with lipopolysaccharide and plays a critical role in the pathogenesis of severe inflammatory responses via Toll-like receptor 2. Accordingly, we elucidate the role of LTA in immune stimulation and induced colitis in vivo. Methods To better understand the molecular mechanisms utilized by the intestinal microbiota and their gene products to induce or subvert inflammation, specifically the effect(s of altered surface layer protein expression on the LTA-mediated pro-inflammatory response, the Lactobacillus acidophilus surface layer protein (Slp genes encoding SlpB and SlpX were deleted resulting in a SlpB- and SlpX- mutant that continued to express SlpA (assigned as NCK2031. Results Our data show profound activation of dendritic cells by NCK2031, wild-type L. acidophilus (NCK56, and purified Staphylococcus aureus-LTA. In contrary to the LTA-deficient strain NCK2025, the LTA-expressing strains NCK2031 and NCK56, as well as S. aureus-LTA, induce pro-inflammatory innate and T cell immune responses in vivo. Additionally, neither NCK2031 nor S. aureus-LTA supplemented in drinking water protected mice from DSS-colitis, but instead, induced significant intestinal inflammation resulting in severe colitis and tissue destruction. Conclusions These findings suggest that directed alteration of two of the L. acidophilus NCFM-Slps did not ameliorate LTA-induced pro-inflammatory signals and subsequent colitis.

  13. c-Myc is essential to prevent endothelial pro-inflammatory senescent phenotype.

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    Victoria Florea

    Full Text Available The proto-oncogene c-Myc is vital for vascular development and promotes tumor angiogenesis, but the mechanisms by which it controls blood vessel growth remain unclear. In the present work we investigated the effects of c-Myc knockdown in endothelial cell functions essential for angiogenesis to define its role in the vasculature. We provide the first evidence that reduction in c-Myc expression in endothelial cells leads to a pro-inflammatory senescent phenotype, features typically observed during vascular aging and pathologies associated with endothelial dysfunction. c-Myc knockdown in human umbilical vein endothelial cells using lentivirus expressing specific anti-c-Myc shRNA reduced proliferation and tube formation. These functional defects were associated with morphological changes, increase in senescence-associated-β-galactosidase activity, upregulation of cell cycle inhibitors and accumulation of c-Myc-deficient cells in G1-phase, indicating that c-Myc knockdown in endothelial cells induces senescence. Gene expression analysis of c-Myc-deficient endothelial cells showed that senescent phenotype was accompanied by significant upregulation of growth factors, adhesion molecules, extracellular-matrix components and remodeling proteins, and a cluster of pro-inflammatory mediators, which include Angptl4, Cxcl12, Mdk, Tgfb2 and Tnfsf15. At the peak of expression of these cytokines, transcription factors known to be involved in growth control (E2f1, Id1 and Myb were downregulated, while those involved in inflammatory responses (RelB, Stat1, Stat2 and Stat4 were upregulated. Our results demonstrate a novel role for c-Myc in the prevention of vascular pro-inflammatory phenotype, supporting an important physiological function as a central regulator of inflammation and endothelial dysfunction.

  14. An intervertebral disc whole organ culture system to investigate proinflammatory and degenerative disc disease condition.

    Science.gov (United States)

    Lang, Gernot; Liu, Yishan; Geries, Janna; Zhou, Zhiyu; Kubosch, David; Südkamp, Norbert; Richards, R Geoff; Alini, Mauro; Grad, Sibylle; Li, Zhen

    2018-04-01

    The aim of this study was to compare the effect of different disease initiators of degenerative disc disease (DDD) within an intervertebral disc (IVD) organ culture system and to understand the interplay between inflammation and degeneration in the early stage of DDD. Bovine caudal IVDs were cultured within a bioreactor for up to 11 days. Control group was cultured under physiological loading (0.02-0.2 MPa; 0.2 Hz; 2 hr/day) and high glucose (4.5 g/L) medium. Detrimental loading (0.32-0.5 MPa, 5 Hz; 2 hr/day) and low glucose (2 g/L) medium were applied to mimic the condition of abnormal mechanical stress and limited nutrition supply. Tumour necrosis factor alpha (TNF-α) was injected into the nucleus pulposus (100 ng per IVD) as a proinflammatory trigger. TNF-α combined with detrimental loading and low glucose medium up-regulated interleukin 1β (IL-1β), IL-6, and IL-8 gene expression in disc tissue, nitric oxide, and IL-8 release from IVD, which indicate a proinflammatory effect. The combined initiators up-regulated matrix metalloproteinase 1 gene expression, down-regulated gene expression of Type I collagen in annulus fibrosus and Type II collagen in nucleus pulposus, and reduced the cell viability. Furthermore, the combined initiators induced a degradative effect, as indicated by markedly higher glycosaminoglycan release into conditioned medium. The combination of detrimental dynamic loading, nutrient deficiency, and TNF-α intradiscal injection can synergistically simulate the proinflammatory and degenerative disease condition within DDD. This model will be of high interest to screen therapeutic agents in further preclinical studies for early intervention and treatment of DDD. Copyright © 2018 John Wiley & Sons, Ltd.

  15. LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

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    van der Does, Anne M; Beekhuizen, Henry; Ravensbergen, Bep; Vos, Tim; Ottenhoff, Tom H M; van Dissel, Jaap T; Drijfhout, Jan W; Hiemstra, Pieter S; Nibbering, Peter H

    2010-08-01

    The human cathelicidin LL-37 has broad-spectrum antimicrobial activity. It also participates at the interface of innate and adaptive immunity by chemoattracting immune effector cells, modulating the production of a variety of inflammatory mediators by different cell types, and regulating the differentiation of monocytes into dendritic cells. In this study, we investigated the effects of LL-37 on the differentiation of human monocytes into anti-inflammatory macrophages (MPhi-2; driven by M-CSF) versus proinflammatory macrophages (MPhi-1; driven by GM-CSF) as well as on fully differentiated MPhi-1 and MPhi-2. Results revealed that monocytes cultured with M-CSF in the presence of LL-37 resulted in macrophages displaying a proinflammatory signature, namely, low expression of CD163 and little IL-10 and profound IL-12p40 production on LPS stimulation. The effects of LL-37 on M-CSF-driven macrophage differentiation were dose- and time-dependent with maximal effects observed at 10 microg/ml when the peptide was present from the start of the cultures. The peptide enhanced the GM-CSF-driven macrophage differentiation. Exposure of fully differentiated MPhi-2 to LL-37 for 6 d resulted in macrophages that produced less IL-10 and more IL-12p40 on LPS stimulation than control MPhi-2. In contrast, LL-37 had no effect on fully differentiated MPhi-1. Peptide mapping using a set of 16 overlapping 22-mer peptides covering the complete LL-37 sequence revealed that the C-terminal portion of LL-37 is responsible for directing macrophage differentiation. Our results furthermore indicate that the effects of LL-37 on macrophage differentiation required internalization of the peptide. Together, we conclude that LL-37 directs macrophage differentiation toward macrophages with a proinflammatory signature.

