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  1. Which biomarkers reveal neonatal sepsis?

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    Kun Wang

    Full Text Available We address the identification of optimal biomarkers for the rapid diagnosis of neonatal sepsis. We employ both canonical correlation analysis (CCA and sparse support vector machine (SSVM classifiers to select the best subset of biomarkers from a large hematological data set collected from infants with suspected sepsis from Yale-New Haven Hospital's Neonatal Intensive Care Unit (NICU. CCA is used to select sets of biomarkers of increasing size that are most highly correlated with infection. The effectiveness of these biomarkers is then validated by constructing a sparse support vector machine diagnostic classifier. We find that the following set of five biomarkers capture the essential diagnostic information (in order of importance: Bands, Platelets, neutrophil CD64, White Blood Cells, and Segs. Further, the diagnostic performance of the optimal set of biomarkers is significantly higher than that of isolated individual biomarkers. These results suggest an enhanced sepsis scoring system for neonatal sepsis that includes these five biomarkers. We demonstrate the robustness of our analysis by comparing CCA with the Forward Selection method and SSVM with LASSO Logistic Regression.

  2. SRRM2, a potential blood biomarker revealing high alternative splicing in Parkinson's disease.

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    Lina A Shehadeh

    Full Text Available BACKGROUND: Parkinson's disease (PD is a progressive neurodegenerative disorder that affects about five million people worldwide. Diagnosis remains clinical, based on phenotypic patterns. The discovery of laboratory markers that will enhance diagnostic accuracy, allow pre-clinical detection and tracking of disease progression is critically needed. These biomarkers may include transcripts with different isoforms. METHODOLOGY/PRINCIPAL FINDINGS: We performed extensive analysis on 3 PD microarray experiments available through GEO and found that the RNA splicing gene SRRM2 (or SRm300, sereine/arginine repetitive matrix 2, was the only gene differentially upregulated among all the three PD experiments. SRRM2 expression was not changed in the blood of other neurological diseased patients versus the healthy controls. Using real-time PCR, we report that the shorter transcript of SRRM2 was 1.7 fold (p = 0.008 upregulated in the substantia nigra of PDs vs controls while the longer transcript was 0.4 downregulated in both the substantia nigra (p = 0.03 and amygdala (p = 0.003. To validate our results and test for the possibility of alternative splicing in PD, we performed independent microarray scans, using Affymetrix Exon_ST1 arrays, from peripheral blood of 28 individuals (17 PDs and 11 Ctrls and found a significant upregulation of the upstream (5' exons of SRRM2 and a downregulation of the downstream exons, causing a total of 0.7 fold down regulation (p = 0.04 of the long isoform. In addition, we report novel information about hundreds of genes with significant alternative splicing (differential exonic expression in PD blood versus controls. CONCLUSIONS/SIGNIFICANCE: The consistent dysregulation of the RNA splicing factor SRRM2 in two different PD neuronal sources and in PD blood but not in blood of other neurologically diseased patients makes SRRM2 a strong candidate gene for PD and draws attention to the role of RNA splicing in the disease.

  3. Delivery of High-Quality Biomarker Assays

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    Brian N. Swanson

    2002-01-01

    Full Text Available Biomarker measurements now support key decisions throughout the drug development process, from lead optimization to regulatory approvals. They are essential for documenting exposure-response relationships, specificity and potency toward the molecular target, untoward effects, and therapeutic applications. In a broader sense, biomarkers constitute the basis of clinical pathology and laboratory medicine. The utility of biomarkers is limited by their specificity and sensitivity toward the drug or disease process and by their overall variability. Understanding and controlling sources of variability is not only imperative for delivering high-quality assay results, but ultimately for controlling the size and expense of research studies. Variability in biomarker measurements is affected by: biological and environmental factors (e.g., gender, age, posture, diet and biorhythms, sample collection factors (e.g., preservatives, transport and storage conditions, and collection technique, and analytical factors (e.g., purity of reference material, pipetting precision, and antibody specificity. The quality standards for biomarker assays used in support of nonclinical safety studies fall under GLP (FDA regulations, whereas, those assays used to support human diagnostics and healthcare are established by CLIA (CMS regulations and accrediting organizations such as the College of American Pathologists. While most research applications of biomarkers are not regulated, biomarker laboratories in all settings are adopting similar laboratory practices in order to deliver high-quality data. Because of the escalation in demand for biomarker measurements, the highly-parallel (multi-plexed assay platforms that have fueled the rise of genomics will likely evolve into the analytical engines that drive the biomarker laboratories of tomorrow.

  4. Metabolomics reveals metabolic biomarkers of Crohn's disease

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    Jansson, J.K.; Willing, B.; Lucio, M.; Fekete, A.; Dicksved, J.; Halfvarson, J.; Tysk, C.; Schmitt-Kopplin, P.

    2009-06-01

    The causes and etiology of Crohn's disease (CD) are currently unknown although both host genetics and environmental factors play a role. Here we used non-targeted metabolic profiling to determine the contribution of metabolites produced by the gut microbiota towards disease status of the host. Ion Cyclotron Resonance Fourier Transform Mass Spectrometry (ICR-FT/MS) was used to discern the masses of thousands of metabolites in fecal samples collected from 17 identical twin pairs, including healthy individuals and those with CD. Pathways with differentiating metabolites included those involved in the metabolism and or synthesis of amino acids, fatty acids, bile acids and arachidonic acid. Several metabolites were positively or negatively correlated to the disease phenotype and to specific microbes previously characterized in the same samples. Our data reveal novel differentiating metabolites for CD that may provide diagnostic biomarkers and/or monitoring tools as well as insight into potential targets for disease therapy and prevention.

  5. Serum Glycoprotein Biomarker Discovery and Qualification Pipeline Reveals Novel Diagnostic Biomarker Candidates for Esophageal Adenocarcinoma.

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    Shah, Alok K; Cao, Kim-Anh Lê; Choi, Eunju; Chen, David; Gautier, Benoît; Nancarrow, Derek; Whiteman, David C; Saunders, Nicholas A; Barbour, Andrew P; Joshi, Virendra; Hill, Michelle M

    2015-11-01

    We report an integrated pipeline for efficient serum glycoprotein biomarker candidate discovery and qualification that may be used to facilitate cancer diagnosis and management. The discovery phase used semi-automated lectin magnetic bead array (LeMBA)-coupled tandem mass spectrometry with a dedicated data-housing and analysis pipeline; GlycoSelector (http://glycoselector.di.uq.edu.au). The qualification phase used lectin magnetic bead array-multiple reaction monitoring-mass spectrometry incorporating an interactive web-interface, Shiny mixOmics (http://mixomics-projects.di.uq.edu.au/Shiny), for univariate and multivariate statistical analysis. Relative quantitation was performed by referencing to a spiked-in glycoprotein, chicken ovalbumin. We applied this workflow to identify diagnostic biomarkers for esophageal adenocarcinoma (EAC), a life threatening malignancy with poor prognosis in the advanced setting. EAC develops from metaplastic condition Barrett's esophagus (BE). Currently diagnosis and monitoring of at-risk patients is through endoscopy and biopsy, which is expensive and requires hospital admission. Hence there is a clinical need for a noninvasive diagnostic biomarker of EAC. In total 89 patient samples from healthy controls, and patients with BE or EAC were screened in discovery and qualification stages. Of the 246 glycoforms measured in the qualification stage, 40 glycoforms (as measured by lectin affinity) qualified as candidate serum markers. The top candidate for distinguishing healthy from BE patients' group was Narcissus pseudonarcissus lectin (NPL)-reactive Apolipoprotein B-100 (p value = 0.0231; AUROC = 0.71); BE versus EAC, Aleuria aurantia lectin (AAL)-reactive complement component C9 (p value = 0.0001; AUROC = 0.85); healthy versus EAC, Erythroagglutinin Phaseolus vulgaris (EPHA)-reactive gelsolin (p value = 0.0014; AUROC = 0.80). A panel of 8 glycoforms showed an improved AUROC of 0.94 to discriminate EAC from BE. Two biomarker candidates

  6. Carbon sources in the Beaufort Sea revealed by molecular lipid biomarkers and compound specific isotope analysis

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    Tolosa, I.; Fiorini, S.; Gasser, B.; Martín, J.; Miquel, J. C.

    2012-10-01

    Molecular lipid biomarkers (hydrocarbons, alcohols, sterols and fatty acids) and compound specific isotope analysis of suspended particulate organic matter (SPM) and surface sediments of the Mackenzie Shelf and slope (Southeast Beaufort Sea, Arctic Ocean), were studied in summer 2009. The concentrations of the molecular lipid markers, characteristic of known organic matter sources, were grouped and used as proxies to evaluate the relative importance of fresh algal, detrital algal, fossil, C3 terrestrial plants, bacterial and zooplankton material in the sedimentary organic matter (OM). Fossil and detrital algal contributions were the major fractions of the freshwater SPM from the Mackenzie River with ~34% each of the total molecular biomarkers. Fresh algal, C3 terrestrial, bacterial and zooplanktonic components represented much lower percentages, 17, 10, 4 and 80%) with a minor contribution of fossil and C3 terrestrial biomarkers. Characterization of the sediments revealed a major sink of refractory algal material mixed with some fresh algal material, fossil hydrocarbons and a small input of C3 terrestrial sources. In particular, the sediments from the shelf and at the mouth of the Amundsen Gulf presented the highest contribution of detrital algal material (60-75%) whereas those from the slope contained the highest proportion of fossil (40%) and C3 terrestrial plant material (10%). Overall, considering that the detrital algal material is marine derived, autochthonous sources contributed more than allochthonous sources to the OM lipid pool. Using the ratio of an allochthonous biomarker (normalized to total organic carbon, TOC) found in the sediments to those measured at the river mouth water, we estimated that the fraction of terrestrial material preserved in the sediments accounted for 30-40% of the total carbon in the inner shelf sediments, 17% in the outer shelf and Amundsen Gulf and up to 25% in the slope sediments.

  7. MicroRNA Profiling of CSF Reveals Potential Biomarkers to Detect Alzheimer`s Disease.

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    Johannes Denk

    Full Text Available The miRBase-21 database currently lists 1881 microRNA (miRNA precursors and 2585 unique mature human miRNAs. Since their discovery, miRNAs have proved to present a new level of epigenetic post-transcriptional control of protein synthesis. Initial results point to a possible involvement of miRNA in Alzheimer's disease (AD. We applied OpenArray technology to profile the expression of 1178 unique miRNAs in cerebrospinal fluid (CSF samples of AD patients (n = 22 and controls (n = 28. Using a Cq of 34 as cut-off, we identified positive signals for 441 miRNAs, while 729 miRNAs could not be detected, indicating that at least 37% of miRNAs are present in the brain. We found 74 miRNAs being down- and 74 miRNAs being up-regulated in AD using a 1.5 fold change threshold. By applying the new explorative "Measure of relevance" method, 6 reliable and 9 informative biomarkers were identified. Confirmatory MANCOVA revealed reliable miR-100, miR-146a and miR-1274a as differentially expressed in AD reaching Bonferroni corrected significance. MANCOVA also confirmed differential expression of informative miR-103, miR-375, miR-505#, miR-708, miR-4467, miR-219, miR-296, miR-766 and miR-3622b-3p. Discrimination analysis using a combination of miR-100, miR-103 and miR-375 was able to detect AD in CSF by positively classifying controls and AD cases with 96.4% and 95.5% accuracy, respectively. Referring to the Ingenuity database we could identify a set of AD associated genes that are targeted by these miRNAs. Highly predicted targets included genes involved in the regulation of tau and amyloid pathways in AD like MAPT, BACE1 and mTOR.

  8. Identification of novel serum peptide biomarkers for high-altitude adaptation: a comparative approach

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    Yang, Juan; Li, Wenhua; Liu, Siyuan; Yuan, Dongya; Guo, Yijiao; Jia, Cheng; Song, Tusheng; Huang, Chen

    2016-05-01

    We aimed to identify serum biomarkers for screening individuals who could adapt to high-altitude hypoxia at sea level. HHA (high-altitude hypoxia acclimated; n = 48) and HHI (high-altitude hypoxia illness; n = 48) groups were distinguished at high altitude, routine blood tests were performed for both groups at high altitude and at sea level. Serum biomarkers were identified by comparing serum peptidome profiling between HHI and HHA groups collected at sea level. Routine blood tests revealed the concentration of hemoglobin and red blood cells were significantly higher in HHI than in HHA at high altitude. Serum peptidome profiling showed that ten significantly differentially expressed peaks between HHA and HHI at sea level. Three potential serum peptide peaks (m/z values: 1061.91, 1088.33, 4057.63) were further sequence identified as regions of the inter-α trypsin inhibitor heavy chain H4 fragment (ITIH4 347-356), regions of the inter-α trypsin inhibitor heavy chain H1 fragment (ITIH1 205-214), and isoform 1 of fibrinogen α chain precursor (FGA 588-624). Expression of their full proteins was also tested by ELISA in HHA and HHI samples collected at sea level. Our study provided a novel approach for identifying potential biomarkers for screening people at sea level who can adapt to high altitudes.

  9. Lipidomic profiling of tryptophan hydroxylase 2 knockout mice reveals novel lipid biomarkers associated with serotonin deficiency.

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    Weng, Rui; Shen, Sensen; Burton, Casey; Yang, Li; Nie, Honggang; Tian, Yonglu; Bai, Yu; Liu, Huwei

    2016-04-01

    Serotonin is an important neurotransmitter that regulates a wide range of physiological, neuropsychological, and behavioral processes. Consequently, serotonin deficiency is involved in a wide variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, schizophrenia, and depression. The pathophysiological mechanisms underlying serotonin deficiency, particularly from a lipidomics perspective, remain poorly understood. This study therefore aimed to identify novel lipid biomarkers associated with serotonin deficiency by lipidomic profiling of tryptophan hydroxylase 2 knockout (Tph2-/-) mice. Using a high-throughput normal-/reversed-phase two-dimensional liquid chromatography-quadrupole time-of-flight mass spectrometry (NP/RP 2D LC-QToF-MS) method, 59 lipid biomarkers encompassing glycerophospholipids (glycerophosphocholines, lysoglycerophosphocholines, glycerophosphoethanolamines, lysoglycerophosphoethanolamines glycerophosphoinositols, and lysoglycerophosphoinositols), sphingolipids (sphingomyelins, ceramides, galactosylceramides, glucosylceramides, and lactosylceramides) and free fatty acids were identified. Systemic oxidative stress in the Tph2-/- mice was significantly elevated, and a corresponding mechanism that relates the lipidomic findings has been proposed. In summary, this work provides preliminary findings that lipid metabolism is implicated in serotonin deficiency.

  10. Biomarker Analysis Revealed Distinct Profiles of Innate and Adaptive Immunity in Infants with Ocular Lesions of Congenital Toxoplasmosis

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    Machado, Anderson Silva; Carneiro, Ana Carolina Aguiar Vasconcelos; Béla, Samantha Ribeiro; Andrade, Gláucia Manzan Queiroz; Vasconcelos-Santos, Daniel Vitor; Januário, José Nélio; Coelho-dos-Reis, Jordana G.; Ferro, Eloisa Amália Vieira; Teixeira-Carvalho, Andréa; Vitor, Ricardo Wagner Almeida; Martins-Filho, Olindo Assis; —UFMG-CTBG, UFMG Congenital Toxoplasmosis Brazilian Group

    2014-01-01

    Toxoplasma gondii is the main infectious cause of human posterior retinochoroiditis, the most frequent clinical manifestation of congenital toxoplasmosis. This investigation was performed after neonatal screening to identify biomarkers of immunity associated with immunopathological features of the disease by flow cytometry. The study included infected infants without NRL and with retinochoroidal lesions (ARL, ACRL, and CRL) as well as noninfected individuals (NI). Our data demonstrated that leukocytosis, with increased monocytes and lymphocytes, was a relevant hematological biomarker of ARL. Immunophenotypic analysis also revealed expansion of CD14+CD16+HLA-DRhigh monocytes and CD56dim cytotoxic NK-cells in ARL. Moreover, augmented TCRγδ+ and CD8+ T-cell counts were apparently good biomarkers of morbidity. Biomarker network analysis revealed that complex and intricated networks underscored the negative correlation of monocytes with NK- and B-cells in NRL. The remarkable lack of connections involving B-cells and a relevant shift of NK-cell connections from B-cells toward T-cells observed in ARL were outstanding. A tightly connected biomarker network was observed in CRL, with relevant connections of NK- and CD8+ T-cells with a broad range of cell subsets. Our findings add novel elements to the current knowledge on the innate and adaptive immune responses in congenital toxoplasmosis. PMID:25328286

  11. Global metabolomics reveals potential urinary biomarkers of esophageal squamous cell carcinoma for diagnosis and staging

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    Xu, Jing; Chen, Yanhua; Zhang, Ruiping; He, Jiuming; Song, Yongmei; Wang, Jingbo; Wang, Huiqing; Wang, Luhua; Zhan, Qimin; Abliz, Zeper

    2016-10-01

    We performed a metabolomics study using liquid chromatography-mass spectrometry (LC-MS) combined with multivariate data analysis (MVDA) to discriminate global urine profiles in urine samples from esophageal squamous cell carcinoma (ESCC) patients and healthy controls (NC). Our work evaluated the feasibility of employing urine metabolomics for the diagnosis and staging of ESCC. The satisfactory classification between the healthy controls and ESCC patients was obtained using the MVDA model, and obvious classification of early-stage and advanced-stage patients was also observed. The results suggest that the combination of LC-MS analysis and MVDA may have potential applications for ESCC diagnosis and staging. We then conducted LC-MS/MS experiments to identify the potential biomarkers with large contributions to the discrimination. A total of 83 potential diagnostic biomarkers for ESCC were screened out, and 19 potential biomarkers were identified; the variations between the differences in staging using these potential biomarkers were further analyzed. These biomarkers may not be unique to ESCCs, but instead result from any malignant disease. To further elucidate the pathophysiology of ESCC, we studied related metabolic pathways and found that ESCC is associated with perturbations of fatty acid β-oxidation and the metabolism of amino acids, purines, and pyrimidines.