  16. Proinflammatory gene polymorphisms are potentially associated with Korean non-Sjogren dry eye patients

    Science.gov (United States)

    Na, Kyung-Sun; Mok, Jee-Won; Kim, Ja Yeon

    2011-01-01

    Purpose To determine whether proinflammatory cytokine genes were potential susceptibility candidate genes for Korean patients with non-Sjogren dry eye, we investigated the association of the interleukin 1 beta (IL1B), interleukin 6 (IL6), and interleukin 6 receptor (IL6R) variations with this disease in Korean patients. Methods Genomic DNA was extracted from blood samples of unrelated non-Sjogren dry eye patients and healthy control individuals who visited the Eye Center and Health Promotion Center of St. Mary’s Hospital in Seoul, Korea. For screening genetic variations in proinflammatory cytokine genes, the 511 (rs16944) and 31 (rs1143627) positions in the promoter region of IL1B, rs1143634 in exon 5 of IL1B, rs1800795 of the IL6 promoter, and Asp358Ala (rs8192284) of IL6R were genotyped using the polymerase chain reaction, restriction fragment length polymorphisms, and direct sequencing. Results Among the polymorphisms, rs1143634 (F105F) in exon 5 of IL1B was significantly different between the patient and control groups. The frequency of the C/T genotype in dry eye patients was decreased relative to that of the control subjects (10.4% versus 3.9%, p=0.043, OR=3.337). For the IL6R gene, the genotypic and allelic distribution of rs8192284 was different between the dry eye patients and the controls: CC genotype (p=0.017, OR=2.12) and C allele (OR=1.26). Conclusions This is the first report of genetic variation screening of proinflammatory cytokine genes in Korean non-Sjogren dry eye patients. It is suggested that rs1143634 of IL1B and rs8192284 of IL6R act as susceptibility variations in Korean non-Sjogren dry eye patients. PMID:22128229

  17. High expression of arachidonate 15-lipoxygenase and proinflammatory markers in human ischemic heart tissue

    International Nuclear Information System (INIS)

    Magnusson, Lisa U.; Lundqvist, Annika; Asp, Julia; Synnergren, Jane; Johansson, Cecilia Thalén; Palmqvist, Lars; Jeppsson, Anders; Hultén, Lillemor Mattsson

    2012-01-01

    Highlights: ► We found a 17-fold upregulation of ALOX15 in the ischemic heart. ► Incubation of human muscle cells in hypoxia showed a 22-fold upregulation of ALOX15. ► We observed increased levels of proinflammatory markers in ischemic heart tissue. ► Suggesting a link between ischemia and inflammation in ischemic heart biopsies. -- Abstract: A common feature of the ischemic heart and atherosclerotic plaques is the presence of hypoxia (insufficient levels of oxygen in the tissue). Hypoxia has pronounced effects on almost every aspect of cell physiology, and the nuclear transcription factor hypoxia inducible factor-1α (HIF-1α) regulates adaptive responses to low concentrations of oxygen in mammalian cells. In our recent work, we observed that hypoxia increases the proinflammatory enzyme arachidonate 15-lipoxygenase (ALOX15B) in human carotid plaques. ALOX15 has recently been shown to be present in the human myocardium, but the effect of ischemia on its expression has not been investigated. Here we test the hypothesis that ischemia of the heart leads to increased expression of ALOX15, and found an almost 2-fold increase in HIF-1α mRNA expression and a 17-fold upregulation of ALOX15 mRNA expression in the ischemic heart biopsies from patients undergoing coronary bypass surgery compared with non ischemic heart tissue. To investigate the effect of low oxygen concentration on ALOX15 we incubated human vascular muscle cells in hypoxia and showed that expression of ALOX15 increased 22-fold compared with cells incubated in normoxic conditions. We also observed increased mRNA levels of proinflammatory markers in ischemic heart tissue compared with non-ischemic controls. In summary, we demonstrate increased ALOX15 in human ischemic heart biopsies. Furthermore we demonstrate that hypoxia increases ALOX15 in human muscle cells. Our results yield important insights into the underlying association between hypoxia and inflammation in the human ischemic heart disease.

  18. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung

    International Nuclear Information System (INIS)

    Ruebe, C.E.; Wilfert, F.; Palm, J.; Burdak-Rothkamm, S.; Ruebe, C.; Koenig, J.; Liu Li; Schuck, A.; Willich, N.

    2004-01-01

    Background and purpose: the precise pathophysiological mechanisms of radiation-induced lung injury are poorly understood, but have been shown to correlate with dysregulation of different cytokines. The purpose of this study was to evaluate the time course of the pro-inflammatory cytokines tumor necrosis factor-(TNF-)α, interleukin-(IL)-1α and IL-6 after whole-lung irradiation. Material and methods: the thoraces of C57BL/6J mice were irradiated with 12 Gy. Treated and control mice were sacrificed at 0.5, 1, 3, 6, 12, 24, 48, 72 h, 1, 2, 4, 8, 16, and 24 weeks post irradiation (p.i.). Real-time multiplex RT-PCR (reverse transcriptase polmyerase chain reaction) was established to evaluate the expression of TNF-α, IL-1α and IL-6 in the lung tissue of the mice. For histological analysis, lung tissue sections were stained by hematoxylin and eosin. Results: multiplex RT-PCR analysis revealed a biphasic expression of these pro-inflammatory cytokines in the lung tissue after irradiation. After an initial increase at 1 h p.i. for TNF-α and at 6 h p.i. for IL-1α and IL-6, the mRNA expression of these pro-inflammatory cytokines returned to basal levels (48 h, 72 h, 1 week, 2 weeks p.i.). During the pneumonic phase, TNF-α, IL-1α and IL-6 were significantly elevated and revealed their maximum at 8 weeks p.i. Histopathologic evaluation of the lung sections obtained within 4 weeks p.i. revealed only minor lung damage in 5-30% of the lung tissue. By contrast, at 8, 16, and 24 weeks p.i., 70-90% of the lung tissue revealed histopathologically detectable organizing alveolitis. Conclusion: irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. The initial transitory cytokine response occurred within the first hours after lung irradiation with no detectable histopathologic alterations. The second, more persistent cytokine elevation coincided with the onset of histologically discernible organizing acute pneumonitis. (orig.)

  19. Phenolic excipients of insulin formulations induce cell death, pro-inflammatory signaling and MCP-1 release

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    Claudia Weber

    2015-01-01

    Insulin solutions displayed cytotoxic and pro-inflammatory potential caused by phenol or m-cresol. We speculate that during insulin pump therapy phenol and m-cresol might induce cell death and inflammatory reactions at the infusion site in vivo. Inflammation is perpetuated by release of MCP-1 by activated monocytic cells leading to enhanced recruitment of inflammatory cells. To minimize acute skin complications caused by phenol/m-cresol accumulation, a frequent change of infusion sets and rotation of the infusion site is recommended.

  20. Cervical cerclage placement decreases local levels of proinflammatory cytokines in patients with cervical insufficiency.

    Science.gov (United States)

    Monsanto, Stephany P; Daher, Silvia; Ono, Erika; Pendeloski, Karen Priscilla Tezotto; Trainá, Évelyn; Mattar, Rosiane; Tayade, Chandrakant

    2017-10-01

    Cervical insufficiency is characterized by premature, progressive dilation and shortening of the cervix during pregnancy. If left unattended, this can lead to the prolapse and rupture of the amniotic membrane, which usually results in midtrimester pregnancy loss or preterm birth. Previous studies have shown that proinflammatory cytokines such as interleukin-1β, interleukin-6, interleukin-8, and tumor necrosis factor alpha are up-regulated in normal parturition but are also associated with preterm birth. Studies evaluating such markers in patients with cervical insufficiency have evaluated only their diagnostic potential. Even fewer studies have studied them within the context of cerclage surgery. The objective of the study was to evaluate the impact of local and systemic inflammatory markers on the pathogenesis of cervical insufficiency and the effect of cerclage surgery on the local immune microenvironment of women with cervical insufficiency. We recruited 28 pregnant women (12-20 weeks' gestation) diagnosed with insufficiency and referred for cerclage surgery and 19 gestational age-matched normal pregnant women as controls. Serum and cervicovaginal fluid samples were collected before and after cerclage surgery and during a routine checkup for normal women and analyzed using a targeted 13-plex proinflammatory cytokine assay. Before surgery, patients with cervical insufficiency had higher levels of interleukin-1β, interleukin-6, interleukin-12, monocyte chemoattractant protein-1 and tumor necrosis factor alpha in cervicovaginal fluid compared to controls, but after surgery, these differences disappeared. No differences were found in serum of insufficiency versus control women. In patients with insufficiency, the levels of interleukin-1β, interleukin-6, interleukin-8, monocyte chemoattractant protein-1, and interferon gamma in cervicovaginal fluid declined significantly after cerclage compared with before intervention, but these changes were not detected in serum

  1. Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung

    Energy Technology Data Exchange (ETDEWEB)

    Ruebe, C.E.; Wilfert, F.; Palm, J.; Burdak-Rothkamm, S.; Ruebe, C. [Dept. of Radiotherapy - Radiooncology, Saarland Univ., Homburg/Saar (Germany); Koenig, J. [Inst. of Medical Biometrics, Epidemiology and Medical Informatics, Saarland Univ., Homburg/Saar (Germany); Liu Li [Dept. of Radiotherapy - Radiooncology, Saarland Univ., Homburg/Saar (Germany); Cancer Center, Union Hospital Tongji Medical Coll., Huazhong Univ. of Science and Technology, Wuhan (China); Schuck, A.; Willich, N. [Dept. of Radiotherapy - Radiooncology, Univ. of Muenster (Germany)

    2004-07-01

    Background and purpose: the precise pathophysiological mechanisms of radiation-induced lung injury are poorly understood, but have been shown to correlate with dysregulation of different cytokines. The purpose of this study was to evaluate the time course of the pro-inflammatory cytokines tumor necrosis factor-(TNF-){alpha}, interleukin-(IL)-1{alpha} and IL-6 after whole-lung irradiation. Material and methods: the thoraces of C57BL/6J mice were irradiated with 12 Gy. Treated and control mice were sacrificed at 0.5, 1, 3, 6, 12, 24, 48, 72 h, 1, 2, 4, 8, 16, and 24 weeks post irradiation (p.i.). Real-time multiplex RT-PCR (reverse transcriptase polmyerase chain reaction) was established to evaluate the expression of TNF-{alpha}, IL-1{alpha} and IL-6 in the lung tissue of the mice. For histological analysis, lung tissue sections were stained by hematoxylin and eosin. Results: multiplex RT-PCR analysis revealed a biphasic expression of these pro-inflammatory cytokines in the lung tissue after irradiation. After an initial increase at 1 h p.i. for TNF-{alpha} and at 6 h p.i. for IL-1{alpha} and IL-6, the mRNA expression of these pro-inflammatory cytokines returned to basal levels (48 h, 72 h, 1 week, 2 weeks p.i.). During the pneumonic phase, TNF-{alpha}, IL-1{alpha} and IL-6 were significantly elevated and revealed their maximum at 8 weeks p.i. Histopathologic evaluation of the lung sections obtained within 4 weeks p.i. revealed only minor lung damage in 5-30% of the lung tissue. By contrast, at 8, 16, and 24 weeks p.i., 70-90% of the lung tissue revealed histopathologically detectable organizing alveolitis. Conclusion: irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung. The initial transitory cytokine response occurred within the first hours after lung irradiation with no detectable histopathologic alterations. The second, more persistent cytokine elevation coincided with the onset of histologically discernible organizing acute

  2. Impaired production of proinflammatory cytokines in response to lipopolysaccharide (LPS) stimulation in elderly humans

    DEFF Research Database (Denmark)

    Bruunsgaard, H.; Pedersen, Agnes Nadelmann; Schroll, M.

    1999-01-01

    following LPS stimulation, representing an ex vivo model of sepsis. Levels of tumour necrosis factor-alpha (TNF-alpha), IL-1 beta and IL-6 in whole blood supernatants were measured after in vitro LPS stimulation for 24 h in 168 elderly humans aged 81 years from the 1914 cohort in Glostrup, Denmark and in 91...... of proinflammatory cytokines compared with young men, but this difference was blurred by ageing. No relation was found between circulating plasma levels of TNF-alpha and levels after in vitro LPS stimulation. In conclusion, decreased production of TNF-alpha and IL-1 beta after exposure to LPS may reflect impaired...

  3. Decreased proinflammatory cytokine production by peripheral blood mononuclear cells from vitiligo patients following aspirin treatment

    International Nuclear Information System (INIS)

    Zailaie, Mohammad Z.

    2005-01-01

    Limited studies have shown that treatment of cells with aspirin modulates their cytokine production. Consequently, the aim of the present study is to investigate the pattern of important proinflammatory cytokines production by stimulated peripheral blood mononuclear cells (PBMC) from patients with active vitiligo following long-term treatment with low-dose oral aspirin. The study was conducted at the Vitiligo Unit, King Abdul-Aziz University Medical Center, Jeddah, Kingdom of Saudi Arabia between March and October 2003. Thirty-two patients (18 females and 14 males) with non-segmental vitiligo were divided into 2 equal groups, one group received a daily single dose of oral aspirin (300 mg) and the other group received placebo for a period of 12 weeks. The concentrations of interleukin (IL)-1beta, IL-6, IL-8 and tumor necrosis factor-alpha (TNF-alpha) were determined in the supernatant of isolated cultured PMBC after being stimulated with bacterial lipopolysaccharide (LPS), before the start of aspirin treatment and at end of treatment period. Cytokine levels were measured using the quantitative sandwich enzyme-linked immunosorbent assay (ELISA) technique, utilizing commercially available kits. The proinflammatory cytokine production by the PBMC of patients with active vitiligo was significantly increased compared to normal controls. Thus, the relative percentage increase in the production of IL-1beta, IL-6, IL-8 and TNF-alpha was: 39.4%, 110.5% (p<0.05), 91.5% (p<0.01), and 37% (p<0.05). At the end of treatment, proinflammatory cytokine production in the aspirin-treated group of active vitiligo patients was significantly decreased compared to the placebo group. Thus, the relative percentage decrease in the production of IL-1beta IL-6, IL-8 and TNF-alpha was: 42.5%, 45.2% (p<0.05), 30.8% (p<0.01), and 50.6% (p<0.05). The vitiligo activity was arrested in all aspirin-treated patients, while 2 patients demonstrated significant repigmentation.Chronic administration of

  4. Clinical findings and pro-inflammatory cytokines in dengue patients in Western India: a facility-based study.

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    D Priyadarshini

    Full Text Available BACKGROUND: Descriptions of dengue immunopathogenesis have largely relied on data from South-east Asia and America, while India is poorly represented. This study characterizes dengue cases from Pune, Western India, with respect to clinical profile and pro-inflammatory cytokines. METHODOLOGY/PRINCIPAL FINDINGS: In 2005, 372 clinically suspected dengue cases were tested by MAC-ELISA and RT-PCR for dengue virus (DENV aetiology. The clinical profile was recorded at the hospital. Circulating levels of IFN-gamma, TNF-alpha, IL-6, and IL-8 were assessed by ELISA and secondary infections were defined by IgM to IgG ratio. Statistical analysis was carried out using the SPSS 11.0 version. Of the 372 individuals, 221 were confirmed to be dengue cases. Three serotypes, DENV-1, 2 and 3 were co-circulating and one case of dual infection was identified. Of 221 cases, 159 presented with Dengue fever (DF and 62 with Dengue hemorrhagic fever (DHF of which six had severe DHF and one died of shock. There was a strong association of rash, abdominal pain and conjunctival congestion with DHF. Levels of IFN-gamma were higher in DF whereas IL-6 and IL-8 were higher in DHF cases (p<0.05. The mean levels of the three cytokines were higher in secondary compared to primary infections. Levels of IFN-gamma and IL-8 were higher in early samples collected 2-5 days after onset than late samples collected 6-15 days after onset. IFN-gamma showed significant decreasing time trend (p = 0.005 and IL-8 levels showed increasing trend towards significance in DHF cases (interaction p = 0.059. There was a significant association of IL-8 levels with thrombocytopenia and both IFN-gamma and IL-8 were positively associated with alanine transaminase levels. CONCLUSIONS/SIGNIFICANCE: Rash, abdominal pain and conjunctival congestion could be prognostic symptoms for DHF. High levels of IL-6 and IL-8 were shown to associate with DHF. The time trend of IFN-gamma and IL-8 levels had greater

  5. Neisseria meningitidis elicits a pro-inflammatory response involving IκBζ in a human blood-cerebrospinal fluid barrier model.