  12. Biomarker identification and effect estimation on schizophrenia –a high dimensional data analysis

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    Yuanzhang eLi

    2015-05-01

    Full Text Available Biomarkers have been examined in schizophrenia research for decades. Medical morbidity and mortality rates, as well as personal and societal costs, are associated with schizophrenia patients. The identification of biomarkers and alleles, which often have a small effect individually, may help to develop new diagnostic tests for early identification and treatment. Currently, there is not a commonly accepted statistical approach to identify predictive biomarkers from high dimensional data. We used space Decomposition-Gradient-Regression method (DGR to select biomarkers, which are associated with the risk of schizophrenia. Then, we used the gradient scores, generated from the selected biomarkers, as the prediction factor in regression to estimate their effects. We also used an alternative approach, classification and regression tree (CART, to compare the biomarker selected by DGR and found about 70% of the selected biomarkers were the same. However, the advantage of DGR is that it can evaluate individual effects for each biomarker from their combined effect. In DGR analysis of serum specimens of US military service members with a diagnosis of schizophrenia from 1992 to 2005 and their controls, Alpha-1-Antitrypsin (AAT, Interleukin-6 receptor (IL-6r and Connective Tissue Growth Factor (CTGF were selected to identify schizophrenia for males; and Alpha-1-Antitrypsin (AAT, Apolipoprotein B (Apo B and Sortilin were selected for females. If these findings from military subjects are replicated by other studies, they suggest the possibility of a novel biomarker panel as an adjunct to earlier diagnosis and initiation of treatment.

  13. Comparisons of microRNA patterns in plasma before and after tumor removal reveal new biomarkers of lung squamous cell carcinoma.

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    Vasily N Aushev

    Full Text Available Lung cancer is the major human malignancy, accounting for 30% of all cancer-related deaths worldwide. Poor survival of lung cancer patients, together with late diagnosis and resistance to classic chemotherapy, highlights the need for identification of new biomarkers for early detection. Among different cancer biomarkers, small non-coding RNAs called microRNAs (miRNAs are considered the most promising, owing to their remarkable stability, their cancer-type specificity, and their presence in body fluids. However, results of multiple previous attempts to identify circulating miRNAs specific for lung cancer are inconsistent, likely due to two main reasons: prominent variability in blood miRNA content among individuals and difficulties in distinguishing tumor-relevant miRNAs in the blood from their non-tumor counterparts. To overcome these impediments, we compared circulating miRNA profiles in patients with lung squamous cell carcinoma (SCC before and after tumor removal, assuming that the levels of all tumor-relevant miRNAs would drop after the surgery. Our results revealed a specific panel of the miRNAs (miR-205, -19a, -19b, -30b, and -20a whose levels decreased strikingly in the blood of patients after lung SCC surgery. Interestingly, miRNA profiling of plasma fractions of lung SCC patients revealed high levels of these miRNA species in tumor-specific exosomes; additionally, some of these miRNAs were also found to be selectively secreted to the medium by cultivated lung cancer cells. These results strengthen the notion that tumor cells secrete miRNA-containing exosomes into circulation, and that miRNA profiling of the exosomal plasma fraction may reveal powerful cancer biomarkers.

  14. Natural history of high-grade cervical intraepithelial neoplasia: a review of prognostic biomarkers.

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    Koeneman, Margot M; Kruitwagen, Roy F P M; Nijman, Hans W; Slangen, Brigitte F M; Van Gorp, Toon; Kruse, Arnold-Jan

    2015-04-01

    The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical excision, leading to overtreatment and unnecessary complications. Prognostic biomarkers may differentiate between lesions that will regress and those that will not, making individualized treatment of high-grade CIN possible. This review identifies several promising prognostic biomarkers. These biomarkers include viral genotype and viral DNA methylation (viral factors), human leukocyte antigen-subtypes, markers of lymphoproliferative response, telomerase amplification and human papillomavirus-induced epigenetic effects (host factors) and Ki-67, p53 and pRb (cellular factors). All identified biomarkers were evaluated according to their role in the natural history of high-grade CIN and according to established criteria for evaluation of biomarkers (prospective-specimen-collection, retrospective-blinded-evaluation [PROBE] criteria). None of the biomarkers meets the PROBE criteria for clinical applicability and more research on prognostic biomarkers in high-grade CIN is necessary.

  15. A novel method for RNA extraction from FFPE samples reveals significant differences in biomarker expression between orthotopic and subcutaneous pancreatic cancer patient-derived xenografts

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    Brown, Mark; Maawy, Ali; Chang, Alexander; Lee, Jacqueline; Gharibi, Armen; Katz, Matthew H; Fleming, Jason; Hoffman, Robert M; Bouvet, Michael; Doebler, Robert; Kelber, Jonathan A

    2017-01-01

    Next-generation sequencing (NGS) can identify and validate new biomarkers of cancer onset, progression and therapy resistance. Substantial archives of formalin-fixed, paraffin-embedded (FFPE) cancer samples from patients represent a rich resource for linking molecular signatures to clinical data. However, performing NGS on FFPE samples is limited by poor RNA purification methods. To address this hurdle, we developed an improved methodology for extracting high-quality RNA from FFPE samples. By briefly integrating a newly-designed micro-homogenizing (mH) tool with commercially available FFPE RNA extraction protocols, RNA recovery is increased by approximately 3-fold while maintaining standard A260/A280 ratios and RNA quality index (RQI) values. Furthermore, we demonstrate that the mH-purified FFPE RNAs are longer and of higher integrity. Previous studies have suggested that pancreatic ductal adenocarcinoma (PDAC) gene expression signatures vary significantly under in vitro versus in vivo and in vivo subcutaneous versus orthotopic conditions. By using our improved mH-based method, we were able to preserve established expression patterns of KRas-dependency genes within these three unique microenvironments. Finally, expression analysis of novel biomarkers in KRas mutant PDAC samples revealed that PEAK1 decreases and MST1R increases by over 100-fold in orthotopic versus subcutaneous microenvironments. Interestingly, however, only PEAK1 levels remain elevated in orthotopically grown KRas wild-type PDAC cells. These results demonstrate the critical nature of the orthotopic tumor microenvironment when evaluating the clinical relevance of new biomarkers in cells or patient-derived samples. Furthermore, this new mH-based FFPE RNA extraction method has the potential to enhance and expand future FFPE-RNA-NGS cancer biomarker studies. PMID:27602776

  16. Metabolic profiling of presymptomatic Huntington’s disease sheep reveals novel biomarkers

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    Skene, Debra J.; Middleton, Benita; Fraser, Cara K.; Pennings, Jeroen L. A.; Kuchel, Timothy R.; Rudiger, Skye R.; Bawden, C. Simon; Morton, A. Jennifer

    2017-01-01

    The pronounced cachexia (unexplained wasting) seen in Huntington’s disease (HD) patients suggests that metabolic dysregulation plays a role in HD pathogenesis, although evidence of metabolic abnormalities in HD patients is inconsistent. We performed metabolic profiling of plasma from presymptomatic HD transgenic and control sheep. Metabolites were quantified in sequential plasma samples taken over a 25 h period using a targeted LC/MS metabolomics approach. Significant changes with respect to genotype were observed in 89/130 identified metabolites, including sphingolipids, biogenic amines, amino acids and urea. Citrulline and arginine increased significantly in HD compared to control sheep. Ten other amino acids decreased in presymptomatic HD sheep, including branched chain amino acids (isoleucine, leucine and valine) that have been identified previously as potential biomarkers of HD. Significant increases in urea, arginine, citrulline, asymmetric and symmetric dimethylarginine, alongside decreases in sphingolipids, indicate that both the urea cycle and nitric oxide pathways are dysregulated at early stages in HD. Logistic prediction modelling identified a set of 8 biomarkers that can identify 80% of the presymptomatic HD sheep as transgenic, with 90% confidence. This level of sensitivity, using minimally invasive methods, offers novel opportunities for monitoring disease progression in HD patients. PMID:28223686

  17. Expression profiling reveals novel hypoxic biomarkers in peripheral blood of adult mice exposed to chronic hypoxia.

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    Matias Mosqueira

    Full Text Available Hypoxia induces a myriad of changes including an increase in hematocrit due to erythropoietin (EPO mediated erythropoiesis. While hypoxia is of importance physiologically and clinically, lacunae exist in our knowledge of the systemic and temporal changes in gene expression occurring in blood during the exposure and recovery from hypoxia. To identify these changes expression profiling was conducted on blood obtained from cohorts of C57Bl-10 wild type mice that were maintained at normoxia (NX, exposed for two weeks to normobaric chronic hypoxia (CH or two weeks of CH followed by two weeks of normoxic recovery (REC. Using stringent bioinformatic cut-offs (0% FDR, 2 fold change cut-off, 230 genes were identified and separated into four distinct temporal categories. Class I contained 1 transcript up-regulated in both CH and REC; Class II contained 202 transcripts up-regulated in CH but down-regulated after REC; Class III contained 9 transcripts down-regulated both in CH and REC; Class IV contained 18 transcripts down-regulated after CH exposure but up-regulated after REC. Profiling was independently validated and extended by analyzing expression levels of selected genes as novel biomarkers from our profile (e.g. spectrin alpha-1, ubiquitin domain family-1 and pyrroline-5-carboxylate reductase-1 by performing qPCR at 7 different time points during CH and REC. Our identification and characterization of these genes define transcriptome level changes occurring during chronic hypoxia and normoxic recovery as well as novel blood biomarkers that may be useful in monitoring a variety of physiological and pathological conditions associated with hypoxia.

  18. Analyses of acute kidney injury biomarkers by ultra-high performance liquid chromatography with mass spectrometry.

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    Al Za'abi, Mohammed; Ali, Badreldin H; ALOthman, Zeid A; Ali, Imran

    2016-01-01

    The newly developed acute kidney injury biomarkers are very important for the early and timely detection of kidney diseases. This review contains details of the analyses of several acute kidney injury biomarkers using ultra-high performance liquid chromatography-mass spectrometry in urine and plasma samples. In this review we attempt to discuss some aspects of the types of the biomarkers, patents, sample preparation, and the analyses. Besides, efforts were also made to discuss the possible uses of superficially porous (core-shell) columns in traditional and inexpensive high-performance liquid chromatography instruments. Additionally, the challenges and the future prospects are also highlighted. The present review will be useful for the academicians, scientists, and clinicians for the early detection of acute kidney injury biomarkers.

  19. The Male Fetal Biomarker INSL3 Reveals Substantial Hormone Exchange between Fetuses in Early Pig Gestation.

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    Andreas Vernunft

    Full Text Available The peptide hormone INSL3 is uniquely produced by the fetal testis to promote the transabdominal phase of testicular descent. Because it is fetal sex specific, and is present in only very low amounts in the maternal circulation, INSL3 acts as an ideal biomarker with which to monitor the movement of fetal hormones within the pregnant uterus of a polytocous species, the pig. INSL3 production by the fetal testis begins at around GD30. At GD45 of the ca. 114 day gestation, a time at which testicular descent is promoted, INSL3 evidently moves from male to female allantoic compartments, presumably impacting also on the female fetal circulation. At later time-points (GD63, GD92 there is less inter-fetal transfer, although there still appears to be significant INSL3, presumably of male origin, in the plasma of female fetuses. This study thus provides evidence for substantial transfer of a peptide hormone between fetuses, and probably also across the placenta, emphasizing the vulnerability of the fetus to extrinsic hormonal influences within the uterus.

  20. Transcriptional activity around bacterial cell death reveals molecular biomarkers for cell viability

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    Schuren Frank H

    2008-12-01

    Full Text Available Abstract Background In bacteriology, the ability to grow in selective media and to form colonies on nutrient agar plates is routinely used as a retrospective criterion for the detection of living bacteria. However, the utilization of indicators for bacterial viability-such as the presence of specific transcripts or membrane integrity-would overcome bias introduced by cultivation and reduces the time span of analysis from initiation to read out. Therefore, we investigated the correlation between transcriptional activity, membrane integrity and cultivation-based viability in the Gram-positive model bacterium Bacillus subtilis. Results We present microbiological, cytological and molecular analyses of the physiological response to lethal heat stress under accurately defined conditions through systematic sampling of bacteria from a single culture exposed to gradually increasing temperatures. We identified a coherent transcriptional program including known heat shock responses as well as the rapid expression of a small number of sporulation and competence genes, the latter only known to be active in the stationary growth phase. Conclusion The observed coordinated gene expression continued even after cell death, in other words after all bacteria permanently lost their ability to reproduce. Transcription of a very limited number of genes correlated with cell viability under the applied killing regime. The transcripts of the expressed genes in living bacteria – but silent in dead bacteria-include those of essential genes encoding chaperones of the protein folding machinery and can serve as molecular biomarkers for bacterial cell viability.

  1. Lacustrine lignin biomarker record reveals a severe drought during the late Younger Dryas in southern Taiwan

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    Ding, Xiaodong; Bao, Hongyan; Zheng, Liwei; Li, Dawei; Kao, Shuh-Ji

    2017-03-01

    The Younger Dryas (YD) event, which punctuated the last glacial-Holocene transition period and had a profound impact on global climate, is the most well studied millennial-scale climate event although the triggering mechanism remains debate. Weakened Asian summer monsoon during the YD is recorded in oxygen isotopes of stalagmite from Mainland China. However, lacustrine climate record of the YD event has not been reported from the subtropical land-ocean boundary of the Asian continent near the Pacific warm pool. We provide a lignin biomarker record covering the last deglaciation and early Holocene (17-9 ka BP) from the Dongyuan Lake, southern Taiwan, located at the frontal zone of typhoon invasion. The lignin phenol ratio S/V shows that the vegetation in the catchments had shifted from gymnosperm dominant to angiosperm dominant plants since 12.2 ka BP. Significantly decreased lignin concentrations (TLP and λ8) and elevated lignin degradation parameters ((Ad/Al)v, P/(V + S), DHBA/V) in combination with other organic proxies (TOC, δ13Corg) during the late YD suggest a severe drought had occurred in southern Taiwan during this specific period. Changes in the lignin proxies from the Dongyuan Lake lagged the climate changes registered in stalagmite records by around 500-800 years, suggesting a slow response of vegetation and soil processes to rapid climate changes.

  2. Serum proteomic analysis reveals potential serum biomarkers for occupational medicamentosa-like dermatitis caused by trichloroethylene.

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    Huang, Peiwu; Ren, Xiaohu; Huang, Zhijun; Yang, Xifei; Hong, Wenxu; Zhang, Yanfang; Zhang, Hang; Liu, Wei; Huang, Haiyan; Huang, Xinfeng; Wu, Desheng; Yang, Linqing; Tang, Haiyan; Zhou, Li; Li, Xuan; Liu, Jianjun

    2014-08-17

    Trichloroethylene (TCE) is an industrial solvent with widespread occupational exposure and also a major environmental contaminant. Occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) is an autoimmune disease and it has become one major hazard in China. In this study, sera from 3 healthy controls and 3 OMLDT patients at different disease stages were used for a screening study by 2D-DIGE and MALDI-TOF-MS/MS. Eight proteins including transthyretin (TTR), retinol binding protein 4 (RBP4), haptoglobin, clusterin, serum amyloid A protein (SAA), apolipoprotein A-I, apolipoprotein C-III and apolipoprotein C-II were found to be significantly altered among the healthy, acute-stage, healing-stage and healed-stage groups. Specifically, the altered expression of TTR, RBP4 and haptoglobin were further validated by Western blot analysis and ELISA. Our data not only suggested that TTR, RBP4 and haptoglobin could serve as potential serum biomarkers of OMLDT, but also indicated that measurement of TTR, RBP4 and haptoglobin or their combination could help aid in the diagnosis, monitoring the progression and therapy of the disease.

  3. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.

    Directory of Open Access Journals (Sweden)

    Brante P Sampey

    Full Text Available Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD to "Cafeteria diets" (CAF consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity

  4. Metabolomic profiling reveals mitochondrial-derived lipid biomarkers that drive obesity-associated inflammation.

    Science.gov (United States)

    Sampey, Brante P; Freemerman, Alex J; Zhang, Jimmy; Kuan, Pei-Fen; Galanko, Joseph A; O'Connell, Thomas M; Ilkayeva, Olga R; Muehlbauer, Michael J; Stevens, Robert D; Newgard, Christopher B; Brauer, Heather A; Troester, Melissa A; Makowski, Liza

    2012-01-01

    Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic

  5. Fluorescent nanodiamonds as highly stable biomarker for endotoxin verification

    Science.gov (United States)

    Bergmann, Thorsten; Burg, Jan Michael; Lilholt, Maria; Maeder, Ulf; Beer, Sebastian; Salzig, Denise; Ebrahimi, Mehrdad; Czermak, Peter; Fiebich, Martin

    2012-03-01

    Fluorescent nanodiamonds (ND) provide advantageous properties as a fluorescent biomarker for in vitro and in vivo studies. The maximum fluorescence occurs around 700 nm, they do not show photobleaching or blinking and seem to be nontoxic. After a pretreatment with strong acid fluorescent ND can be functionalized and coupled to endotoxin. Endotoxin is a decay product of bacteria and causes strong immune reactions. Therefore endotoxin has to be removed for most applications. An effective removal procedure is membrane filtration. The endotoxin, coupled to fluorescent ND can be visualized by using confocal microscopy which allows the investigation of the separation mechanisms of the filtration process within the membranes.

  6. Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker.

    Science.gov (United States)

    Textoris, Julien; Ivorra, Delphine; Ben Amara, Amira; Sabatier, Florence; Ménard, Jean-Pierre; Heckenroth, Hélène; Bretelle, Florence; Mege, Jean-Louis

    2013-01-01

    Preeclampsia is a placental disease characterized by hypertension and proteinuria in pregnant women, and it is associated with a high maternal and neonatal morbidity. However, circulating biomarkers that are able to predict the prognosis of preeclampsia are lacking. Thirty-eight women were included in the current study. They consisted of 19 patients with preeclampsia (13 with severe preeclampsia and 6 with non-severe preeclampsia) and 19 gestational age-matched women with normal pregnancies as controls. We measured circulating factors that are associated with the coagulation pathway (including fibrinogen, fibronectin, factor VIII, antithrombin, protein S and protein C), endothelial activation (such as soluble endoglin and CD146), and the release of total and platelet-derived microparticles. These markers enabled us to discriminate the preeclampsia condition from a normal pregnancy but were not sufficient to distinguish severe from non-severe preeclampsia. We then used a microarray to study the transcriptional signature of blood samples. Preeclampsia patients exhibited a specific transcriptional program distinct from that of the control group of women. Interestingly, we also identified a severity-related transcriptional signature. Functional annotation of the upmodulated signature in severe preeclampsia highlighted two main functions related to "ribosome" and "complement". Finally, we identified 8 genes that were specifically upmodulated in severe preeclampsia compared with non-severe preeclampsia and the normotensive controls. Among these genes, we identified VSIG4 as a potential diagnostic marker of severe preeclampsia. The determination of this gene may improve the prognostic assessment of severe preeclampsia.

  7. Evaluation of current and new biomarkers in severe preeclampsia: a microarray approach reveals the VSIG4 gene as a potential blood biomarker.

    Directory of Open Access Journals (Sweden)

    Julien Textoris

    Full Text Available Preeclampsia is a placental disease characterized by hypertension and proteinuria in pregnant women, and it is associated with a high maternal and neonatal morbidity. However, circulating biomarkers that are able to predict the prognosis of preeclampsia are lacking. Thirty-eight women were included in the current study. They consisted of 19 patients with preeclampsia (13 with severe preeclampsia and 6 with non-severe preeclampsia and 19 gestational age-matched women with normal pregnancies as controls. We measured circulating factors that are associated with the coagulation pathway (including fibrinogen, fibronectin, factor VIII, antithrombin, protein S and protein C, endothelial activation (such as soluble endoglin and CD146, and the release of total and platelet-derived microparticles. These markers enabled us to discriminate the preeclampsia condition from a normal pregnancy but were not sufficient to distinguish severe from non-severe preeclampsia. We then used a microarray to study the transcriptional signature of blood samples. Preeclampsia patients exhibited a specific transcriptional program distinct from that of the control group of women. Interestingly, we also identified a severity-related transcriptional signature. Functional annotation of the upmodulated signature in severe preeclampsia highlighted two main functions related to "ribosome" and "complement". Finally, we identified 8 genes that were specifically upmodulated in severe preeclampsia compared with non-severe preeclampsia and the normotensive controls. Among these genes, we identified VSIG4 as a potential diagnostic marker of severe preeclampsia. The determination of this gene may improve the prognostic assessment of severe preeclampsia.

  8. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer.

    Science.gov (United States)

    van Ginkel, Joost H; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M

    2016-09-20

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post treatment surveillance. We retrospectively analyzed mutational hotspots using targeted next-generation sequencing (NGS) of 239 HNSCC tumor samples in order to examine the mutational profile of HNSCC. Furthermore, we assessed prevalence, co-occurrence, and synonymy of gene mutations in (matched) tumor samples. TP53 was found mutated the most frequent with mutation rates of up to 83% in all tumors, compared to mutation rates of between 0 and 21% of CDKN2A, PIK3CA, HRAS, CDK4, FBXW7 and RB1. Mutational co-occurrence predominantly existed between TP53 and PIK3CA, TP53 and CDKN2A, and HRAS and PIK3CA. Mutational synonymy between primary tumor and associated metastasis and recurrence was present in respectively 88% and 89%. TP53 mutations were concordantly mutated in 95% of metastases and in 91% of recurrences. This indicates TP53 mutations to be highly prevalent and concordant in primary tumors and associated locoregional metastases and recurrences. In turn, this provides ground for further investigating the use of TP53 mutations as diagnostic biomarkers in HNSCC patients.

  9. A systems biology strategy reveals biological pathways and plasma biomarker candidates for potentially toxic statin-induced changes in muscle.

    Directory of Open Access Journals (Sweden)

    Reijo Laaksonen

    Full Text Available BACKGROUND: Aggressive lipid lowering with high doses of statins increases the risk of statin-induced myopathy. However, the cellular mechanisms leading to muscle damage are not known and sensitive biomarkers are needed to identify patients at risk of developing statin-induced serious side effects. METHODOLOGY: We performed bioinformatics analysis of whole genome expression profiling of muscle specimens and UPLC/MS based lipidomics analyses of plasma samples obtained in an earlier randomized trial from patients either on high dose simvastatin (80 mg, atorvastatin (40 mg, or placebo. PRINCIPAL FINDINGS: High dose simvastatin treatment resulted in 111 differentially expressed genes (1.5-fold change and p-value<0.05, while expression of only one and five genes was altered in the placebo and atorvastatin groups, respectively. The Gene Set Enrichment Analysis identified several affected pathways (23 gene lists with False Discovery Rate q-value<0.1 in muscle following high dose simvastatin, including eicosanoid synthesis and Phospholipase C pathways. Using lipidomic analysis we identified previously uncharacterized drug-specific changes in the plasma lipid profile despite similar statin-induced changes in plasma LDL-cholesterol. We also found that the plasma lipidomic changes following simvastatin treatment correlate with the muscle expression of the arachidonate 5-lipoxygenase-activating protein. CONCLUSIONS: High dose simvastatin affects multiple metabolic and signaling pathways in skeletal muscle, including the pro-inflammatory pathways. Thus, our results demonstrate that clinically used high statin dosages may lead to unexpected metabolic effects in non-hepatic tissues. The lipidomic profiles may serve as highly sensitive biomarkers of statin-induced metabolic alterations in muscle and may thus allow us to identify patients who should be treated with a lower dose to prevent a possible toxicity.

  10. Gene co-expression networks and profiles reveal potential biomarkers of boar taint in pigs

    DEFF Research Database (Denmark)

    Drag, Markus; Skinkyté-Juskiené, Rúta; Do, Duy Ngoc

    Boar taint (BT) is an offensive odour or taste of porcine meat which may occur in entire male pigs due to skatole and androstenone accumulation. To avoid BT, castration of young piglets is performed but this strategy is under debate due to animal welfare concerns. The study aimed to reveal...... synthesis. In testis, >80 DE genes were functionally classified by the PANTHER tool to “Gonadotropin releasing hormone receptor” and “Wnt signaling” pathways which play a role in reproductive maturation and proliferation of spermatogonia, respectively. WGCNA was used to build co-expression modules...... and enrichment analysis and semantic filtering revealed the GO terms “catalytic activity” and “transferase activity” to be overrepresented (p hormones. Extraction of hub...

  11. Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.

    LENUS (Irish Health Repository)

    Watson, Chris J

    2011-03-01

    Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF.

  12. Biomarkers reveal sea turtles remained in oiled areas following the Deepwater Horizon oil spill.

    Science.gov (United States)

    Vander Zanden, Hannah B; Bolten, Alan B; Tucker, Anton D; Hart, Kristen M; Lamont, Margaret M; Fujisaki, Ikuko; Reich, Kimberly J; Addison, David S; Mansfield, Katherine L; Phillips, Katrina F; Pajuelo, Mariela; Bjorndal, Karen A

    2016-10-01

    Assessments of large-scale disasters, such as the Deepwater Horizon oil spill, are problematic because while measurements of post-disturbance conditions are common, measurements of pre-disturbance baselines are only rarely available. Without adequate observations of pre-disaster organismal and environmental conditions, it is impossible to assess the impact of such catastrophes on animal populations and ecological communities. Here, we use long-term biological tissue records to provide pre-disaster data for a vulnerable marine organism. Keratin samples from the carapace of loggerhead sea turtles record the foraging history for up to 18 years, allowing us to evaluate the effect of the oil spill on sea turtle foraging patterns. Samples were collected from 76 satellite-tracked adult loggerheads in 2011 and 2012, approximately one to two years after the spill. Of the 10 individuals that foraged in areas exposed to surface oil, none demonstrated significant changes in foraging patterns post spill. The observed long-term fidelity to foraging sites indicates that loggerheads in the northern Gulf of Mexico likely remained in established foraging sites, regardless of the introduction of oil and chemical dispersants. More research is needed to address potential long-term health consequences to turtles in this region. Mobile marine organisms present challenges for researchers to monitor effects of environmental disasters, both spatially and temporally. We demonstrate that biological tissues can reveal long-term histories of animal behavior and provide critical pre-disaster baselines following an anthropogenic disturbance or natural disaster.

  13. Biomarkers reveal sea turtles remained in oiled areas following the Deepwater Horizon oil spill

    Science.gov (United States)

    Vander Zanden, Hannah B.; Bolten, Alan B.; Tucker, Anton D.; Hart, Kristen M.; Lamont, Margaret M.; Fujisaki, Ikuko; Reich, Kimberly J.; Addison, David S.; Mansfield, Katherine L.; Phillips, Katrina F.; Pajuelo, Mariela; Bjorndal, Karen A.

    2016-01-01

    Assessments of large-scale disasters, such as the Deepwater Horizon oil spill, are problematic because while measurements of post-disturbance conditions are common, measurements of pre-disturbance baselines are only rarely available. Without adequate observations of pre-disaster organismal and environmental conditions, it is impossible to assess the impact of such catastrophes on animal populations and ecological communities. Here, we use long-term biological tissue records to provide pre-disaster data for a vulnerable marine organism. Keratin samples from the carapace of loggerhead sea turtles record the foraging history for up to 18 years, allowing us to evaluate the effect of the oil spill on sea turtle foraging patterns. Samples were collected from 76 satellite-tracked adult loggerheads in 2011 and 2012, approximately one to two years after the spill. Of the 10 individuals that foraged in areas exposed to surface oil, none demonstrated significant changes in foraging patterns post spill. The observed long-term fidelity to foraging sites indicates that loggerheads in the northern Gulf of Mexico likely remained in established foraging sites, regardless of the introduction of oil and chemical dispersants. More research is needed to address potential long-term health consequences to turtles in this region. Mobile marine organisms present challenges for researchers to monitor effects of environmental disasters, both spatially and temporally. We demonstrate that biological tissues can reveal long-term histories of animal behavior and provide critical pre-disaster baselines following an anthropogenic disturbance or natural disaster.

  14. Targeted sequencing reveals TP53 as a potential diagnostic biomarker in the post-treatment surveillance of head and neck cancer

    NARCIS (Netherlands)

    van Ginkel, Joost H.; de Leng, Wendy W J; de Bree, Remco; van Es, Robert J J; Willems, Stefan M.

    2016-01-01

    Head and neck squamous cell carcinomas (HNSCC) form a large heterogeneous group of tumors and have a relatively poor outcome in advanced cases. Revealing the underlying genetic mutations in HNSCC facilitates the development of diagnostic biomarkers, which might lead to improved diagnosis and post tr

  15. Multiplexed homogeneous proximity ligation assays for high throughput protein biomarker research in serological material

    DEFF Research Database (Denmark)

    Lundberg, Martin; Thorsen, Stine Buch; Assarsson, Erika;

    2011-01-01

    A high throughput protein biomarker discovery tool has been developed based on multiplexed proximity ligation assays (PLA) in a homogeneous format in the sense of no washing steps. The platform consists of four 24-plex panels profiling 74 putative biomarkers with sub pM sensitivity each consuming...... only 1 micro Litre of human plasma sample. The system uses either matched monoclonal antibody pairs or the more readily available single batches of affinity purified polyclonal antibodies to generate the target specific reagents by covalently linking with unique nucleic acid sequences. These paired...

  16. Metabolomics approach reveals metabolic disorders and potential biomarkers associated with the developmental toxicity of tetrabromobisphenol A and tetrachlorobisphenol A

    Science.gov (United States)

    Ye, Guozhu; Chen, Yajie; Wang, Hong-Ou; Ye, Ting; Lin, Yi; Huang, Qiansheng; Chi, Yulang; Dong, Sijun

    2016-10-01

    Tetrabromobisphenol A and tetrachlorobisphenol A are halogenated bisphenol A (H-BPA), and has raised concerns about their adverse effects on the development of fetuses and infants, however, the molecular mechanisms are unclear, and related metabolomics studies are limited. Accordingly, a metabolomics study based on gas chromatography-mass spectrometry was employed to elucidate the molecular developmental toxicology of H-BPA using the marine medaka (Oryzias melastigmas) embryo model. Here, we revealed decreased synthesis of nucleosides, amino acids and lipids, and disruptions in the TCA (tricarboxylic acid) cycle, glycolysis and lipid metabolism, thus inhibiting the developmental processes of embryos exposed to H-BPA. Unexpectedly, we observed enhanced neural activity accompanied by lactate accumulation and accelerated heart rates due to an increase in dopamine pathway and a decrease in inhibitory neurotransmitters following H-BPA exposure. Notably, disorders of the neural system, and disruptions in glycolysis, the TCA cycle, nucleoside metabolism, lipid metabolism, glutamate and aspartate metabolism induced by H-BPA exposure were heritable. Furthermore, lactate and dopa were identified as potential biomarkers of the developmental toxicity of H-BPA and related genetic effects. This study has demonstrated that the metabolomics approach is a useful tool for obtaining comprehensive and novel insights into the molecular developmental toxicity of environmental pollutants.

  17. Microbial ecology of the stratified water column of the Black Sea as revealed by a comprehensive biomarker study

    DEFF Research Database (Denmark)

    Wakeham, Stuart G.; Amann, Rudi; Freemann, Katherine H.;

    2007-01-01

    ) and sulfate reducing bacteria. We also measured a wide range of bacterial and archaeal lipid biomarkers. Depth distributions of diagnostic biomarkers are matched with zonation of microbial processes, including aerobic bacterial oxidation of methane, oxidation of ammonium by bacteria and archaea, metal...... reduction, and sulfide oxidation at the chemocline, and bacterial sulfate reduction and anaerobic oxidation of methane by archaea in the anoxic zone. Cell densities for archaea and sulfate reducing bacteria are estimated based on water column biomarker concentrations and compared with CARD-FISH results....

  18. AOPs & Biomarkers: Bridging High Throughput Screening and Regulatory Decision Making.

    Science.gov (United States)

    As high throughput screening (HTS) approaches play a larger role in toxicity testing, computational toxicology has emerged as a critical component in interpreting the large volume of data produced. Computational models for this purpose are becoming increasingly more sophisticated...

  19. Elevated morning cortisol is a stratified population-level biomarker for major depression in boys only with high depressive symptoms.

    Science.gov (United States)

    Owens, Matthew; Herbert, Joe; Jones, Peter B; Sahakian, Barbara J; Wilkinson, Paul O; Dunn, Valerie J; Croudace, Timothy J; Goodyer, Ian M

    2014-03-04

    Major depressive disorder (MD) is a debilitating public mental health problem with severe societal and personal costs attached. Around one in six people will suffer from this complex disorder at some point in their lives, which has shown considerable etiological and clinical heterogeneity. Overall there remain no validated biomarkers in the youth population at large that can aid the detection of at-risk groups for depression in general and for boys and young men in particular. Using repeated measurements of two well-known correlates of MD (self-reported current depressive symptoms and early-morning cortisol), we undertook a population-based investigation to ascertain subtypes of adolescents that represent separate longitudinal phenotypes. Subsequently, we tested for differential risks for MD and other mental illnesses and cognitive differences between subtypes. Through the use of latent class analysis, we revealed a high-risk subtype (17% of the sample) demarcated by both high depressive symptoms and elevated cortisol levels. Membership of this class of individuals was associated with increased levels of impaired autobiographical memory recall in both sexes and the greatest likelihood of experiencing MD in boys only. These previously unidentified findings demonstrate at the population level a class of adolescents with a common physiological biomarker specifically for MD in boys and for a mnemonic vulnerability in both sexes. We suggest that the biobehavioral combination of high depressive symptoms and elevated morning cortisol is particularly hazardous for adolescent boys.