    Science.gov (United States)

    Borkowski, Julia; Li, Li; Steinmann, Ulrike; Quednau, Natascha; Stump-Guthier, Carolin; Weiss, Christel; Findeisen, Peter; Gretz, Norbert; Ishikawa, Hiroshi; Tenenbaum, Tobias; Schroten, Horst; Schwerk, Christian

    2014-09-13

    The human-specific, Gram-negative bacterium Neisseria meningitidis (Nm) is a leading cause of bacterial meningitis worldwide. The blood-cerebrospinal fluid barrier (BCSFB), which is constituted by the epithelial cells of the choroid plexus (CP), has been suggested as one of the potential entry sites of Nm into the CSF and can contribute to the inflammatory response during infectious diseases of the brain. Toll-like receptors (TLRs) are involved in mediating signal transduction caused by the pathogens. Using a recently established in vitro model of the human BCSFB based on human malignant CP papilloma (HIBCPP) cells we investigated the cellular response of HIBCPP cells challenged with the meningitis-causing Nm strain, MC58, employing transcriptome and RT-PCR analysis, cytokine bead array, and enzyme-linked immunosorbent assay (ELISA). In comparison, we analyzed the answer to the closely related unencapsulated carrier isolate Nm α14. The presence of TLRs in HIBCPP and their role during signal transduction caused by Nm was studied by RT-PCR and the use of specific agonists and mutant bacteria. We observed a stronger transcriptional response after infection with strain MC58, in particular with its capsule-deficient mutant MC58siaD-, which correlated with bacterial invasion levels. Expression evaluation and Gene Set Enrichment Analysis pointed to a NFκB-mediated pro-inflammatory immune response involving up-regulation of the transcription factor IκBζ. Infected cells secreted significant levels of pro-inflammatory chemokines and cytokines, including, among others, IL8, CXCL1-3, and the IκBζ target gene product IL6. The expression profile of pattern recognition receptors in HIBCPP cells and the response to specific agonists indicates that TLR2/TLR6, rather than TLR4 or TLR2/TLR1, is involved in the cellular reaction following Nm infection. Our data show that Nm can initiate a pro-inflammatory response in human CP epithelial cells probably involving TLR2/TLR6

  6. The host response to the probiotic Escherichia coli strain Nissle 1917: Specific up-regulation of the proinflammatory chemokine MCP-1

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    Ukena Sya N

    2005-12-01

    Full Text Available Abstract Background The use of live microorganisms to influence positively the course of intestinal disorders such as infectious diarrhea or chronic inflammatory conditions has recently gained increasing interest as a therapeutic alternative. In vitro and in vivo investigations have demonstrated that probiotic-host eukaryotic cell interactions evoke a large number of responses potentially responsible for the effects of probiotics. The aim of this study was to improve our understanding of the E. coli Nissle 1917-host interaction by analyzing the gene expression pattern initiated by this probiotic in human intestinal epithelial cells. Methods Gene expression profiles of Caco-2 cells treated with E. coli Nissle 1917 were analyzed with microarrays. A second human intestinal cell line and also pieces of small intestine from BALB/c mice were used to confirm regulatory data of selected genes by real-time RT-PCR and cytometric bead array (CBA to detect secretion of corresponding proteins. Results Whole genome expression analysis revealed 126 genes specifically regulated after treatment of confluent Caco-2 cells with E. coli Nissle 1917. Among others, expression of genes encoding the proinflammatory molecules monocyte chemoattractant protein-1 ligand 2 (MCP-1, macrophage inflammatory protein-2 alpha (MIP-2α and macrophage inflammatory protein-2 beta (MIP-2β was increased up to 10 fold. Caco-2 cells cocultured with E. coli Nissle 1917 also secreted high amounts of MCP-1 protein. Elevated levels of MCP-1 and MIP-2α mRNA could be confirmed with Lovo cells. MCP-1 gene expression was also up-regulated in mouse intestinal tissue. Conclusion Thus, probiotic E. coli Nissle 1917 specifically upregulates expression of proinflammatory genes and proteins in human and mouse intestinal epithelial cells.

  7. Pro-inflammatory interleukins in middle ear effusions from atopic and non-atopic children with chronic otitis media with effusion.

    Science.gov (United States)

    Zielnik-Jurkiewicz, Beata; Stankiewicz-Szymczak, Wanda

    2016-06-01

    Chronic otitis media with effusion (OME) is associated with irreversible changes in the middle ear, sometimes leading to hearing loss and abnormal language development in children. While the pathogenesis of OME is not fully understood, inflammatory and allergic factors are thought to be involved. The study aimed to investigate the role of cytokines in the local development of chronic OME, and assess differences in the cytokine profiles between atopic and non-atopic children. 84 atopic and non-atopic children with chronic OME (mean age of 6 years 7 months) were studied. Age-matched children with hypertrophy of the adenoids and Eustachian tube dysfunction served as the control group. The number of past acute otitis media (AOM) episodes, their age, and the type of effusion were recorded for all children. Pro-inflammatory cytokine concentrations (TNF-α, IL-1β, IL-6 and IL-8) were determined and the presence of pathogenic bacteria in the patients' effusions was examined. High concentrations of TNF-α, IL-1β, IL-6 and IL-8 were found in the effusions in all children with chronic OME, with the highest levels observed in the non-atopic group. The atopic group showed persistently high IL-1β levels, while in the non-atopic children, IL-1β and TNF-α levels positively correlated with the patient's age and the number of past AOM episodes. Pathogenic bacteria were more frequently isolated from effusions in non-atopic children. In both atopic and non-atopic children, pro-inflammatory cytokines are found at high concentrations. This argues in favor of instituting anti-inflammatory management for treating OME, regardless of atopy.

  8. Proinflammatory interleukins' production by adipose tissue-derived mesenchymal stromal cells: the impact of cell culture conditions and cell-to-cell interaction.

    Science.gov (United States)

    Andreeva, Elena; Andrianova, Irina; Rylova, Julia; Gornostaeva, Aleksandra; Bobyleva, Polina; Buravkova, Ludmila

    2015-08-01

    The impact of culture conditions and interaction with activated peripheral blood mononuclear cells on the interleukin (IL) gene expression profile and proinflammatory IL-6 and IL-8 production by adipose-derived stromal cells (ASCs) was investigated. A microarray analysis revealed a wide range of IL genes either under standard (20%) or hypoxic (5%) O2 concentrations, some highly up-regulated at hypoxia. IL-6 and IL-8 production was inversely dependent on cell culture density. In early (first-third) passages, IL-6 and IL-8 concentration was higher at 20% O2 and in late (8th-12th) passages under 5% O2. Interaction between ASCs and mononuclear cells in indirect setting was accompanied with a significant decrease of IL-6 and did not result in the elevation of IL-8 concentration. Thereby, the production of proinflammatory interleukins (IL-6 and IL-8) may be affected by the ASC intrinsic features (density in culture, and duration of expansion), as well as by microenvironmental factors, such as hypoxia and the presence of blood-borne cells. These data are important for elucidating ASC paracrine activity regulation in vitro. They would also be on demand for optimisation of the cell therapy protocols, based on the application of ASC biologically active substances. SIGNIFICANCE PARAGRAPH: Ex vivo expansion is widely used for increasing the number of adipose-derived stromal cells (ASCs) and improving of their quality. The present study was designed to elucidate the particular factors influencing the interleukin production in ASCs. The presented data specified the parameters (i.e. cell density, duration of cultivation, hypoxia, etc.) that should be taken in mind when ASCs are intended to be used in protocols implying their paracrine activity. These data would be of considerable interest for researchers and clinicians working in the biomedical science. Copyright © 2015 John Wiley & Sons, Ltd.