  20. ADC texture—An imaging biomarker for high-grade glioma?

    Energy Technology Data Exchange (ETDEWEB)

    Brynolfsson, Patrik; Hauksson, Jón; Karlsson, Mikael; Garpebring, Anders; Nyholm, Tufve, E-mail: tufve.nyholm@radfys.umu.se [Department of Radiation Sciences, Radiation Physics, Umeå University, Umeå SE-901 87 (Sweden); Nilsson, David; Trygg, Johan [Computational Life Science Cluster (CLiC), Department of Chemistry, Umeå University, Umeå SE-901 87 (Sweden); Henriksson, Roger [Department of Radiation Sciences, Oncology, Umeå University, Umeå SE-901 87, Sweden and Regionalt Cancercentrum Stockholm, Karolinska Universitetssjukhuset, Solna, Stockholm SE-102 39 (Sweden); Birgander, Richard [Department of Radiation Sciences, Diagnostic Radiology, Umeå University, Umeå SE-901 87 (Sweden); Asklund, Thomas [Department of Radiation Sciences, Oncology, Umeå University, Umeå SE-901 87 (Sweden)

    2014-10-15

    Purpose: Survival for high-grade gliomas is poor, at least partly explained by intratumoral heterogeneity contributing to treatment resistance. Radiological evaluation of treatment response is in most cases limited to assessment of tumor size months after the initiation of therapy. Diffusion-weighted magnetic resonance imaging (MRI) and its estimate of the apparent diffusion coefficient (ADC) has been widely investigated, as it reflects tumor cellularity and proliferation. The aim of this study was to investigate texture analysis of ADC images in conjunction with multivariate image analysis as a means for identification of pretreatment imaging biomarkers. Methods: Twenty-three consecutive high-grade glioma patients were treated with radiotherapy (2 Gy/60 Gy) with concomitant and adjuvant temozolomide. ADC maps and T1-weighted anatomical images with and without contrast enhancement were collected prior to treatment, and (residual) tumor contrast enhancement was delineated. A gray-level co-occurrence matrix analysis was performed on the ADC maps in a cuboid encapsulating the tumor in coronal, sagittal, and transversal planes, giving a total of 60 textural descriptors for each tumor. In addition, similar examinations and analyses were performed at day 1, week 2, and week 6 into treatment. Principal component analysis (PCA) was applied to reduce dimensionality of the data, and the five largest components (scores) were used in subsequent analyses. MRI assessment three months after completion of radiochemotherapy was used for classifying tumor progression or regression. Results: The score scatter plots revealed that the first, third, and fifth components of the pretreatment examinations exhibited a pattern that strongly correlated to survival. Two groups could be identified: one with a median survival after diagnosis of 1099 days and one with 345 days, p = 0.0001. Conclusions: By combining PCA and texture analysis, ADC texture characteristics were identified, which seems

  1. Genomic and protein expression analysis reveals Flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

    Science.gov (United States)

    Abdel-Fatah, Tarek MA; Russell, Roslin; Albarakati, Nada; Maloney, David J; Dorjsuren, Dorjbal; Rueda, Oscar M; Moseley, Paul; Mohan, Vivek; Sun, Hongmao; Abbotts, Rachel; Mukherjee, Abhik; Agarwal, Devika; Illuzzi, Jennifer L.; Jadhav, Ajit; Simeonov, Anton; Ball, Graham; Chan, Stephen; Caldas, Carlos; Ellis, Ian O; Wilson, David M; Madhusudan, Srinivasan

    2015-01-01

    FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p=4.89 × 10−57), high mitotic index (p=5.25 × 10−28), pleomorphism (p=6.31 × 10−19), ER negative (p=9.02 × 10−35), PR negative (p=9.24 × 10−24), triple negative phenotype (p=6.67 × 10−21), PAM50.Her2 (p=5.19 × 10−13), PAM50.Basal (p=2.7 × 10−41), PAM50.LumB (p=1.56 × 10−26), integrative molecular cluster 1 (intClust.1) (p=7.47 × 10−12), intClust.5 (p=4.05 × 10−12) and intClust. 10 (p=7.59 × 10−38) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p= 4.4 × 10−16) and multivariate analysis (p= 9.19 × 10−7). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps<0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps<0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps<0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps<0.05). We conclude that FEN1 is a promising biomarker in breast

  2. A new device for liver cancer biomarker detection with high accuracy

    Directory of Open Access Journals (Sweden)

    Shuaipeng Wang

    2015-06-01

    Full Text Available A novel cantilever array-based bio-sensor was batch-fabricated with IC compatible MEMS technology for precise liver cancer bio-marker detection. A micro-cavity was designed in the free end of the cantilever for local antibody-immobilization, thus adsorption of the cancer biomarker is localized in the micro-cavity, and the adsorption-induced k variation can be dramatically reduced with comparison to that caused by adsorption of the whole lever. The cantilever is pizeoelectrically driven into vibration which is pizeoresistively sensed by Wheatstone bridge. These structural features offer several advantages: high sensitivity, high throughput, high mass detection accuracy, and small volume. In addition, an analytical model has been established to eliminate the effect of adsorption-induced lever stiffness change and has been applied to precise mass detection of cancer biomarker AFP, the detected AFP antigen mass (7.6 pg/ml is quite close to the calculated one (5.5 pg/ml, two orders of magnitude better than the value by the fully antibody-immobilized cantilever sensor. These approaches will promote real application of the cantilever sensors in early diagnosis of cancer.

  3. Identification of an epigenetic biomarker panel with high sensitivity and specificity for colorectal cancer and adenomas

    Directory of Open Access Journals (Sweden)

    Lind Guro E

    2011-07-01

    Full Text Available Abstract Background The presence of cancer-specific DNA methylation patterns in epithelial colorectal cells in human feces provides the prospect of a simple, non-invasive screening test for colorectal cancer and its precursor, the adenoma. This study investigates a panel of epigenetic markers for the detection of colorectal cancer and adenomas. Methods Candidate biomarkers were subjected to quantitative methylation analysis in test sets of tissue samples from colorectal cancers, adenomas, and normal colonic mucosa. All findings were verified in independent clinical validation series. A total of 523 human samples were included in the study. Receiver operating characteristic (ROC curve analysis was used to evaluate the performance of the biomarker panel. Results Promoter hypermethylation of the genes CNRIP1, FBN1, INA, MAL, SNCA, and SPG20 was frequent in both colorectal cancers (65-94% and adenomas (35-91%, whereas normal mucosa samples were rarely (0-5% methylated. The combined sensitivity of at least two positives among the six markers was 94% for colorectal cancers and 93% for adenoma samples, with a specificity of 98%. The resulting areas under the ROC curve were 0.984 for cancers and 0.968 for adenomas versus normal mucosa. Conclusions The novel epigenetic marker panel shows very high sensitivity and specificity for both colorectal cancers and adenomas. Our findings suggest this biomarker panel to be highly suitable for early tumor detection.

  4. Cell surface profiling using high-throughput flow cytometry: a platform for biomarker discovery and analysis of cellular heterogeneity.

    Directory of Open Access Journals (Sweden)

    Craig A Gedye

    Full Text Available Cell surface proteins have a wide range of biological functions, and are often used as lineage-specific markers. Antibodies that recognize cell surface antigens are widely used as research tools, diagnostic markers, and even therapeutic agents. The ability to obtain broad cell surface protein profiles would thus be of great value in a wide range of fields. There are however currently few available methods for high-throughput analysis of large numbers of cell surface proteins. We describe here a high-throughput flow cytometry (HT-FC platform for rapid analysis of 363 cell surface antigens. Here we demonstrate that HT-FC provides reproducible results, and use the platform to identify cell surface antigens that are influenced by common cell preparation methods. We show that multiple populations within complex samples such as primary tumors can be simultaneously analyzed by co-staining of cells with lineage-specific antibodies, allowing unprecedented depth of analysis of heterogeneous cell populations. Furthermore, standard informatics methods can be used to visualize, cluster and downsample HT-FC data to reveal novel signatures and biomarkers. We show that the cell surface profile provides sufficient molecular information to classify samples from different cancers and tissue types into biologically relevant clusters using unsupervised hierarchical clustering. Finally, we describe the identification of a candidate lineage marker and its subsequent validation. In summary, HT-FC combines the advantages of a high-throughput screen with a detection method that is sensitive, quantitative, highly reproducible, and allows in-depth analysis of heterogeneous samples. The use of commercially available antibodies means that high quality reagents are immediately available for follow-up studies. HT-FC has a wide range of applications, including biomarker discovery, molecular classification of cancers, or identification of novel lineage specific or stem cell

  5. High-contrast grating resonators for label-free detection of disease biomarkers

    Science.gov (United States)

    Sun, Tianbo; Kan, Shu; Marriott, Gerard; Chang-Hasnain, Connie

    2016-06-01

    A label-free optical biosensor is described that employs a silicon-based high-contrast grating (HCG) resonator with a spectral linewidth of ~500 pm that is sensitive to ligand-induced changes in surface properties. The device is used to generate thermodynamic and kinetic data on surface-attached antibodies with their respective antigens. The device can detect serum cardiac troponin I, a biomarker of cardiac disease to 100 pg/ml within 4 mins, which is faster, and as sensitive as current enzyme-linked immuno-assays for cTnI.

  6. Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition.

    Science.gov (United States)

    Ko, Gang Jee; Grigoryev, Dmitry N; Linfert, Douglas; Jang, Hye Ryoun; Watkins, Tonya; Cheadle, Chris; Racusen, Lorraine; Rabb, Hamid

    2010-06-01

    Acute kidney injury (AKI) is being increasingly shown to be a risk factor for chronic kidney disease (CKD), but little is known about the possible mechanistic links. We hypothesized that analysis of the genomic signature in the repair stage after AKI would reveal pathways that could link AKI and CKD. Unilateral renal pedicle clamping for 45 min was performed in male C57BL/6J mice. Mice were euthanized at 3, 10, and 28 days after ischemia-reperfusion injury (IRI). Total RNA was isolated from kidney and analyzed using an Illumina mouse array. Among 24,600 tested genes, 242, 146, and 46 genes were upregulated at days 3, 10, and 28 after IRI, and 85, 35, and 0 genes were downregulated, respectively. Gene ontology analysis showed that gene expression changes were primarily related to immune and inflammatory pathways both early and late after AKI. The most highly upregulated genes late after AKI were hepatitis A virus cellular receptor 1 (Havcr1) and lipocalin 2 (Lcn2), which code for kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL), respectively. This was unexpected since they are both primarily potential biomarkers of the early stage of AKI. Furthermore, increases observed in gene expression in amiloride binding protein 1, vascular cell adhesion molecule-1, and endothelin 1 could explain the salt-sensitive hypertension that can follow AKI. These data suggested that 1) persistent inflammation and immune responses late after AKI could contribute to the pathogenesis of CKD, 2) late upregulation of KIM-1 and NGAL could be a useful marker for sustained renal injury after AKI, and 3) hypertension-related gene changes could underlie mechanisms for persistent renal and vascular injury after AKI.

  7. High-resolution taxonomic profiling of the subgingival microbiome for biomarker discovery and periodontitis diagnosis.

    Science.gov (United States)

    Szafranski, Szymon P; Wos-Oxley, Melissa L; Vilchez-Vargas, Ramiro; Jáuregui, Ruy; Plumeier, Iris; Klawonn, Frank; Tomasch, Jürgen; Meisinger, Christa; Kühnisch, Jan; Sztajer, Helena; Pieper, Dietmar H; Wagner-Döbler, Irene

    2015-02-01

    The oral microbiome plays a key role for caries, periodontitis, and systemic diseases. A method for rapid, high-resolution, robust taxonomic profiling of subgingival bacterial communities for early detection of periodontitis biomarkers would therefore be a useful tool for individualized medicine. Here, we used Illumina sequencing of the V1-V2 and V5-V6 hypervariable regions of the 16S rRNA gene. A sample stratification pipeline was developed in a pilot study of 19 individuals, 9 of whom had been diagnosed with chronic periodontitis. Five hundred twenty-three operational taxonomic units (OTUs) were obtained from the V1-V2 region and 432 from the V5-V6 region. Key periodontal pathogens like Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia could be identified at the species level with both primer sets. Principal coordinate analysis identified two outliers that were consistently independent of the hypervariable region and method of DNA extraction used. The linear discriminant analysis (LDA) effect size algorithm (LEfSe) identified 80 OTU-level biomarkers of periodontitis and 17 of health. Health- and periodontitis-related clusters of OTUs were identified using a connectivity analysis, and the results confirmed previous studies with several thousands of samples. A machine learning algorithm was developed which was trained on all but one sample and then predicted the diagnosis of the left-out sample (jackknife method). Using a combination of the 10 best biomarkers, 15 of 17 samples were correctly diagnosed. Training the algorithm on time-resolved community profiles might provide a highly sensitive tool to detect the onset of periodontitis.

  8. A biomarker study of high resolution sedimentary records in the eastern Mediterranean Sea since the last glacial maximum

    Science.gov (United States)

    Katsouras, G.; Gogou, A.; Bouloubassi, I.; Emeis, K.-C.; Triantaphyllou, M. V.; Lykousis, V.

    2009-04-01

    Information stored in sedimentary records provides evidence on climate and environmental variability at decadal to centennial time scales. The eastern Mediterranean Sea and the related Aegean Sea exhibit high sedimentation rates in certain areas and are considered as sensitive regions to record paleo-environmental and -climatic changes. The aim of our study is to reconstruct high-frequency paleoclimatic variations and identify associated changes in the physical, chemical and biological environment in selected basins of the eastern Mediterranean Sea, using molecular biogeochemical proxies. Here we present a high-resolution multi-proxy study along two Aegean Sea cores (north (152SL) and southeast (NS-14)) and a Libyan Sea core (HCM2/22). An important time marker and indicator of remarkable climatic and environmental changes is sapropel S1, a sediment layer rich in organic carbon. Depending on the water column depth, the sediment accumulation rates and the proximity to freshwater and water formation sources, S1 deposited between ~9.8 to 6.4 kyr BP, with an apparent interruption in the S1 deposition that occurred from ~8.6 to 7.6 kyr BP. SSTs based on alkenone unsaturation index Uḱ 37, ^15tot, ^13Corg and various marine and terrestrial biomarkers are used to investigate the region's climatic variability, and the modifications in the biogeochemical functioning of the eastern Mediterranean Sea. Uḱ 37 SST distribution in our records reveals significant fluctuations in temperature over the last 20.000 yrs. Organic carbon stable isotopes values span a narrow range over the whole sequence, with values varying to typical marine origin. The distributions of land-plant biomarkers are indicative of variable terrigenous organic matter supply and the concomitant transport of nutrients to surface waters. Furthermore, the distribution patterns and characteristic ratios of marine biomarkers exhibit differences in the paleoproductivity trends and ventilation changes over the last

  9. Biomarker screening of oral cancer cell lines revealed sub-populations of CD133-, CD44-, CD24- and ALDH1- positive cancer stem cells

    Directory of Open Access Journals (Sweden)

    Kendall K

    2013-05-01

    Full Text Available Head and neck squamous cell carcinoma (HNSCC ranks sixth worldwide for cancer-related mortality. For the past several decades the mainstay of treatment for HNSCC has been surgery and external beam radiation, although more recent trials combining chemotherapy and radiation have demonstrated improvements. However, cancer recurrence and treatment failures continue to occur in a significant percentage of patients. Recent advances in tumor biology have led to the discovery that many cancers, including HNSCC, may contain subpopulations of cells with stem cell-like properties that may explain relapse and recurrence. The objective of this study was to screen existing oral cancer cell lines for biomarkers specific for cells with stem cell-like properties. RNA was isolated for RT-PCR screening using primers for specific mRNA of the biomarkers: CD44, CD24, CD133, NANOG, Nestin, ALDH1, and ABCG2 in CAL27, SCC25 and SCC15 cells. This analysis revealed that some oral cancer cell lines (CAL27 and SCC25 may contain small subpopulations of adhesion- and contact-independent cells (AiDC that also express tumor stem cell markers, including CD44, CD133, and CD24. In addition, CAL27 cells also expressed the intracellular tumor stem cell markers, ALDH1 and ABCG2. Isolation and culture of the adhesion- and contact-independent cells from CAL27 and SCC25 populations revealed differential proliferation rates and more robust inhibition by the MEK inhibitor PD98059, as well as the chemotherapeutic agents Cisplatin and Paclitaxel, within the AiDC CAL27 cells. At least one oral cancer cell line (CAL27 contained subpopulations of cells that express specific biomarkers associated with tumor stem cells which were morphologically and phenotypically distinct from other cells within this cell line.

  10. NGS-based transcriptome profiling reveals biomarkers for companion diagnostics of the TGF-β receptor blocker galunisertib in HCC.

    Science.gov (United States)

    Cao, Yuan; Agarwal, Rahul; Dituri, Francesco; Lupo, Luigi; Trerotoli, Paolo; Mancarella, Serena; Winter, Peter; Giannelli, Gianluigi

    2017-02-23

    Transforming growth factor-beta (TGF-β) signaling has gained extensive interest in hepatocellular carcinoma (HCC). The small molecule kinase inhibitor galunisertib, targeting the TGF-β receptor I (TGF-βRI), blocks HCC progression in preclinical models and shows promising effects in ongoing clinical trials. As the drug is not similarly effective in all patients, this study was aimed at identifying new companion diagnostics biomarkers for patient stratification. Next-generation sequencing-based massive analysis of cDNA ends was used to investigate the transcriptome of an invasive HCC cell line responses to TGF-β1 and galunisertib. These identified mRNA were validated in 78 frozen HCC samples and in 26 ex-vivo HCC tissues treated in culture with galunisertib. Respective protein levels in patients blood were measured by enzyme-linked immunosorbent assay. SKIL, PMEPA1 ANGPTL4, SNAI1, Il11 and c4orf26 were strongly upregulated by TGF-β1 and downregulated by galunisertib in different HCC cell lines. In the 78 HCC samples, only SKIL and PMEPA1 (P<0.001) were correlated with endogenous TGF-β1. In ex-vivo samples, SKIL and PMEPA1 were strongly downregulated (P<0.001), and correlated (P<0.001) with endogenous TGF-β1. SKIL and PMEPA1 mRNA expression in tumor tissues was significantly increased compared with controls and not correlated with protein levels in the blood of paired HCC patients. SKIL and PMEPA1 mRNA levels were positively correlated with TGF-β1 mRNA concentrations in HCC tissues and strongly downregulated by galunisertib. The target genes identified here may serve as biomarkers for the stratification of HCC patients undergoing treatment with galunisertib.

  11. Imaging Biomarkers or Biomarker Imaging?

    Directory of Open Access Journals (Sweden)

    Markus Mitterhauser

    2014-06-01

    Full Text Available Since biomarker imaging is traditionally understood as imaging of molecular probes, we highly recommend to avoid any confusion with the previously defined term “imaging biomarkers” and, therefore, only use “molecular probe imaging (MPI” in that context. Molecular probes (MPs comprise all kinds of molecules administered to an organism which inherently carry a signalling moiety. This review highlights the basic concepts and differences of molecular probe imaging using specific biomarkers. In particular, PET radiopharmaceuticals are discussed in more detail. Specific radiochemical and radiopharmacological aspects as well as some legal issues are presented.

  12. Differentially expressed androgen-regulated genes in androgen-sensitive tissues reveal potential biomarkers of early prostate cancer.

    Directory of Open Access Journals (Sweden)

    Dogus Murat Altintas

    Full Text Available BACKGROUND: Several data favor androgen receptor implication in prostate cancer initiation through the induction of several gene activation programs. The aim of the study is to identify potential biomarkers for early diagnosis of prostate cancer (PCa among androgen-regulated genes (ARG and to evaluate comparative expression of these genes in normal prostate and normal prostate-related androgen-sensitive tissues that do not (or rarely give rise to cancer. METHODS: ARG were selected in non-neoplastic adult human prostatic epithelial RWPE-1 cells stably expressing an exogenous human androgen receptor, using RNA-microarrays and validation by qRT-PCR. Expression of 48 preselected genes was quantified in tissue samples (seminal vesicles, prostate transitional zones and prostate cancers, benign prostatic hypertrophy obtained from surgical specimens using TaqMan® low-density arrays. The diagnostic performances of these potential biomarkers were compared to that of genes known to be associated with PCa (i.e. PCA3 and DLX1. RESULTS AND DISCUSSION: By crossing expression studies in 26 matched PCa and normal prostate transitional zone samples, and 35 matched seminal vesicle and PCa samples, 14 genes were identified. Similarly, 9 genes were overexpressed in 15 benign prostatic hypertrophy samples, as compared to PCa samples. Overall, we selected 8 genes of interest to evaluate their diagnostic performances in comparison with that of PCA3 and DLX1. Among them, 3 genes: CRYAB, KCNMA1 and SDPR, were overexpressed in all 3 reference non-cancerous tissues. The areas under ROC curves of these genes reached those of PCA3 (0.91 and DLX1 (0.94. CONCLUSIONS: We identified ARG with reduced expression in PCa and with significant diagnostic values for discriminating between cancerous and non-cancerous prostatic tissues, similar that of PCA3. Given their expression pattern, they could be considered as potentially protective against prostate cancer. Moreover, they could

  13. Carbon sources in suspended particles and surface sediments from the Beaufort Sea revealed by molecular lipid biomarkers and compound-specific isotope analysis

    Science.gov (United States)

    Tolosa, I.; Fiorini, S.; Gasser, B.; Martín, J.; Miquel, J. C.

    2013-03-01

    Molecular lipid biomarkers (hydrocarbons, alcohols, sterols and fatty acids) and compound-specific isotope analysis of suspended particulate organic matter (SPM) and surface sediments of the Mackenzie Shelf and slope (southeast Beaufort Sea, Arctic Ocean) were studied in summer 2009. The concentrations of the molecular lipid markers, characteristic of known organic matter sources, were grouped and used as proxies to evaluate the relative importance of fresh algal, detrital algal, fossil, C3 terrestrial plants, bacterial and zooplankton material in the organic matter (OM) of this area. Fossil and detrital algal contributions were the major fractions of the freshwater SPM from the Mackenzie River with ~34% each of the total molecular biomarkers. Fresh algal, C3 terrestrial, bacterial and zooplanktonic components represented much lower percentages, 17, 10, 4 and 80%), with a minor contribution of fossil and C3 terrestrial biomarkers. Characterization of the sediments revealed a major sink of refractory algal material mixed with some fresh algal material, fossil hydrocarbons and a small input of C3 terrestrial sources. In particular, the sediments from the shelf and at the mouth of the Amundsen Gulf presented the highest contribution of detrital algal material (60-75%), whereas those from the slope contained the highest proportion of fossil (40%) and C3 terrestrial plant material (10%). Overall, considering that the detrital algal material is marine derived, autochthonous sources contributed more than allochthonous sources to the OM lipid pool. Using the ratio of an allochthonous biomarker (normalized to total organic carbon, TOC) found in the sediments to those measured at the river mouth water, we estimated that the fraction of terrestrial material preserved in the sediments accounted for 30-40% of the total carbon in the inner shelf sediments, 17% in the outer shelf and Amundsen Gulf and up to 25% in the slope sediments. These estimates are low compared to other

  14. Carbon sources in suspended particles and surface sediments from the Beaufort Sea revealed by molecular lipid biomarkers and compound-specific isotope analysis

    Directory of Open Access Journals (Sweden)

    I. Tolosa

    2013-03-01

    Full Text Available Molecular lipid biomarkers (hydrocarbons, alcohols, sterols and fatty acids and compound-specific isotope analysis of suspended particulate organic matter (SPM and surface sediments of the Mackenzie Shelf and slope (southeast Beaufort Sea, Arctic Ocean were studied in summer 2009. The concentrations of the molecular lipid markers, characteristic of known organic matter sources, were grouped and used as proxies to evaluate the relative importance of fresh algal, detrital algal, fossil, C3 terrestrial plants, bacterial and zooplankton material in the organic matter (OM of this area. Fossil and detrital algal contributions were the major fractions of the freshwater SPM from the Mackenzie River with ~34% each of the total molecular biomarkers. Fresh algal, C3 terrestrial, bacterial and zooplanktonic components represented much lower percentages, 17, 10, 4 and 80%, with a minor contribution of fossil and C3 terrestrial biomarkers. Characterization of the sediments revealed a major sink of refractory algal material mixed with some fresh algal material, fossil hydrocarbons and a small input of C3 terrestrial sources. In particular, the sediments from the shelf and at the mouth of the Amundsen Gulf presented the highest contribution of detrital algal material (60–75%, whereas those from the slope contained the highest proportion of fossil (40% and C3 terrestrial plant material (10%. Overall, considering that the detrital algal material is marine derived, autochthonous sources contributed more than allochthonous sources to the OM lipid pool. Using the ratio of an allochthonous biomarker (normalized to total organic carbon, TOC found in the sediments to those measured at the river mouth water, we estimated that the fraction of terrestrial material preserved in the sediments accounted for 30–40% of the total carbon in the inner shelf sediments, 17% in the outer shelf and Amundsen Gulf and up to 25% in the slope sediments. These estimates are low

  15. High-field magnetic resonance imaging of brain iron: birth of a biomarker?

    Science.gov (United States)

    Schenck, John F; Zimmerman, Earl A

    2004-11-01

    The brain has an unusually high concentration of iron, which is distributed in an unusual pattern unlike that in any other organ. The physiological role of this iron and the reasons for this pattern of distribution are not yet understood. There is increasing evidence that several neurodegenerative diseases are associated with altered brain iron metabolism. Understanding these dysmetabolic conditions may provide important information for their diagnosis and treatment. For many years the iron distribution in the human brain could be studied effectively only under postmortem conditions. This situation was changed dramatically by the finding that T2-weighted MR imaging at high field strength (initially 1.5 T) appears to demonstrate the pattern of iron distribution in normal brains and that this imaging technique can detect changes in brain iron concentrations associated with disease states. Up to the present time this imaging capability has been utilized in many research applications but it has not yet been widely applied in the routine diagnosis and management of neurodegenerative disorders. However, recent advances in the basic science of brain iron metabolism, the clinical understanding of neurodegenerative diseases and in MRI technology, particularly in the availability of clinical scanners operating at the higher field strength of 3 T, suggest that iron-dependent MR imaging may soon provide biomarkers capable of characterizing the presence and progression of important neurological disorders. Such biomarkers may be of crucial assistance in the development and utilization of effective new therapies for Alzheimer's and Parkinson's diseases, multiple sclerosis and other iron-related CNS disorders which are difficult to diagnose and treat.

  16. Proteomic analysis of coronary sinus serum reveals leucine-rich alpha2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure.

    LENUS (Irish Health Repository)

    Watson, Chris J

    2012-02-01

    BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF. METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich alpha2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P<\\/=0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-alpha (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-betaR1 (P<0.001) and alpha-smooth muscle actin (P=0.025) expression. CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, beta-blocker therapy, and BNP.

  17. Determination of gouty arthritis' biomarkers in human urine using reversed-phase high-performance liquid chromatography

    Institute of Scientific and Technical Information of China (English)

    Lei-Wen Xiang; Jing Li; Jin-Ming Lin; Hai-Fang Li

    2014-01-01

    Creatinine, uric acid, hypoxanthine and xanthine are important diagnostic biomarkers in human urine for gouty arthritis or renal disease diacrisis. A simple method for simultaneous determination of these biomarkers in urine based on reversed-phase high-performance liquid chromatography (RP-HPLC) with ultraviolet (UV) detector was proposed. After pretreatment by dilution, centrifugation and filtration, the biomarkers in urine samples were separated by ODS-BP column by elution with methanol/50 mM NaH2PO4 buffer solution at pH 5.26 (5:95). Good linearity between peak areas and concentrations of standards was obtained for the biomarkers with correlation coefficients in the range of 0.9957-0.9993. The proposed analytical method has satisfactory repeatability (the recovery of data in a range of creatinine, uric acid, hypoxanthine and xanthine was 93.49-97.90%, 95.38-96.45%, 112.46-115.78%and 90.82-97.13%with standard deviation of o5%, respectively) and the limits of detection (LODs, S/N Z 3) for creatinine, uric acid, hypoxanthine, and xanthine were 0.010, 0.025, 0.050 and 0.025 mg/L, respectively. The established method was proved to be simple, accurate, sensitive and reliable for the quantitation of gouty arthritis' biomarkers in human urine samples. The ratio of creatinine to uric acid was found to be a possible factor for assessment of gouty arthritis.

  18. New sepsis biomarkers

    Directory of Open Access Journals (Sweden)

    Dolores Limongi

    2016-06-01

    Full Text Available Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  19. New sepsis biomarkers

    Institute of Scientific and Technical Information of China (English)

    Dolores Limongi; Cartesio D’Agostini; Marco Ciotti

    2016-01-01

    Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes.Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity,specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis,timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  20. New sepsis biomarkers

    Institute of Scientific and Technical Information of China (English)

    Dolores Limongi; Cartesio DAgostini; Marco Ciotti

    2016-01-01

    Sepsis remains a leading cause of death in the intensive care units and in all age groups worldwide. Early recognition and diagnosis are key to achieving improved outcomes. Therefore, novel biomarkers that might better inform clinicians treating such patients are surely needed. The main attributes of successful biomarkers would be high sensitivity, specificity, possibility of bedside monitoring and financial accessibility. A panel of sepsis biomarkers along with currently used laboratory tests will facilitate earlier diagnosis, timely treatment and improved outcome may be more effective than single biomarkers. In this review, we summarize the most recent advances on sepsis biomarkers evaluated in clinical and experimental studies.

  1. Highly selective biomarkers for pesticides developed in Eisenia fetida using SELDI-TOF MS.

    Science.gov (United States)

    Park, Doo-San; Jeon, Hwang-Ju; Park, Eun-Sil; Bae, In Kyung; Kim, Yong-Eun; Lee, Sung-Eun

    2015-03-01

    The repeated use of pesticides, and their subsequent residues, has contributed to severe adverse effects on the environment, including risks to human health. Therefore, it is important to assess the quality of the environment to ensure it remains free from pesticide residues. The six pesticides tested in this study showed high mortality on Eisenia fetida with LC50 values ranging from 7.7 to 37.9 g L(-1). The strongest lethal effect resulted from the organochlorine insecticide endosulfan (LC50=7.7 g L(-1)). Following exposure to the carbamate pesticides, acetylcholinesterase activity in E. fetida decreased dramatically in comparison to the control. Carboxylesterase activity was only lowered in E. fetida exposed to propoxur, when compared to the control. The remaining five pesticides had no significant effect on carboxylesterase activity in E. fetida. In order to discover pesticide-specific biomarkers with differentially expressed proteins after exposure to pesticides, protein patterns of pesticide-treated E. fetida were analyzed using SELDI-TOF MS with Q10 ProteinChips. Protein patterns were compared with their intensities at the same mass-to-charge ratios (m/z). All 42 peaks had intensities with associated p-values less than 0.089, and 40 of these peaks had associated p-values of 0.05. Using SELDI-TOF MS technology, selective biomarkers for the six pesticides tested were found in E. fetida; four proteins with 5425, 5697, 9523, and 9868 m/z were consistently observed in the earthworms following exposure to the carbamates.

  2. Interictal High Frequency Oscillations Detected with Simultaneous Magnetoencephalography and Electroencephalography as Biomarker of Pediatric Epilepsy

    Science.gov (United States)

    Papadelis, Christos; Tamilia, Eleonora; Stufflebeam, Steven; Grant, Patricia E.; Madsen, Joseph R.; Pearl, Phillip L.; Tanaka, Naoaki

    2016-01-01

    Crucial to the success of epilepsy surgery is the availability of a robust biomarker that identifies the Epileptogenic Zone (EZ). High Frequency Oscillations (HFOs) have emerged as potential presurgical biomarkers for the identification of the EZ in addition to Interictal Epileptiform Discharges (IEDs) and ictal activity. Although they are promising to localize the EZ, they are not yet suited for the diagnosis or monitoring of epilepsy in clinical practice. Primary barriers remain: the lack of a formal and global definition for HFOs; the consequent heterogeneity of methodological approaches used for their study; and the practical difficulties to detect and localize them noninvasively from scalp recordings. Here, we present a methodology for the recording, detection, and localization of interictal HFOs from pediatric patients with refractory epilepsy. We report representative data of HFOs detected noninvasively from interictal scalp EEG and MEG from two children undergoing surgery. The underlying generators of HFOs were localized by solving the inverse problem and their localization was compared to the Seizure Onset Zone (SOZ) as this was defined by the epileptologists. For both patients, Interictal Epileptogenic Discharges (IEDs) and HFOs were localized with source imaging at concordant locations. For one patient, intracranial EEG (iEEG) data were also available. For this patient, we found that the HFOs localization was concordant between noninvasive and invasive methods. The comparison of iEEG with the results from scalp recordings served to validate these findings. To our best knowledge, this is the first study that presents the source localization of scalp HFOs from simultaneous EEG and MEG recordings comparing the results with invasive recordings. These findings suggest that HFOs can be reliably detected and localized noninvasively with scalp EEG and MEG. We conclude that the noninvasive localization of interictal HFOs could significantly improve the

  3. Novel approach to meta-analysis of microarray datasets reveals muscle remodeling-related drug targets and biomarkers in Duchenne muscular dystrophy.

    Directory of Open Access Journals (Sweden)

    Ekaterina Kotelnikova

    2012-02-01

    Full Text Available Elucidation of new biomarkers and potential drug targets from high-throughput profiling data is a challenging task due to a limited number of available biological samples and questionable reproducibility of differential changes in cross-dataset comparisons. In this paper we propose a novel computational approach for drug and biomarkers discovery using comprehensive analysis of multiple expression profiling datasets.The new method relies on aggregation of individual profiling experiments combined with leave-one-dataset-out validation approach. Aggregated datasets were studied using Sub-Network Enrichment Analysis algorithm (SNEA to find consistent statistically significant key regulators within the global literature-extracted expression regulation network. These regulators were linked to the consistent differentially expressed genes.We have applied our approach to several publicly available human muscle gene expression profiling datasets related to Duchenne muscular dystrophy (DMD. In order to detect both enhanced and repressed processes we considered up- and down-regulated genes separately. Applying the proposed approach to the regulators search we discovered the disturbance in the activity of several muscle-related transcription factors (e.g. MYOG and MYOD1, regulators of inflammation, regeneration, and fibrosis. Almost all SNEA-derived regulators of down-regulated genes (e.g. AMPK, TORC2, PPARGC1A correspond to a single common pathway important for fast-to-slow twitch fiber type transition. We hypothesize that this process can affect the severity of DMD symptoms, making corresponding regulators and downstream genes valuable candidates for being potential drug targets and exploratory biomarkers.