  9. Cellular Mechanics of Primary Human Cervical Fibroblasts: Influence of Progesterone and a Pro-inflammatory Cytokine.

    Science.gov (United States)

    Shukla, Vasudha; Barnhouse, Victoria; Ackerman, William E; Summerfield, Taryn L; Powell, Heather M; Leight, Jennifer L; Kniss, Douglas A; Ghadiali, Samir N

    2018-01-01

    The leading cause of neonatal mortality, pre-term birth, is often caused by pre-mature ripening/opening of the uterine cervix. Although cervical fibroblasts play an important role in modulating the cervix's extracellular matrix (ECM) and mechanical properties, it is not known how hormones, i.e., progesterone, and pro-inflammatory insults alter fibroblast mechanics, fibroblast-ECM interactions and the resulting changes in tissue mechanics. Here we investigate how progesterone and a pro-inflammatory cytokine, IL-1β, alter the biomechanical properties of human cervical fibroblasts and the fibroblast-ECM interactions that govern tissue-scale mechanics. Primary human fibroblasts were isolated from non-pregnant cervix and treated with estrogen/progesterone, IL-1β or both. The resulting changes in ECM gene expression, matrix remodeling, traction force generation, cell-ECM adhesion and tissue contractility were monitored. Results indicate that IL-1β induces a significant reduction in traction force and ECM adhesion independent of pre-treatment with progesterone. These cell level effects altered tissue-scale mechanics where IL-1β inhibited the contraction of a collagen gel over 6 days. Interestingly, progesterone treatment alone did not modulate traction forces or gel contraction but did result in a dramatic increase in cell-ECM adhesion. Therefore, the protective effect of progesterone may be due to altered adhesion dynamics as opposed to altered ECM remodeling.

  10. Medium-chain fatty acid-sensing receptor, GPR84, is a proinflammatory receptor.

    Science.gov (United States)

    Suzuki, Masakatsu; Takaishi, Sachiko; Nagasaki, Miyuki; Onozawa, Yoshiko; Iino, Ikue; Maeda, Hiroaki; Komai, Tomoaki; Oda, Tomiichiro

    2013-04-12

    G protein-coupled receptor 84 (GPR84) is a putative receptor for medium-chain fatty acids (MCFAs), whose pathophysiological roles have not yet been clarified. Here, we show that GPR84 was activated by MCFAs with the hydroxyl group at the 2- or 3-position more effectively than nonhydroxylated MCFAs. We also identified a surrogate agonist, 6-n-octylaminouracil (6-OAU), for GPR84. These potential ligands and the surrogate agonist, 6-OAU, stimulated [(35)S]GTP binding and accumulated phosphoinositides in a GPR84-dependent manner. The surrogate agonist, 6-OAU, internalized GPR84-EGFP from the cell surface. Both the potential ligands and 6-OAU elicited chemotaxis of human polymorphonuclear leukocytes (PMNs) and macrophages and amplified LPS-stimulated production of the proinflammatory cytokine IL-8 from PMNs and TNFα from macrophages. Furthermore, the intravenous injection of 6-OAU raised the blood CXCL1 level in rats, and the inoculation of 6-OAU into the rat air pouch accumulated PMNs and macrophages in the site. Our results indicate a proinflammatory role of GPR84, suggesting that the receptor may be a novel target to treat chronic low grade inflammation associated-disease.

  11. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines.

    Science.gov (United States)

    Zong, L; Yu, Q H; Du, Y X; Deng, X M

    2014-02-01

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  12. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Energy Technology Data Exchange (ETDEWEB)

    Zong, L. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China); No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Yu, Q. H. [Second Military Medical University, Changhai Hospital, Department of Gastroenterology, Shanghai, China, Department of Gastroenterology, Changhai Hospital, Second Military Medical University, Shanghai (China); Du, Y. X. [No. 82 Hospital of People' s Liberation Army, Department of Anesthesiology, Jiangsu, China, Department of Anesthesiology, No. 82 Hospital of People' s Liberation Army, Jiangsu (China); Deng, X. M. [Second Military Medical University, Changhai Hospital, Department of Anesthesiology, Shanghai, China, Department of Anesthesiology, Changhai Hospital, Second Military Medical University, Shanghai (China)

    2014-03-03

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  13. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    Directory of Open Access Journals (Sweden)

    L. Zong

    2014-03-01

    Full Text Available Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN and lipopolysaccharide (LPS in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST and alanine aminotransferase (ALT. Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis.

  14. Edaravone protects endotoxin-induced liver injury by inhibiting apoptosis and reducing proinflammatory cytokines

    International Nuclear Information System (INIS)

    Zong, L.; Yu, Q.H.; Du, Y.X.; Deng, X.M.

    2014-01-01

    Studies have shown that edaravone may prevent liver injury. This study aimed to investigate the effects of edaravone on the liver injury induced by D-galactosamine (GalN) and lipopolysaccharide (LPS) in female BALB/c mice. Edaravone was injected into mice 30 min before and 4 h after GalN/LPS injection. The survival rate was determined within the first 24 h. Animals were killed 8 h after GalN/LPS injection, and liver injury was biochemically and histologically assessed. Hepatocyte apoptosis was measured by TUNEL staining; proinflammatory cytokines [tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] in the liver were assayed by ELISA; expression of caspase-8 and caspase-3 proteins was detected by Western blot assay; and caspase-3 activity was also determined. Results showed that GalN/LPS induced marked elevations in serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Edaravone significantly inhibited elevation of serum AST and ALT, accompanied by an improvement in histological findings. Edaravone lowered the levels of TNF-α and IL-6 and reduced the number of TUNEL-positive cells. In addition, 24 h after edaravone treatment, caspase-3 activity and mortality were reduced. Edaravone may effectively ameliorate GalN/LPS-induced liver injury in mice by reducing proinflammatory cytokines and inhibiting apoptosis

  15. The pro-inflammatory effects of platelet contamination in plasma and mitigation strategies for avoidance

    Science.gov (United States)

    Bercovitz, R. S.; Kelher, M. R.; Khan, S. Y.; Land, K. J.; Berry, T. H.; Silliman, C. C.

    2013-01-01

    Background and Objectives Plasma and platelet concentrates are disproportionately implicated in transfusion-related acute lung injury (TRALI). Platelet-derived pro-inflammatory mediators, including soluble CD40 ligand (sCD40L), accumulate during storage. We hypothesized that platelet contamination induces sCD40L generation that causes neutrophil [polymorphonuclear leucocyte (PMN)] priming and PMN-mediated cytotoxicity. Materials and Methods Plasma was untreated, centrifuged (12 500 g) or separated from leucoreduced whole blood (WBLR) prior to freezing. Platelet counts and sCD40L concentrations were measured 1–5 days post-thaw. The plasma was assayed for PMN priming activity and was used in a two-event in vitro model of PMN-mediated human pulmonary microvascular endothelial cell (HMVEC) cytotoxicity. Results Untreated plasma contained 42 ± 4.2 × 103/μl platelets, which generated sCD40L accumulation (1.6-eight-fold vs. controls). Priming activity and HMVEC cytotoxicity were directly proportional to sCD40L concentration. WBLR and centrifugation reduced platelet and sCD40L contamination, abrogating the pro-inflammatory potential. Conclusion Platelet contamination causes sCD40L accumulation in stored plasma that may contribute to TRALI. Platelet reduction is potentially the first TRALI mitigation effort in plasma manufacturing. PMID:22092073