  4. Differential profiling of breast cancer plasma proteome by isotope-coded affinity tagging method reveals biotinidase as a breast cancer biomarker

    Directory of Open Access Journals (Sweden)

    Yu Myeong-Hee

    2010-03-01

    Full Text Available Abstract Background Breast cancer is one of the leading causes of women's death worldwide. It is important to discover a reliable biomarker for the detection of breast cancer. Plasma is the most ideal source for cancer biomarker discovery since many cells cross-communicate through the secretion of soluble proteins into blood. Methods Plasma proteomes obtained from 6 breast cancer patients and 6 normal healthy women were analyzed by using the isotope-coded affinity tag (ICAT labeling approach and tandem mass spectrometry. All the plasma samples used were depleted of highly abundant 6 plasma proteins by immune-affinity column chromatography before ICAT labeling. Several proteins showing differential abundance level were selected based on literature searches and their specificity to the commercially available antibodies, and then verified by immunoblot assays. Results A total of 155 proteins were identified and quantified by ICAT method. Among them, 33 proteins showed abundance changes by more than 1.5-fold between the plasmas of breast cancer patients and healthy women. We chose 5 proteins for the follow-up confirmation in the individual plasma samples using immunoblot assay. Four proteins, α1-acid glycoprotein 2, monocyte differentiation antigen CD14, biotinidase (BTD, and glutathione peroxidase 3, showed similar abundance ratio to ICAT result. Using a blind set of plasmas obtained from 21 breast cancer patients and 21 normal healthy controls, we confirmed that BTD was significantly down-regulated in breast cancer plasma (Wilcoxon rank-sum test, p = 0.002. BTD levels were lowered in all cancer grades (I-IV except cancer grade zero. The area under the receiver operating characteristic curve of BTD was 0.78. Estrogen receptor status (p = 0.940 and progesterone receptor status (p = 0.440 were not associated with the plasma BTD levels. Conclusions Our study suggests that BTD is a potential serological biomarker for the detection of breast cancer.

  5. A vegetable/fruit concentrate with high antioxidant capacity has no effect on biomarkers of antioxidant status in male smokers

    NARCIS (Netherlands)

    Berg, R. van den; Vliet, T. van; Broekmans, W.M.R.; Cnubben, N.H.P.; Vaes, W.H.J.; Roza, L.; Haenen, G.R.M.M.; Bast, A.; Berg, H. van den

    2001-01-01

    The potential benefits of a high fruit and vegetable intake on the antioxidant status and on relevant biomarkers of oxidative damage to lipids, proteins and DNA and on (functional) markers of oxidative stress were evaluated. A randomized, free living, open placebo-controlled cross-over trial of 3 wk

  6. Novel diagnostic biomarkers for prostate cancer

    Directory of Open Access Journals (Sweden)

    Chikezie O. Madu, Yi Lu

    2010-01-01

    Full Text Available Prostate cancer is the most frequently diagnosed malignancy in American men, and a more aggressive form of the disease is particularly prevalent among African Americans. The therapeutic success rate for prostate cancer can be tremendously improved if the disease is diagnosed early. Thus, a successful therapy for this disease depends heavily on the clinical indicators (biomarkers for early detection of the presence and progression of the disease, as well as the prediction after the clinical intervention. However, the current clinical biomarkers for prostate cancer are not ideal as there remains a lack of reliable biomarkers that can specifically distinguish between those patients who should be treated adequately to stop the aggressive form of the disease and those who should avoid overtreatment of the indolent form.A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker reveals further information to presently existing clinical and pathological analysis. It facilitates screening and detecting the cancer, monitoring the progression of the disease, and predicting the prognosis and survival after clinical intervention. A biomarker can also be used to evaluate the process of drug development, and, optimally, to improve the efficacy and safety of cancer treatment by enabling physicians to tailor treatment for individual patients. The form of the prostate cancer biomarkers can vary from metabolites and chemical products present in body fluid to genes and proteins in the prostate tissues.Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for prostate cancer. These emerging biomarkers will be beneficial and critical in developing new and clinically reliable indicators that will have a high specificity for the diagnosis and prognosis of

  7. Novel diagnostic biomarkers for prostate cancer.

    Science.gov (United States)

    Madu, Chikezie O; Lu, Yi

    2010-10-06

    Prostate cancer is the most frequently diagnosed malignancy in American men, and a more aggressive form of the disease is particularly prevalent among African Americans. The therapeutic success rate for prostate cancer can be tremendously improved if the disease is diagnosed early. Thus, a successful therapy for this disease depends heavily on the clinical indicators (biomarkers) for early detection of the presence and progression of the disease, as well as the prediction after the clinical intervention. However, the current clinical biomarkers for prostate cancer are not ideal as there remains a lack of reliable biomarkers that can specifically distinguish between those patients who should be treated adequately to stop the aggressive form of the disease and those who should avoid overtreatment of the indolent form.A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. A biomarker reveals further information to presently existing clinical and pathological analysis. It facilitates screening and detecting the cancer, monitoring the progression of the disease, and predicting the prognosis and survival after clinical intervention. A biomarker can also be used to evaluate the process of drug development, and, optimally, to improve the efficacy and safety of cancer treatment by enabling physicians to tailor treatment for individual patients. The form of the prostate cancer biomarkers can vary from metabolites and chemical products present in body fluid to genes and proteins in the prostate tissues.Current advances in molecular techniques have provided new tools facilitating the discovery of new biomarkers for prostate cancer. These emerging biomarkers will be beneficial and critical in developing new and clinically reliable indicators that will have a high specificity for the diagnosis and prognosis of prostate cancer. The

  8. IMAC fractionation in combination with LC-MS reveals H2B and NIF-1 peptides as potential bladder cancer biomarkers.

    Science.gov (United States)

    Frantzi, Maria; Zoidakis, Jerome; Papadopoulos, Theofilos; Zürbig, Petra; Katafigiotis, Ioannis; Stravodimos, Konstantinos; Lazaris, Andreas; Giannopoulou, Ioanna; Ploumidis, Achilles; Mischak, Harald; Mullen, William; Vlahou, Antonia

    2013-09-06

    Improvement in bladder cancer (BC) management requires more effective diagnosis and prognosis of disease recurrence and progression. Urinary biomarkers attract special interest because of the noninvasive means of urine collection. Proteomic analysis of urine entails the adoption of a fractionation methodology to reduce sample complexity. In this study, we applied immobilized metal affinity chromatography in combination with high-resolution LC-MS/MS for the discovery of native urinary peptides potentially associated with BC aggressiveness. This approach was employed toward urine samples from patients with invasive BC, noninvasive BC, and benign urogenital diseases. A total of 1845 peptides were identified, corresponding to a total of 638 precursor proteins. Specific enrichment for proteins involved in nucleosome assembly and for zinc-finger transcription factors was observed. The differential expression of two candidate biomarkers, histone H2B and NIF-1 (zinc finger 335) in BC, was verified in independent sets of urine samples by ELISA and by immunohistochemical analysis of BC tissue. The results collectively support changes in the expression of both of these proteins with tumor progression, suggesting their potential role as markers for discriminating BC stages. In addition, the data indicate a possible involvement of NIF-1 in BC progression, likely as a suppressor and through interactions with Sox9 and HoxA1.

  9. Proteomic analysis in type 2 diabetes patients before and after a very low calorie diet reveals potential disease state and intervention specific biomarkers.

    Directory of Open Access Journals (Sweden)

    Maria A Sleddering

    Full Text Available Very low calorie diets (VLCD with and without exercise programs lead to major metabolic improvements in obese type 2 diabetes patients. The mechanisms underlying these improvements have so far not been elucidated fully. To further investigate the mechanisms of a VLCD with or without exercise and to uncover possible biomarkers associated with these interventions, blood samples were collected from 27 obese type 2 diabetes patients before and after a 16-week VLCD (Modifast ∼ 450 kcal/day. Thirteen of these patients followed an exercise program in addition to the VCLD. Plasma was obtained from 27 lean and 27 obese controls as well. Proteomic analysis was performed using mass spectrometry (MS and targeted multiple reaction monitoring (MRM and a large scale isobaric tags for relative and absolute quantitation (iTRAQ approach. After the 16-week VLCD, there was a significant decrease in body weight and HbA1c in all patients, without differences between the two intervention groups. Targeted MRM analysis revealed differences in several proteins, which could be divided in diabetes-associated (fibrinogen, transthyretin, obesity-associated (complement C3, and diet-associated markers (apolipoproteins, especially apolipoprotein A-IV. To further investigate the effects of exercise, large scale iTRAQ analysis was performed. However, no proteins were found showing an exercise effect. Thus, in this study, specific proteins were found to be differentially expressed in type 2 diabetes patients versus controls and before and after a VLCD. These proteins are potential disease state and intervention specific biomarkers.Controlled-Trials.com ISRCTN76920690.

  10. Sediment biomarker, bacterial community characterization of high arsenic aquifers in Jianghan Plain, China

    Science.gov (United States)

    Ye, Hengpeng; Yang, Zeyu; Wu, Xiang; Wang, Jingwen; Du, Dongyun; Cai, Jian; Lv, Kangle; Chen, Huiyun; Mei, Jingkun; Chen, Mengqi; Du, Hong

    2017-01-01

    Representative biomarkers (e.g., n-alkanes), diversity and microbial community in the aquifers contaminated by high concentration of arsenic (As) in different sediment depth (0–30 m) in Jianghan Plain, Hubei, China, were analyzed to investigate the potential mechanism of As enrichment in groundwater. The concentration of As was abundant in top soil and sand, but not in clay. The analysis of the distribution of n-alkanes, CPI values, and wax to total n-alkane ratio (Wax(n)%) indicated that the organic matter (OM) from fresh terrestrial plants were abundant in the shallow sediment. However, n-alkanes have suffered from significant biodegradation from the depth of 16 m to 30 m. The deposition of fresh terrestrial derived organic matters may facilitate the release of As from sediment to groundwater in the sediment of 0–16 m. However, the petroleum derived organic matters may do the favor to the release of As in the deeper section of borehole (16 m to 30 m). The 16S rRNA gene sequences identification indicated that Acidobacteria, Actinomycetes and Hydrogenophaga are abundant in the sediments with high arsenic. Therefore, microbes and organic matters from different sources may play important roles in arsenic mobilization in the aquifers of the study area. PMID:28165031

  11. Highly sensitive detection of protein biomarkers via nuclear magnetic resonance biosensor with magnetically engineered nanoferrite particles.

    Science.gov (United States)

    Jeun, Minhong; Park, Sungwook; Lee, Hakho; Lee, Kwan Hyi

    Magnetic-based biosensors are attractive for on-site detection of biomarkers due to the low magnetic susceptibility of biological samples. Here, we report a highly sensitive magnetic-based biosensing system that is composed of a miniaturized nuclear magnetic resonance (NMR) device and magnetically engineered nanoferrite particles (NFPs). The sensing performance, also identified as the transverse relaxation (R2) rate, of the NMR device is directly related to the magnetic properties of the NFPs. Therefore, we developed magnetically engineered NFPs (MnMg-NFP) and used them as NMR agents to exhibit a significantly improved R2 rate. The magnetization of the MnMg-NFPs was increased by controlling the Mn and Mg cation concentration and distribution during the synthesis process. This modification of the Mn and Mg cation directly contributed to improving the R2 rate. The miniaturized NMR system, combined with the magnetically engineered MnMg-NFPs, successfully detected a small amount of infectious influenza A H1N1 nucleoprotein with high sensitivity and stability.

  12. Inference of Causal Relationships between Biomarkers and Outcomes in High Dimensions

    Directory of Open Access Journals (Sweden)

    Felix Agakov

    2011-12-01

    Full Text Available We describe a unified computational framework for learning causal dependencies between genotypes, biomarkers, and phenotypic outcomes from large-scale data. In contrast to previous studies, our framework allows for noisy measurements, hidden confounders, missing data, and pleiotropic effects of genotypes on outcomes. The method exploits the use of genotypes as “instrumental variables” to infer causal associations between phenotypic biomarkers and outcomes, without requiring the assumption that genotypic effects are mediated only through the observed biomarkers. The framework builds on sparse linear methods developed in statistics and machine learning and modified here for inferring structures of richer networks with latent variables. Where the biomarkers are gene transcripts, the method can be used for fine mapping of quantitative trait loci (QTLs detected in genetic linkage studies. To demonstrate our method, we examined effects of gene transcript levels in the liver on plasma HDL cholesterol levels in a sample of 260 mice from a heterogeneous stock.

  13. High resolution FESEM and TEM reveal bacterial spore attachment.

    Science.gov (United States)

    Panessa-Warren, Barbara J; Tortora, George T; Warren, John B

    2007-08-01

    Transmission electron microscopy (TEM) studies in the 1960s and early 1970s using conventional thin section and freeze fracture methodologies revealed ultrastructural bacterial spore appendages. However, the limited technology at that time necessitated the time-consuming process of imaging serial sections and reconstructing each structure. Consequently, the distribution and function of these appendages and their possible role in colonization or pathogenesis remained unknown. By combining high resolution field emission electron microscopy with TEM images of identical bacterial spore preparations, we have been able to obtain images of intact and sectioned Bacillus and Clostridial spores to clearly visualize the appearance, distribution, resistance (to trypsin, chloramphenicol, and heat), and participation of these structures to facilitate attachment of the spores to glass, agar, and human cell substrates. Current user-friendly commercial field emission scanning electron microscopes (FESEMs), permit high resolution imaging, with high brightness guns at lower accelerating voltages for beam sensitive intact biological samples, providing surface images at TEM magnifications for making direct comparisons. For the first time, attachment structures used by pathogenic, environmental, and thermophile bacterial spores could be readily visualized on intact spores to reveal how specific appendages and outer spore coats participated in spore attachment, colonization, and invasion.

  14. Finding diabetic nephropathy biomarkers in the plasma peptidome by high-throughput magnetic bead processing and MALDI-TOF-MS analysis

    DEFF Research Database (Denmark)

    Hansen, Henning G; Overgaard, Julie; Lajer, Maria

    2010-01-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease and improved biomarkers would help identify high-risk individuals. The aim of this study was to discover candidate biomarkers for DN in the plasma peptidome in an in-house cross-sectional cohort (n=122) of type 1 diabetic...

  15. The acute effect of cigarette smoking on the high-sensitivity CRP and fibrinogen biomarkers in chronic obstructive pulmonary disease patients

    NARCIS (Netherlands)

    Dijk, W.D. van; Akkermans, R.P.; Heijdra, Y.F.; Weel, C. van; Schermer, T.R.J.; Scheepers, P.T.J.; Lenders, J.W.M.

    2013-01-01

    Aim: The evidence on the acute effects of smoking on biomarkers is limited. Our aim was to study the acute effect of smoking on disease-related biomarkers. Methods: The acute effect of smoking on serum high sensitivity CRP (hs-CRP) and plasma fibrinogen and its association with disease severity was

  16. Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer.

    Science.gov (United States)

    Abdel-Fatah, Tarek M A; Russell, Roslin; Albarakati, Nada; Maloney, David J; Dorjsuren, Dorjbal; Rueda, Oscar M; Moseley, Paul; Mohan, Vivek; Sun, Hongmao; Abbotts, Rachel; Mukherjee, Abhik; Agarwal, Devika; Illuzzi, Jennifer L; Jadhav, Ajit; Simeonov, Anton; Ball, Graham; Chan, Stephen; Caldas, Carlos; Ellis, Ian O; Wilson, David M; Madhusudan, Srinivasan

    2014-10-01

    FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 × 10(-57)), high mitotic index (p = 5.25 × 10(-28)), pleomorphism (p = 6.31 × 10(-19)), ER negative (p = 9.02 × 10(-35)), PR negative (p = 9.24 × 10(-24)), triple negative phenotype (p = 6.67 × 10(-21)), PAM50.Her2 (p = 5.19 × 10(-13)), PAM50. Basal (p = 2.7 × 10(-41)), PAM50.LumB (p = 1.56 × 10(-26)), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10(-12)), intClust.5 (p = 4.05 × 10(-12)) and intClust. 10 (p = 7.59 × 10(-38)) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10(-16)) and multivariate analysis (p = 9.19 × 10(-7)). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps breast and ovarian epithelial cancer.

  17. Epigenetic landscape of the TERT promoter: a potential biomarker for high risk AML/MDS.

    Science.gov (United States)

    Zhao, Xin; Tian, Xin; Kajigaya, Sachiko; Cantilena, Caroline R; Strickland, Stephen; Savani, Bipin N; Mohan, Sanjay; Feng, Xingmin; Keyvanfar, Keyvan; Dunavin, Neil; Townsley, Danielle M; Dumitriu, Bogdan; Battiwalla, Minoo; Rezvani, Katayoun; Young, Neal S; Barrett, A John; Ito, Sawa

    2016-11-01

    Although recent observations implicate the importance of telomerase activity in acute myeloid leukaemia (AML), the roles of epigenetic regulations of the TERT gene in leukaemogenesis, drug resistance and clinical prognosis in AML are not fully understood. We developed a quantitative pyrosequencing-based methylation assay covering the TERT proximal promoter and a partial exon 1 (TERTpro/Ex1) region and tested both cell lines and primary leukaemia cells derived from AML and AML with preceding myelodysplastic syndrome (AML/MDS) patients (n = 43). Prognostic impact of methylation status of the upstream TERT promoter region was assessed by the Kaplan-Meier method. The activity of the telomerase inhibitor, imetelstat, was measured using leukaemia cell lines. The TERTpro/Ex1 region was highly methylated in all cell lines and primary leukaemia cells showed diverse methylation profiles. Most cases showed hypermethylated regions at the upstream TERTpro/Ex1 region, which were associated with inferior patient survival. TERTpro/Ex1 methylation status was correlated with the cytotoxicity to imetelstat and its combination with hypomethylating agent enhanced the cytotoxicity of imetelstat. AML cell lines and primary blasts harbour distinct TERTpro/Ex1 methylation profiles that could serve as a prognostic biomarker of AML. However, validation in a large cohort of patients is necessary to confirm our findings.

  18. High-Sensitivity and Low-Toxicity Fucose Probe for Glycan Imaging and Biomarker Discovery.

    Science.gov (United States)

    Kizuka, Yasuhiko; Funayama, Sho; Shogomori, Hidehiko; Nakano, Miyako; Nakajima, Kazuki; Oka, Ritsuko; Kitazume, Shinobu; Yamaguchi, Yoshiki; Sano, Masahiro; Korekane, Hiroaki; Hsu, Tsui-Ling; Lee, Hsiu-Yu; Wong, Chi-Huey; Taniguchi, Naoyuki

    2016-07-21

    Fucose, a terminal sugar in glycoconjugates, critically regulates various physiological and pathological phenomena, including cancer development and inflammation. However, there are currently no probes for efficient labeling and detection of this sugar. We chemically synthesized a novel series of alkynyl-fucose analogs as probe candidates and found that 7-alkynyl-fucose gave the highest labeling efficiency and low cytotoxicity. Among the fucose analogs, 7-alkynyl-fucose was the best substrate against all five fucosyltransferases examined. We confirmed its conversion to the corresponding guanosine diphosphate derivative in cells and found that cellular glycoproteins were labeled much more efficiently with 7-alkynyl-fucose than with an existing probe. 7-Alkynyl-fucose was detected in the N-glycan core by mass spectrometry, and 7-alkynyl-fucose-modified proteins mostly disappeared in core-fucose-deficient mouse embryonic fibroblasts, suggesting that this analog mainly labeled core fucose in these cells. These results indicate that 7-alkynyl-fucose is a highly sensitive and powerful tool for basic glycobiology research and clinical application for biomarker discovery.

  19. Accumulated metabolites of hydroxybutyric acid serve as diagnostic and prognostic biomarkers of ovarian high-grade serous carcinomas

    Science.gov (United States)

    Hilvo, Mika; de Santiago, Ines; Gopalacharyulu, Peddinti; Schmitt, Wolfgang D.; Budczies, Jan; Kuhberg, Marc; Dietel, Manfred; Aittokallio, Tero; Markowetz, Florian; Denkert, Carsten; Sehouli, Jalid; Frezza, Christian

    2016-01-01

    Ovarian cancer is a heterogeneous disease of low prevalence, but poor survival. Early diagnosis is critical for survival, but is often challenging because the symptoms of ovarian cancer are subtle and become apparent only during advanced stages of the disease. Therefore, the identification of robust biomarkers of early disease is a clinical priority. Metabolomic profiling is an emerging diagnostic tool enabling the detection of biomarkers reflecting alterations in tumor metabolism, a hallmark of cancer. In this study, we performed metabolomic profiling of serum and tumor tissue from 158 patients with high-grade serous ovarian cancer (HGSOC) and 100 control patients with benign or non-neoplastic lesions. We report metabolites of hydroxybutyric acid (HBA) as novel diagnostic and prognostic biomarkers associated with tumor burden and patient survival. The accumulation of HBA metabolites caused by HGSOC was also associated with reduced expression of succinic semialdehyde dehydrogenase (encoded by ALDH5A1), and with the presence of an epithelial-to-mesenchymal transition (EMT) gene signature, implying a role for these metabolic alterations in cancer cell migration and invasion. In conclusion, our findings represent the first comprehensive metabolomics analysis in HGSOC and propose a new set of metabolites as biomarkers of disease with diagnostic and prognostic capabilities. PMID:26685161

  20. Proteomic Analysis of Plasma from California Sea Lions (Zalophus californianus Reveals Apolipoprotein E as a Candidate Biomarker of Chronic Domoic Acid Toxicosis.

    Directory of Open Access Journals (Sweden)

    Benjamin A Neely

    Full Text Available Domoic acid toxicosis (DAT in California sea lions (Zalophus californianus is caused by exposure to the marine biotoxin domoic acid and has been linked to massive stranding events and mortality. Diagnosis is based on clinical signs in addition to the presence of domoic acid in body fluids. Chronic DAT further is characterized by reoccurring seizures progressing to status epilepticus. Diagnosis of chronic DAT is often slow and problematic, and minimally invasive tests for DAT have been the focus of numerous recent biomarker studies. The goal of this study was to retrospectively profile plasma proteins in a population of sea lions with chronic DAT and those without DAT using two dimensional gel electrophoresis to discover whether individual, multiple, or combinations of protein and clinical data could be utilized to identify sea lions with DAT. Using a training set of 32 sea lion sera, 20 proteins and their isoforms were identified that were significantly different between the two groups (p<0.05. Interestingly, 11 apolipoprotein E (ApoE charge forms were decreased in DAT samples, indicating that ApoE charge form distributions may be important in the progression of DAT. In order to develop a classifier of chronic DAT, an independent blinded test set of 20 sea lions, seven with chronic DAT, was used to validate models utilizing ApoE charge forms and eosinophil counts. The resulting support vector machine had high sensitivity (85.7% with 92.3% negative predictive value and high specificity (92.3% with 85.7% positive predictive value. These results suggest that ApoE and eosinophil counts along with machine learning can perform as a robust and accurate tool to diagnose chronic DAT. Although this analysis is specifically focused on blood biomarkers and routine clinical data, the results demonstrate promise for future studies combining additional variables in multidimensional space to create robust classifiers.

  1. Determination of gouty arthritis' biomarkers in human urine using reversed-phase high-performance liquid chromatography

    Directory of Open Access Journals (Sweden)

    Lei-Wen Xiang

    2014-04-01

    Full Text Available Creatinine, uric acid, hypoxanthine and xanthine are important diagnostic biomarkers in human urine for gouty arthritis or renal disease diacrisis. A simple method for simultaneous determination of these biomarkers in urine based on reversed-phase high-performance liquid chromatography (RP-HPLC with ultraviolet (UV detector was proposed. After pretreatment by dilution, centrifugation and filtration, the biomarkers in urine samples were separated by ODS-BP column by elution with methanol/50 mM NaH2PO4 buffer solution at pH 5.26 (5:95. Good linearity between peak areas and concentrations of standards was obtained for the biomarkers with correlation coefficients in the range of 0.9957–0.9993. The proposed analytical method has satisfactory repeatability (the recovery of data in a range of creatinine, uric acid, hypoxanthine and xanthine was 93.49–97.90%, 95.38–96.45%, 112.46–115.78% and 90.82–97.13% with standard deviation of <5%, respectively and the limits of detection (LODs, S/N≥3 for creatinine, uric acid, hypoxanthine, and xanthine were 0.010, 0.025, 0.050 and 0.025 mg/L, respectively. The established method was proved to be simple, accurate, sensitive and reliable for the quantitation of gouty arthritis' biomarkers in human urine samples. The ratio of creatinine to uric acid was found to be a possible factor for assessment of gouty arthritis.

  2. A TMA de-arraying method for high throughput biomarker discovery in tissue research.

    Directory of Open Access Journals (Sweden)

    Yinhai Wang

    Full Text Available BACKGROUND: Tissue MicroArrays (TMAs represent a potential high-throughput platform for the analysis and discovery of tissue biomarkers. As TMA slides are produced manually and subject to processing and sectioning artefacts, the layout of TMA cores on the final slide and subsequent digital scan (TMA digital slide is often disturbed making it difficult to associate cores with their original position in the planned TMA map. Additionally, the individual cores can be greatly altered and contain numerous irregularities such as missing cores, grid rotation and stretching. These factors demand the development of a robust method for de-arraying TMAs which identifies each TMA core, and assigns them to their appropriate coordinates on the constructed TMA slide. METHODOLOGY: This study presents a robust TMA de-arraying method consisting of three functional phases: TMA core segmentation, gridding and mapping. The segmentation of TMA cores uses a set of morphological operations to identify each TMA core. Gridding then utilises a Delaunay Triangulation based method to find the row and column indices of each TMA core. Finally, mapping correlates each TMA core from a high resolution TMA whole slide image with its name within a TMAMap. CONCLUSION: This study describes a genuine robust TMA de-arraying algorithm for the rapid identification of TMA cores from digital slides. The result of this de-arraying algorithm allows the easy partition of each TMA core for further processing. Based on a test group of 19 TMA slides (3129 cores, 99.84% of cores were segmented successfully, 99.81% of cores were gridded correctly and 99.96% of cores were mapped with their correct names via TMAMaps. The gridding of TMA cores were also extensively tested using a set of 113 pseudo slide (13,536 cores with a variety of irregular grid layouts including missing cores, rotation and stretching. 100% of the cores were gridded correctly.

  3. High-Dimensional Medial Lobe Morphometry: An Automated MRI Biomarker for the New AD Diagnostic Criteria

    Directory of Open Access Journals (Sweden)

    Simon Duchesne

    2014-01-01

    Full Text Available Introduction. Medial temporal lobe atrophy assessment via magnetic resonance imaging (MRI has been proposed in recent criteria as an in vivo diagnostic biomarker of Alzheimer’s disease (AD. However, practical application of these criteria in a clinical setting will require automated MRI analysis techniques. To this end, we wished to validate our automated, high-dimensional morphometry technique to the hypothetical prediction of future clinical status from baseline data in a cohort of subjects in a large, multicentric setting, compared to currently known clinical status for these subjects. Materials and Methods. The study group consisted of 214 controls, 371 mild cognitive impairment (147 having progressed to probable AD and 224 stable, and 181 probable AD from the Alzheimer’s Disease Neuroimaging Initiative, with data acquired on 58 different 1.5 T scanners. We measured the sensitivity and specificity of our technique in a hierarchical fashion, first testing the effect of intensity standardization, then between different volumes of interest, and finally its generalizability for a large, multicentric cohort. Results. We obtained 73.2% prediction accuracy with 79.5% sensitivity for the prediction of MCI progression to clinically probable AD. The positive predictive value was 81.6% for MCI progressing on average within 1.5 (0.3 s.d. year. Conclusion. With high accuracy, the technique’s ability to identify discriminant medial temporal lobe atrophy has been demonstrated in a large, multicentric environment. It is suitable as an aid for clinical diagnostic of AD.

  4. High throughput sequencing reveals a novel fabavirus infecting sweet cherry.

    Science.gov (United States)

    Villamor, D E V; Pillai, S S; Eastwell, K C

    2017-03-01

    The genus Fabavirus currently consists of five species represented by viruses that infect a wide range of hosts but none reported from temperate climate fruit trees. A virus with genomic features resembling fabaviruses (tentatively named Prunus virus F, PrVF) was revealed by high throughput sequencing of extracts from a sweet cherry tree (Prunus avium). PrVF was subsequently shown to be graft transmissible and further identified in three other non-symptomatic Prunus spp. from different geographical locations. Two genetic variants of RNA1 and RNA2 coexisted in the same samples. RNA1 consisted of 6,165 and 6,163 nucleotides, and RNA2 consisted of 3,622 and 3,468 nucleotides.

  5. High levels of biomarkers of collagen remodeling are associated with increased mortality in COPD

    DEFF Research Database (Denmark)

    Sand, Jannie M B; Leeming, Diana J; Byrjalsen, Inger

    2016-01-01

    immunoassays measuring serological neo-epitopes produced by proteolytic cleavage associated with degradation of collagen type I, III, IV, and VI, elastin, and biglycan, and formation of collagen type VI as well as fibrinogen and C-reactive protein were used. Multivariate models were used to assess...... with mortality in COPD and measured neo-epitopes originating from ECM proteins associated with lung tissue remodeling. METHODS: Biomarkers of ECM remodeling were assessed in a subpopulation (n = 1000) of the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. Validated...... the prognostic value of these biomarkers. RESULTS: Thirty subjects (3.0 %) died during follow-up. Non-survivors were older, had reduced exercise capacity, increased dyspnea score, and included fewer current smokers. All collagen biomarkers were significantly elevated in non-survivors compared to survivors...

  6. Functional connectivity classification of autism identifies highly predictive brain features but falls short of biomarker standards

    Directory of Open Access Journals (Sweden)

    Mark Plitt

    2015-01-01

    Conclusions: While individuals can be classified as having ASD with statistically significant accuracy from their rs-fMRI scans alone, this method falls short of biomarker standards. Classification methods provided further evidence that ASD functional connectivity is characterized by dysfunction of large-scale functional networks, particularly those involved in social information processing.

  7. Respiratory Toxicity Biomarkers

    Science.gov (United States)

    The advancement in high throughput genomic, proteomic and metabolomic techniques have accelerated pace of lung biomarker discovery. A recent growth in the discovery of new lung toxicity/disease biomarkers have led to significant advances in our understanding of pathological proce...

  8. Development of a high-throughput ultra performance liquid chromatography-mass spectrometry assay to profile 18 eicosanoids as exploratory biomarkers for atherosclerotic diseases.

    Science.gov (United States)

    Rago, Brian; Fu, Cexiong

    2013-10-01

    Abundant evidence suggests a prominent role for eicosanoids and metabolites in the pathogenesis and prognosis of inflammatory diseases. A sensitive and high-throughput SPE UPLC-MS/MS method was developed to quantitatively interrogate the levels of 18 eicosanoids in human and monkey plasma samples. A limit of quantitation of 0.25ng/mL was achieved for all 18 investigated compounds with linear ranges spanning four orders of magnitude. Bioanalytical performance of this assay was fully characterized including SPE extraction efficiency, matrix effect, autosampler stability, benchtop stability and freeze-thaw cycle variability. Endogenous levels of the eicosanoids and analogs within a set of monkey plasma samples challenged with lipopolysaccharide and human plasma samples were quantified by this ultra performance liquid chromatography-mass spectrometry (UPLC-MS/MS) assay. Quantitative eicosanoid profiles of the human samples were further analyzed by a non-supervised cluster analysis, which revealed a set of potential positive and negative lipid biomarkers to distinguish the following three groups: healthy individuals, hypertensive patients and severe atherosclerosis patients. The components of the negative biomarker cluster (8-HETE, LTB4, 9-HODE and 13-HODE) are putative ligands of peroxisome proliferator-activated receptors (PPARs), a family of master genes controlling the resolution of inflammatory signaling.

  9. High resolution spectroscopy reveals fibrillation inhibition pathways of insulin

    Science.gov (United States)

    Deckert-Gaudig, Tanja; Deckert, Volker

    2016-12-01

    Fibril formation implies the conversion of a protein’s native secondary structure and is associated with several neurodegenerative diseases. A better understanding of fibrillation inhibition and fibril dissection requires nanoscale molecular characterization of amyloid structures involved. Tip-enhanced Raman scattering (TERS) has already been used to chemically analyze amyloid fibrils on a sub-protein unit basis. Here, TERS in combination with atomic force microscopy (AFM), and conventional Raman spectroscopy characterizes insulin assemblies generated during inhibition and dissection experiments in the presence of benzonitrile, dimethylsulfoxide, quercetin, and β-carotene. The AFM topography indicates formation of filamentous or bead-like insulin self-assemblies. Information on the secondary structure of bulk samples and of single aggregates is obtained from standard Raman and TERS measurements. In particular the high spatial resolution of TERS reveals the surface conformations associated with the specific agents. The insulin aggregates formed under different inhibition and dissection conditions can show a similar morphology but differ in their β-sheet structure content. This suggests different aggregation pathways where the prevention of the β-sheet stacking of the peptide chains plays a major role. The presented approach is not limited to amyloid-related reasearch but can be readily applied to systems requiring extremely surface-sensitive characterization without the need of labels.

  10. High-throughput sequencing of microRNAs in peripheral blood mononuclear cells: identification of potential weight loss biomarkers.