  16. Metoprolol Reduces Proinflammatory Cytokines and Atherosclerosis in ApoE−/− Mice

    Directory of Open Access Journals (Sweden)

    Marcus A. Ulleryd

    2014-01-01

    Full Text Available A few studies in animals and humans suggest that metoprolol (β1-selective adrenoceptor antagonist may have a direct antiatherosclerotic effect. However, the mechanism behind this protective effect has not been established. The aim of the present study was to evaluate the effect of metoprolol on development of atherosclerosis in ApoE−/− mice and investigate its effect on the release of proinflammatory cytokines. Male ApoE−/− mice were treated with metoprolol (2.5 mg/kg/h or saline for 11 weeks via osmotic minipumps. Atherosclerosis was assessed in thoracic aorta and aortic root. Total cholesterol levels and Th1/Th2 cytokines were analyzed in serum and macrophage content in lesions by immunohistochemistry. Metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta (P<0.05 versus Control. Further, metoprolol reduced serum TNFα and the chemokine CXCL1 (P<0.01 versus Control for both as well as decreasing the macrophage content in the plaques (P<0.01 versus Control. Total cholesterol levels were not affected. In this study we found that a moderate dose of metoprolol significantly reduced atherosclerotic plaque area in thoracic aorta of ApoE−/− mice. Metoprolol also decreased serum levels of proinflammatory cytokines TNFα and CXCL1 and macrophage content in the plaques, showing that metoprolol has an anti-inflammatory effect.

  17. Proinflammatory Factors Mediate Paclitaxel-Induced Impairment of Learning and Memory

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    Zhao Li

    2018-01-01

    Full Text Available The chemotherapeutic agent paclitaxel is widely used for cancer treatment. Paclitaxel treatment impairs learning and memory function, a side effect that reduces the quality of life of cancer survivors. However, the neural mechanisms underlying paclitaxel-induced impairment of learning and memory remain unclear. Paclitaxel treatment leads to proinflammatory factor release and neuronal apoptosis. Thus, we hypothesized that paclitaxel impairs learning and memory function through proinflammatory factor-induced neuronal apoptosis. Neuronal apoptosis was assessed by TUNEL assay in the hippocampus. Protein expression levels of tumor necrosis factor-α (TNF-α and interleukin-1β (IL-1β in the hippocampus tissue were analyzed by Western blot assay. Spatial learning and memory function were determined by using the Morris water maze (MWM test. Paclitaxel treatment significantly increased the escape latencies and decreased the number of crossing in the MWM test. Furthermore, paclitaxel significantly increased the number of TUNEL-positive neurons in the hippocampus. Also, paclitaxel treatment increased the expression levels of TNF-α and IL-1β in the hippocampus tissue. In addition, the TNF-α synthesis inhibitor thalidomide significantly attenuated the number of paclitaxel-induced TUNEL-positive neurons in the hippocampus and restored the impaired spatial learning and memory function in paclitaxel-treated rats. These data suggest that TNF-α is critically involved in the paclitaxel-induced impairment of learning and memory function.

  18. Controlled Inhibition of the Mesenchymal Stromal Cell Pro-inflammatory Secretome via Microparticle Engineering

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    Sudhir H. Ranganath

    2016-06-01

    Full Text Available Mesenchymal stromal cells (MSCs are promising therapeutic candidates given their potent immunomodulatory and anti-inflammatory secretome. However, controlling the MSC secretome post-transplantation is considered a major challenge that hinders their clinical efficacy. To address this, we used a microparticle-based engineering approach to non-genetically modulate pro-inflammatory pathways in human MSCs (hMSCs under simulated inflammatory conditions. Here we show that microparticles loaded with TPCA-1, a small-molecule NF-κB inhibitor, when delivered to hMSCs can attenuate secretion of pro-inflammatory factors for at least 6 days in vitro. Conditioned medium (CM derived from TPCA-1-loaded hMSCs also showed reduced ability to attract human monocytes and prevented differentiation of human cardiac fibroblasts to myofibroblasts, compared with CM from untreated or TPCA-1-preconditioned hMSCs. Thus, we provide a broadly applicable bioengineering solution to facilitate intracellular sustained release of agents that modulate signaling. We propose that this approach could be harnessed to improve control over MSC secretome post-transplantation, especially to prevent adverse remodeling post-myocardial infarction.

  19. Shigella dysenteriae infection activates proinflammatory response through β-catenin/NF-κB signaling pathway.

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    Ashidha Gopal

    Full Text Available Shigella dysenteriae (S.dysenteriae the causative agent of bacillary dysentery invades the human colonic epithelium resulting in severe intestinal inflammatory response and epithelial destruction. However, the mechanism by which S.dysenteriae infection regulates proinflammatory cytokines during intestinal inflammation is still obscure. In this study, we evaluated whether the interaction of β-catenin and NF-κB regulates proinflammatory cytokines TNF-α and IL-8 by modulating GSK-3β activity during S.dysenteriae infection in rat ileal loop model. Here we demonstrated that S.dysenteriae infection stimulate β-catenin degradation which in turn decreased the association between NF-κB and β-catenin. Also, we showed that S.dysenteriae infection increased GSK-3β kinase activity which in turn phosphorylates β-catenin for its degradation by ubiquitination and upregulates IL-8 through NF-κB activation thereby leading to inflammation. Thus these findings revealed the role of β-catenin/ NF-κB and GSK-3β in modulating the inflammatory response during bacterial infection and also showed that β-catenin acts as a critical regulator of inflammation.

  20. Pro-inflammatory cytokines play a key role in the development of radiotherapy-induced gastrointestinal mucositis

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    Logan Richard M

    2010-03-01

    Full Text Available Abstract Background Mucositis is a toxic side effect of anti-cancer treatments and is a major focus in cancer research. Pro-inflammatory cytokines have previously been implicated in the pathophysiology of chemotherapy-induced gastrointestinal mucositis. However, whether they play a key role in the development of radiotherapy-induced gastrointestinal mucositis is still unknown. Therefore, the aim of the present study was to characterise the expression of pro-inflammatory cytokines in the gastrointestinal tract using a rat model of fractionated radiotherapy-induced toxicity. Methods Thirty six female Dark Agouti rats were randomly assigned into groups and received 2.5 Gys abdominal radiotherapy three times a week over six weeks. Real time PCR was conducted to determine the relative change in mRNA expression of pro-inflammatory cytokines IL-1β, IL-6 and TNF in the jejunum and colon. Protein expression of IL-1β, IL-6 and TNF in the intestinal epithelium was investigated using qualitative immunohistochemistry. Results Radiotherapy-induced sub-acute damage was associated with significantly upregulated IL-1β, IL-6 and TNF mRNA levels in the jejunum and colon. The majority of pro-inflammatory cytokine protein expression in the jejunum and colon exhibited minimal change following fractionated radiotherapy. Conclusions Pro-inflammatory cytokines play a key role in radiotherapy-induced gastrointestinal mucositis in the sub-acute onset setting.

  1. Holi colours contain PM10 and can induce pro-inflammatory responses.

    Science.gov (United States)

    Bossmann, Katrin; Bach, Sabine; Höflich, Conny; Valtanen, Kerttu; Heinze, Rita; Neumann, Anett; Straff, Wolfgang; Süring, Katrin

    2016-01-01

    At Holi festivals, originally celebrated in India but more recently all over the world, people throw coloured powder (Holi powder, Holi colour, Gulal powder) at each other. Adverse health effects, i.e. skin and ocular irritations as well as respiratory problems may be the consequences. The aim of this study was to uncover some of the underlying mechanisms. We analysed four different Holi colours regarding particle size using an Electric field cell counting system. In addition, we incubated native human cells with different Holi colours and determined their potential to induce a pro-inflammatory response by quantifying the resulting cytokine production by means of ELISA (Enzyme Linked Immunosorbent Assay) and the resulting leukocyte oxidative burst by flow cytometric analysis. Moreover, we performed the XTT (2,3-Bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide) and Propidium iodide cytotoxicity tests and we measured the endotoxin content of the Holi colour samples by means of the Limulus Amebocyte Lysate test (LAL test). We show here that all tested Holi colours consist to more than 40 % of particles with an aerodynamic diameter smaller than 10 μm, so called PM10 particles (PM, particulate matter). Two of the analysed Holi powders contained even more than 75 % of PM10 particles. Furthermore we demonstrate in cell culture experiments that Holi colours can induce the production of the pro-inflammatory cytokines TNF-α (Tumor necrosis factor-α), IL-6 (Interleukine-6) and IL-1β (Interleukine-1β). Three out of the four analysed colours induced a significantly higher cytokine response in human PBMCs (Peripheral Blood Mononuclear Cells) and whole blood than corn starch, which is often used as carrier substance for Holi colours. Moreover we show that corn starch and two Holi colours contain endotoxin and that certain Holi colours display concentration dependent cytotoxic effects in higher concentration. Furthermore we reveal that in principle Holi

  2. A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

    International Nuclear Information System (INIS)

    Liu, Shuai; Lv, Jiaju; Han, Liping; Ichikawa, Tomonaga; Wang, Wenjuan; Li, Siying; Wang, Xing Li; Tang, Dongqi; Cui, Taixing

    2012-01-01

    Highlights: ► Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. ► Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. ► CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-κB) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-κB activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-κB activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNFα)-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-κB transcriptional activity in RASMCs; however, did not affect the TNFα-induced NF-κB activity. Intriguingly, the TNFα-induced IκB phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of IκBα and IκBβ proteins, it did not alter the kinetics of TNFα-induced IκB protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-κB activity and TNFα-induced IκB kinase activation without affecting TNFα-induced NF-κB activity in VSMCs. In addition, knocking down of Cyld suppressed TNFα-induced activation of mitogen activated protein kinases (MAPKs) including extracellular signal-activated kinases (ERK), c-Jun N-terminal kinase (JNK), and p38 in RASMCs. TNFα-induced RASMC migration and monocyte adhesion to

  3. Proinflammatory effect in whole blood by free soluble bacterial components released from planktonic and biofilm cells

    Directory of Open Access Journals (Sweden)

    Thay Bernard

    2008-11-01

    Full Text Available Abstract Background Aggregatibacter actinomycetemcomitans is an oral bacterium associated with aggressive forms of periodontitis. Increasing evidence points to a link between periodontitis and cardiovascular diseases, however, the underlying mechanisms are poorly understood. This study investigated the pathogenic potential of free-soluble surface material, released from live planktonic and biofilm A. actinomycetemcomitans cells. Results By employing an ex vivo insert model (filter pore size 20 nm we demonstrated that the A. actinomycetemcomitans strain D7S and its derivatives, in both planktonic and in biofilm life-form, released free-soluble surface material independent of outer membrane vesicles. This material clearly enhanced the production of several proinflammatory cytokines (IL-1β, TNF-α, IL-6, IL-8, MIP-1β in human whole blood, as evidenced by using a cytokine antibody array and dissociation-enhanced-lanthanide-fluorescent-immunoassay. In agreement with this, quantitative real-time PCR indicated a concomitant increase in transcription of each of these cytokine genes. Experiments in which the LPS activity was blocked with polymyxin B showed that the stimulatory effect was only partly LPS-dependent, suggesting the involvement of additional free-soluble factors. Consistent with this, MALDI-TOF-MS and immunoblotting revealed release of GroEL-like protein in free-soluble form. Conversely, the immunomodulatory toxins, cytolethal distending toxin and leukotoxin, and peptidoglycan-associated lipoprotein, appeared to be less important, as evidenced by studying strain D7S cdt/ltx double, and pal single mutants. In addition to A. actinomycetemcomitans a non-oral species, Escherichia coli strain IHE3034, tested in the same ex vivo model also released free-soluble surface material with proinflammatory activity. Conclusion A. actinomycetemcomitans, grown in biofilm and planktonic form, releases free-soluble surface material independent of outer

  4. Proinflammatory effect in whole blood by free soluble bacterial components released from planktonic and biofilm cells.

    Science.gov (United States)

    Oscarsson, Jan; Karched, Maribasappa; Thay, Bernard; Chen, Casey; Asikainen, Sirkka

    2008-11-27

    Aggregatibacter actinomycetemcomitans is an oral bacterium associated with aggressive forms of periodontitis. Increasing evidence points to a link between periodontitis and cardiovascular diseases, however, the underlying mechanisms are poorly understood. This study investigated the pathogenic potential of free-soluble surface material, released from live planktonic and biofilm A. actinomycetemcomitans cells. By employing an ex vivo insert model (filter pore size 20 nm) we demonstrated that the A. actinomycetemcomitans strain D7S and its derivatives, in both planktonic and in biofilm life-form, released free-soluble surface material independent of outer membrane vesicles. This material clearly enhanced the production of several proinflammatory cytokines (IL-1 beta, TNF-alpha, IL-6, IL-8, MIP-1 beta) in human whole blood, as evidenced by using a cytokine antibody array and dissociation-enhanced-lanthanide-fluorescent-immunoassay. In agreement with this, quantitative real-time PCR indicated a concomitant increase in transcription of each of these cytokine genes. Experiments in which the LPS activity was blocked with polymyxin B showed that the stimulatory effect was only partly LPS-dependent, suggesting the involvement of additional free-soluble factors. Consistent with this, MALDI-TOF-MS and immunoblotting revealed release of GroEL-like protein in free-soluble form. Conversely, the immunomodulatory toxins, cytolethal distending toxin and leukotoxin, and peptidoglycan-associated lipoprotein, appeared to be less important, as evidenced by studying strain D7S cdt/ltx double, and pal single mutants. In addition to A. actinomycetemcomitans a non-oral species, Escherichia coli strain IHE3034, tested in the same ex vivo model also released free-soluble surface material with proinflammatory activity. A. actinomycetemcomitans, grown in biofilm and planktonic form, releases free-soluble surface material independent of outer membrane vesicles, which induces proinflammatory

  5. Minocycline counter-regulates pro-inflammatory microglia responses in the retina and protects from degeneration.

    Science.gov (United States)

    Scholz, Rebecca; Sobotka, Markus; Caramoy, Albert; Stempfl, Thomas; Moehle, Christoph; Langmann, Thomas

    2015-11-17

    Microglia reactivity is a hallmark of retinal degenerations and overwhelming microglial responses contribute to photoreceptor death. Minocycline, a semi-synthetic tetracycline analog, has potent anti-inflammatory and neuroprotective effects. Here, we investigated how minocycline affects microglia in vitro and studied its immuno-modulatory properties in a mouse model of acute retinal degeneration using bright white light exposure. LPS-treated BV-2 microglia were stimulated with 50 μg/ml minocycline for 6 or 24 h, respectively. Pro-inflammatory gene transcription was determined by real-time RT-PCR and nitric oxide (NO) secretion was assessed using the Griess reagent. Caspase 3/7 levels were determined in 661W photoreceptors cultured with microglia-conditioned medium in the absence or presence of minocycline supplementation. BALB/cJ mice received daily intraperitoneal injections of 45 mg/kg minocycline, starting 1 day before exposure to 15.000 lux white light for 1 hour. The effect of minocycline treatment on microglial reactivity was analyzed by immunohistochemical stainings of retinal sections and flat-mounts, and messenger RNA (mRNA) expression of microglia markers was determined using real-time RT-PCR and RNA-sequencing. Optical coherence tomography (OCT) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings were used to measure the extent of retinal degeneration and photoreceptor apoptosis. Stimulation of LPS-activated BV-2 microglia with minocycline significantly diminished the transcription of the pro-inflammatory markers CCL2, IL6, and inducible nitric oxide synthase (iNOS). Minocycline also reduced the production of NO and dampened microglial neurotoxicity on 661W photoreceptors. Furthermore, minocycline had direct protective effects on 661W photoreceptors by decreasing caspase 3/7 activity. In mice challenged with white light, injections of minocycline strongly decreased the number of amoeboid alerted microglia in the outer

  6. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    Energy Technology Data Exchange (ETDEWEB)

    Itoi, Saori; Terao, Mika, E-mail: mterao@derma.med.osaka-u.ac.jp; Murota, Hiroyuki; Katayama, Ichiro

    2013-10-18

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10{sup −13} M cortisol, whereas 1 × 10{sup −5} M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol

  7. 11β-Hydroxysteroid dehydrogenase 1 contributes to the pro-inflammatory response of keratinocytes

    International Nuclear Information System (INIS)

    Itoi, Saori; Terao, Mika; Murota, Hiroyuki; Katayama, Ichiro

    2013-01-01

    Highlights: •We investigate the role of 11β-HSD1 in skin inflammation. •Various stimuli increase expression of 11β-HSD1 in keratinocytes. •11β-HSD1 knockdown by siRNA decreases cortisol levels in media. •11β-HSD1 knockdown abrogates the response to pro-inflammatory cytokines. •Low-dose versus high-dose cortisol has opposing effects on keratinocyte inflammation. -- Abstract: The endogenous glucocorticoid, cortisol, is released from the adrenal gland in response to various stress stimuli. Extra-adrenal cortisol production has recently been reported to occur in various tissues. Skin is known to synthesize cortisol through a de novo pathway and through an activating enzyme. The enzyme that catalyzes the intracellular conversion of hormonally-inactive cortisone into active cortisol is 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1). We recently reported that 11β-HSD1 is expressed in normal human epidermal keratinocytes (NHEKs) and negatively regulates proliferation of NHEKs. In this study, we investigated the role of 11β-HSD1 in skin inflammation. Expression of 11β-HSD1 was induced by UV-B irradiation and in response to the pro-inflammatory cytokines, IL-1β and TNFα. Increased cortisol concentrations in culture media also increased in response to these stimuli. To investigate the function of increased 11β-HSD1 in response to pro-inflammatory cytokines, we knocked down 11β-HSD1 by transfecting siRNA. Production of IL-6 and IL-8 in response to IL-1β or TNFα stimulation was attenuated in NHEKs transfected with si11β-HSD1 compared with control cells. In addition, IL-1β-induced IL-6 production was enhanced in cultures containing 1 × 10 −13 M cortisol, whereas 1 × 10 −5 M cortisol attenuated production of IL-6. Thus, cortisol showed immunostimulatory and immunosuppressive activities depending on its concentration. Our results indicate that 11β-HSD1 expression is increased by various stimuli. Thus, regulation of cytosolic cortisol concentrations

  8. A pro-inflammatory role of deubiquitinating enzyme cylindromatosis (CYLD) in vascular smooth muscle cells

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shuai [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Lv, Jiaju [Department of Urology, Shandong Provincial Hospital, Shandong University, Jinan 250021 (China); Han, Liping; Ichikawa, Tomonaga; Wang, Wenjuan; Li, Siying [Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States); Wang, Xing Li [Shandong University Qilu Hospital Research Center for Cell Therapy, Key Laboratory of Cardiovascular Remodeling and Function Research, Qilu Hospital of Shandong University, Jinan 250012 (China); Tang, Dongqi, E-mail: tangdq@pathology.ufl.edu [Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL 32610-0275 (United States); Cui, Taixing, E-mail: taixing.cui@uscmed.sc.edu [Department of Cell Biology and Anatomy, University of South Carolina School of Medicine, Columbia, SC 29208 (United States)

    2012-03-30

    Highlights: Black-Right-Pointing-Pointer Cyld deficiency suppresses pro-inflammatory phenotypic switch of VSMCs. Black-Right-Pointing-Pointer Cyld deficiency inhibits MAPK rather than NF-kB activity in inflamed VSMCs. Black-Right-Pointing-Pointer CYLD is up-regulated in the coronary artery with neointimal hyperplasia. -- Abstract: CYLD, a deubiquitinating enzyme (DUB), is a critical regulator of diverse cellular processes, ranging from proliferation and differentiation to inflammatory responses, via regulating multiple key signaling cascades such as nuclear factor kappa B (NF-{kappa}B) pathway. CYLD has been shown to inhibit vascular lesion formation presumably through suppressing NF-{kappa}B activity in vascular cells. However, herein we report a novel role of CYLD in mediating pro-inflammatory responses in vascular smooth muscle cells (VSMCs) via a mechanism independent of NF-{kappa}B activity. Adenoviral knockdown of Cyld inhibited basal and the tumor necrosis factor alpha (TNF{alpha})-induced mRNA expression of pro-inflammatory cytokines including monocyte chemotactic protein-1 (Mcp-1), intercellular adhesion molecule (Icam-1) and interleukin-6 (Il-6) in rat adult aortic SMCs (RASMCs). The CYLD deficiency led to increases in the basal NF-{kappa}B transcriptional activity in RASMCs; however, did not affect the TNF{alpha}-induced NF-{kappa}B activity. Intriguingly, the TNF{alpha}-induced I{kappa}B phosphorylation was enhanced in the CYLD deficient RASMCs. While knocking down of Cyld decreased slightly the basal expression levels of I{kappa}B{alpha} and I{kappa}B{beta} proteins, it did not alter the kinetics of TNF{alpha}-induced I{kappa}B protein degradation in RASMCs. These results indicate that CYLD suppresses the basal NF-{kappa}B activity and TNF{alpha}-induced I{kappa}B kinase activation without affecting TNF{alpha}-induced NF-{kappa}B activity in VSMCs. In addition, knocking down of Cyld suppressed TNF{alpha}-induced activation of mitogen activated protein

  9. Investigation of the proinflammatory activity of bronchoalveolar lavage fluid in lung cancer and inflammatory diseases of respiratory organs

    Directory of Open Access Journals (Sweden)

    O. P. Makarova

    2014-01-01

    Full Text Available The proinflammatory activity of bronchoalveolar lavage fluid (BALF was investigated using the biological test system (donor blood in 71 patients with lung cancer and inflammatory disease of respiratory organs (lung abscess, infiltrative tuberculosis, tuberculoma, fibrocavernous tuberculosis. The supernatant of BALF was purified by filtration through millipores and added to blood, and a nitroblue tetrazolium recovery test (HBT was carried out. Hank’s balanced salt solution was used in the control. The proinflammatory effect of BALF was defined as a diformazan-positive neutrophil count ratio in the experimental and control samples (stimulation index. The inflammatory process developing in lung cancer was active, as suggested by the accumulation of neutrophils in the lung and by the high proinflammatory activity of BALF, which were comparable with the similar indicators in lung abscess and fibrocavernous tuberculosis.

  10. Oxidative stress and proinflammatory cytokines contribute to demyelination and axonal damage in a cerebellar culture model of neuroinflammation.

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X; Villoslada, Pablo

    2013-01-01

    Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage. The model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines

  11. Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

    Science.gov (United States)

    di Penta, Alessandra; Moreno, Beatriz; Reix, Stephanie; Fernandez-Diez, Begoña; Villanueva, Maite; Errea, Oihana; Escala, Nagore; Vandenbroeck, Koen; Comella, Joan X.; Villoslada, Pablo

    2013-01-01

    Background Demyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage. Methods/Principal Findings To monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of