    Directory of Open Access Journals (Sweden)

    Fermín I Milagro

    Full Text Available INTRODUCTION: MicroRNAs (miRNAs are being increasingly studied in relation to energy metabolism and body composition homeostasis. Indeed, the quantitative analysis of miRNAs expression in different adiposity conditions may contribute to understand the intimate mechanisms participating in body weight control and to find new biomarkers with diagnostic or prognostic value in obesity management. OBJECTIVE: The aim of this study was the search for miRNAs in blood cells whose expression could be used as prognostic biomarkers of weight loss. METHODS: Ten Caucasian obese women were selected among the participants in a weight-loss trial that consisted in following an energy-restricted treatment. Weight loss was considered unsuccessful when 5% (responders. At baseline, total miRNA isolated from peripheral blood mononuclear cells (PBMC was sequenced with SOLiD v4. The miRNA sequencing data were validated by RT-PCR. RESULTS: Differential baseline expression of several miRNAs was found between responders and non-responders. Two miRNAs were up-regulated in the non-responder group (mir-935 and mir-4772 and three others were down-regulated (mir-223, mir-224 and mir-376b. Both mir-935 and mir-4772 showed relevant associations with the magnitude of weight loss, although the expression of other transcripts (mir-874, mir-199b, mir-766, mir-589 and mir-148b also correlated with weight loss. CONCLUSIONS: This research addresses the use of high-throughput sequencing technologies in the search for miRNA expression biomarkers in obesity, by determining the miRNA transcriptome of PBMC. Basal expression of different miRNAs, particularly mir-935 and mir-4772, could be prognostic biomarkers and may forecast the response to a hypocaloric diet.

  11. Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies.

    Science.gov (United States)

    Rouillon, Jérémy; Poupiot, Jérôme; Zocevic, Aleksandar; Amor, Fatima; Léger, Thibaut; Garcia, Camille; Camadro, Jean-Michel; Wong, Brenda; Pinilla, Robin; Cosette, Jérémie; Coenen-Stass, Anna M L; Mcclorey, Graham; Roberts, Thomas C; Wood, Matthew J A; Servais, Laurent; Udd, Bjarne; Voit, Thomas; Richard, Isabelle; Svinartchouk, Fedor

    2015-09-01

    Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments are currently in clinical trials. By using a comprehensive high-resolution mass spectrometry approach and western blot validation, we found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) are abnormally present in sera of Duchenne muscular dystrophy (DMD) patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and their respective animal models. Levels of MYOM3 fragments were assayed in therapeutic model systems: (1) restoration of dystrophin expression by antisense oligonucleotide-mediated exon-skipping in mdx mice and (2) stable restoration of α-sarcoglycan expression in KO-SGCA mice by systemic injection of a viral vector. Following administration of the therapeutic agents MYOM3 was restored toward wild-type levels. In the LGMD model, where different doses of vector were used, MYOM3 restoration was dose-dependent. MYOM3 fragments showed lower inter-individual variability compared with the commonly used creatine kinase assay, and correlated better with the restoration of the dystrophin-associated protein complex and muscle force. These data suggest that the MYOM3 fragments hold promise for minimally invasive assessment of experimental therapies for DMD and other neuromuscular disorders.

  12. Trophic ecology of two cold-water coral species from the Mediterranean Sea revealed by lipid biomarkers and compound-specific isotope analyses

    Science.gov (United States)

    Naumann, Malik S.; Tolosa, Imma; Taviani, Marco; Grover, Renaud; Ferrier-Pagès, Christine

    2015-12-01

    Scleractinian cold-water corals (CWC) act as key ecosystem engineers in deep-sea reef environments worldwide. However, our current understanding of their trophic ecology is still limited, particularly in understudied temperate oceanic regions such as the Mediterranean Sea. Hence, this study investigated the trophic ecology of the CWC Desmophyllum dianthus and Madrepora oculata by employing lipid biomarker techniques and compound-specific isotope analyses on coral tissues, suspended particulate organic matter (sPOM), and surface sediment sampled in a Mediterranean CWC habitat. CWC exhibited high contents of poly- and monounsaturated fatty acids (FA) (≥49 and 32 % of FA, respectively) and cholesterol (≥67 % of sterols), while sPOM and sediment samples were enriched in saturated FA (≥44 % of FA) and sitosterol (≥35 % of sterols). CWC contained some rare very long-chained polyunsaturated FA (>C22) and ergosterol absent in sPOM and sediment samples. Our results indicate that Mediterranean CWC mainly consume living food items, rather than detrital sPOM or resuspended sediment, and provide evidence for preferred feeding on omnivorous and carnivorous zooplankton. Overall, these findings provide new insights to the trophic ecology of two common CWC from the Mediterranean Sea.

  13. High-Throughput Proteomic Approaches to the Elucidation of Potential Biomarkers of Chronic Allograft Injury (CAI

    Directory of Open Access Journals (Sweden)

    Hilary Cassidy

    2013-09-01

    Full Text Available This review focuses on the role of OMICs technologies, concentrating in particular on proteomics, in biomarker discovery in chronic allograft injury (CAI. CAI is the second most prevalent cause of allograft dysfunction and loss in the first decade post-transplantation, after death with functioning graft (DWFG. The term CAI, sometimes referred to as chronic allograft nephropathy (CAN, describes the deterioration of renal allograft function and structure as a result of immunological processes (chronic antibody-mediated rejection, and other non-immunological factors such as calcineurin inhibitor (CNI induced nephrotoxicity, hypertension and infection. Current methods for assessing allograft function are costly, insensitive and invasive; traditional kidney function measurements such as serum creatinine and glomerular filtration rate (GFR display poor predictive abilities, while the current “gold-standard” involving histological diagnosis with a renal biopsy presents its own inherent risks to the overall health of the allograft. As early as two years post-transplantation, protocol biopsies have shown more than 50% of allograft recipients have mild CAN; ten years post-transplantation more than 50% of the allograft recipients have progressed to severe CAN which is associated with diminishing graft function. Thus, there is a growing medical requirement for minimally invasive biomarkers capable of identifying the early stages of the disease which would allow for timely intervention. Proteomics involves the study of the expression, localization, function and interaction of the proteome. Proteomic technologies may be powerful tools used to identify novel biomarkers which would predict CAI in susceptible individuals. In this paper we will review the use of proteomics in the elucidation of novel predictive biomarkers of CAI in clinical, animal and in vitro studies.

  14. Applying petroleum biomarkers as a tool for confirmation of petroleum hydrocarbons in high organic content soils

    Energy Technology Data Exchange (ETDEWEB)

    O' Sullivan, G.; Martin, E.J.; Waddell, J.; Sandau, C.D. [TRIUM Environmental Solutions, Cochrane, AB (Canada); Denham, G. [Nexen Inc., Calgary, AB (Canada); Samis, M.W. [Great Plains Environmental Management Ltd., Medecine Hat, AB (Canada)

    2009-10-01

    It is often difficult to separate naturally occurring phytogenic organic materials from petrogenic sources in routine gas chromatography flame ionization detection (GC-FID) analyses. Phytogenic compounds include tannins, waxes, terpenes, fats and oils. This study examined the use of petroleum biomarkers as a means of determining the nature, sources, type and geological conditions of the formation of petroleum hydrocarbons (PHCs). The analysis was conducted at a former well site consisting of low-lying peat marshlands that had the potential to interfere with the delineation of PHC impacts. Fourteen boreholes and 8 hand auger holes were placed at the site. Soil samples were analyzed for salinity, metals, and PHC constituents. Biomarker targets included acyclic isoprenoid compounds, polycyclic aromatic hydrocarbon (PAH) compounds, terpanes, hopanes, and triaromatic steranes. A grain-size analysis showed the presence of peat materials within the saturated zone. Results of the study demonstrated the presence of PHC constituents that exceeded applicable guidelines. The biomarker analysis was used to statistically determine site-specific background levels of hydrocarbons. Nearly 3000 tonnes of soil were excavated from the site. It was concluded that site-specific conditions should be taken into consideration when evaluating reclamation targets. 3 refs., 6 figs.

  15. Highly sensitive covalently functionalized light-addressable potentiometric sensor for determination of biomarker.

    Science.gov (United States)

    Liang, Jintao; Guan, Mingyuan; Huang, Guoyin; Qiu, Hengming; Chen, Zhengcheng; Li, Guiyin; Huang, Yong

    2016-06-01

    A biomarker is related to the biological status of a living organism and shows great promise for the early prediction of a related disease. Herein we presented a novel structured light-addressable potentiometric sensor (LAPS) for the determination of a model biomarker, human immunoglobulin G (hIgG). In this system, the goat anti-human immunoglobulin G antibody was used as recognition element and covalently immobilized on the surface of light-addressable potentiometric sensor chip to capture human immunoglobulin G. Due to the light addressable capability of light-addressable potentiometric sensor, human immunoglobulin G dissolved in the supporting electrolyte solution can be detected by monitoring the potential shifts of the sensor. In order to produce a stable photocurrent, the laser diode controlled by field-programmable gate array was used as the light emitter to drive the light-addressable potentiometric sensor. A linear correlation between the potential shift response and the concentration of human immunoglobulin G was achieved and the corresponding regression equation was ΔV (V)=0.00714ChIgG (μg/mL)-0.0147 with a correlation coefficient of 0.9968 over a range 0-150 μg/mL. Moreover, the light-addressable potentiometric sensor system also showed acceptable stability and reproducibility. All the results demonstrated that the system was more applicable to detection of disease biomarkers with simple operation, multiple-sample format and might hold great promise in various environmental, food, and clinical applications.

  16. Biomarkers for systemic lupus erythematosus.

    Science.gov (United States)

    Ahearn, Joseph M; Liu, Chau-Ching; Kao, Amy H; Manzi, Susan

    2012-04-01

    The urgent need for lupus biomarkers was demonstrated in September 2011 during a Workshop sponsored by the Food and Drug Administration: Potential Biomarkers Predictive of Disease Flare. After 2 days of discussion and more than 2 dozen presentations from thought leaders in both industry and academia, it became apparent that highly sought biomarkers to predict lupus flare have not yet been identified. Even short of the elusive biomarker of flare, few biomarkers for systemic lupus erythematosus (SLE) diagnosis, monitoring, and stratification have been validated and employed for making clinical decisions. This lack of reliable, specific biomarkers for SLE hampers proper clinical management of patients with SLE and impedes development of new lupus therapeutics. As such, the intensity of investigation to identify lupus biomarkers is climbing a steep trajectory, lending cautious optimism that a validated panel of biomarkers for lupus diagnosis, monitoring, stratification, and prediction of flare may soon be in hand.

  17. A Systems Biology Approach to Reveal Putative Host-Derived Biomarkers of Periodontitis by Network Topology Characterization of MMP-REDOX/NO and Apoptosis Integrated Pathways.

    Science.gov (United States)

    Zeidán-Chuliá, Fares; Gürsoy, Mervi; Neves de Oliveira, Ben-Hur; Özdemir, Vural; Könönen, Eija; Gürsoy, Ulvi K

    2015-01-01

    Periodontitis, a formidable global health burden, is a common chronic disease that destroys tooth-supporting tissues. Biomarkers of the early phase of this progressive disease are of utmost importance for global health. In this context, saliva represents a non-invasive biosample. By using systems biology tools, we aimed to (1) identify an integrated interactome between matrix metalloproteinase (MMP)-REDOX/nitric oxide (NO) and apoptosis upstream pathways of periodontal inflammation, and (2) characterize the attendant topological network properties to uncover putative biomarkers to be tested in saliva from patients with periodontitis. Hence, we first generated a protein-protein network model of interactions ("BIOMARK" interactome) by using the STRING 10 database, a search tool for the retrieval of interacting genes/proteins, with "Experiments" and "Databases" as input options and a confidence score of 0.400. Second, we determined the centrality values (closeness, stress, degree or connectivity, and betweenness) for the "BIOMARK" members by using the Cytoscape software. We found Ubiquitin C (UBC), Jun proto-oncogene (JUN), and matrix metalloproteinase-14 (MMP14) as the most central hub- and non-hub-bottlenecks among the 211 genes/proteins of the whole interactome. We conclude that UBC, JUN, and MMP14 are likely an optimal candidate group of host-derived biomarkers, in combination with oral pathogenic bacteria-derived proteins, for detecting periodontitis at its early phase by using salivary samples from patients. These findings therefore have broader relevance for systems medicine in global health as well.

  18. Role of Protein Biomarkers in the Detection of High-Grade Disease in Cervical Cancer Screening Programs

    Directory of Open Access Journals (Sweden)

    Charlotte A. Brown

    2012-01-01

    Full Text Available Since the Pap test was introduced in the 1940s, there has been an approximately 70% reduction in the incidence of squamous cell cervical cancers in many developed countries by the application of organized and opportunistic screening programs. The efficacy of the Pap test, however, is hampered by high interobserver variability and high false-negative and false-positive rates. The use of biomarkers has demonstrated the ability to overcome these issues, leading to improved positive predictive value of cervical screening results. In addition, the introduction of HPV primary screening programs will necessitate the use of a follow-up test with high specificity to triage the high number of HPV-positive tests. This paper will focus on protein biomarkers currently available for use in cervical cancer screening, which appear to improve the detection of women at greatest risk for developing cervical cancer, including Ki-67, p16INK4a, BD ProEx C, and Cytoactiv HPV L1.

  19. Wafer-scale high-resolution patterning of reduced graphene oxide films for detection of low concentration biomarkers in plasma

    Science.gov (United States)

    Kim, Jinsik; Chae, Myung-Sic; Lee, Sung Min; Jeong, Dahye; Lee, Byung Chul; Lee, Jeong Hoon; Kim, Youngsoo; Chang, Suk Tai; Hwang, Kyo Seon

    2016-08-01

    Given that reduced graphene oxide (rGO)-based biosensors allow disposable and repeatable biomarker detection at the point of care, we developed a wafer-scale rGO patterning method with mass productivity, uniformity, and high resolution by conventional micro-electro-mechanical systems (MEMS) techniques. Various rGO patterns were demonstrated with dimensions ranging from 5 μm up to several hundred μm. Manufacture of these patterns was accomplished through the optimization of dry etching conditions. The axis-homogeneity and uniformity were also measured to verify the uniform patternability in 4-inch wafer with dry etching. Over 66.2% of uniform rGO patterns, which have deviation of resistance within range of ±10%, formed the entire wafer. We selected amyloid beta (Aβ) peptides in the plasma of APP/PS1 transgenic mice as a study model and measured the peptide level by resistance changes of highly uniform rGO biosensor arrays. Aβ is a pathological hallmark of Alzheimer’s disease and its plasma concentration is in the pg mL-1 range. The sensor detected the Aβ peptides with ultra-high sensitivity; the LOD was at levels as low as 100 fg mL-1. Our results provide biological evidences that this wafer-scale high-resolution patterning method can be used in rGO-based electrical diagnostic devices for detection of low-level protein biomarkers in biofluids.

  20. Highly ionized region surrounding SN Refsdal revealed by MUSE

    NARCIS (Netherlands)

    Karman, W.; Grillo, C.; Balestra, I.; Rosati, P.; Caputi, K. I.; Di Teodoro, E.; Fraternali, F.; Gavazzi, R.; Mercurio, A.; Prochaska, J. X.; Rodney, S.; Treu, T.

    2016-01-01

    Supernova (SN) Refsdal is the first multiply imaged, highly magnified, and spatially resolved SN ever observed. The SN exploded in a highly magnified spiral galaxy at z = 1.49 behind the Frontier Fields cluster MACS1149, and provides a unique opportunity to study the environment of SNe at high z. We

  1. Application of Holistic Liquid Chromatography-High Resolution Mass Spectrometry Based Urinary Metabolomics for Prostate Cancer Detection and Biomarker Discovery.

    Directory of Open Access Journals (Sweden)

    Tong Zhang

    Full Text Available Human exhibit wide variations in their metabolic profiles because of differences in genetic factors, diet and lifestyle. Therefore in order to detect metabolic differences between individuals robust analytical methods are required. A protocol was produced based on the use of Liquid Chromatography- High Resolution Mass Spectrometry (LC-HRMS in combination with orthogonal Hydrophilic Interaction (HILIC and Reversed Phase (RP liquid chromatography methods for the analysis of the urinary metabolome, which was then evaluated as a diagnostic tool for prostate cancer (a common but highly heterogeneous condition. The LC-HRMS method was found to be robust and exhibited excellent repeatability for retention times (0.9. In addition, using the receiver operator characteristics (ROC test, the area under curve (AUC for the combination of the four best characterised biomarker compounds was 0.896. The four biomarker compounds were also found to differ significantly (P<0.05 between an independent patient cohort and controls. This is the first time such a rigorous test has been applied to this type of model. If validated, the established protocol provides a robust approach with a potentially wide application to metabolite profiling of human biofluids in health and disease.

  2. Label-Free LC-MS Profiling of Skeletal Muscle Reveals Heart-Type Fatty Acid Binding Protein as a Candidate Biomarker of Aerobic Capacity.

    Science.gov (United States)

    Malik, Zulezwan Ab; Cobley, James N; Morton, James P; Close, Graeme L; Edwards, Ben J; Koch, Lauren G; Britton, Steven L; Burniston, Jatin G

    2013-12-01

    transcriptome profiling work and show LC-MS is a viable means of profiling the abundance of almost all major metabolic enzymes of skeletal muscle in a highly parallel manner. Moreover, our approach is relatively more time efficient than techniques relying on orthogonal separations, and we demonstrate LC-MS profiling of the HCR/LCR selection model was able to highlight biomarkers that also exhibit differences in trained and untrained human muscle.

  3. Sequencing of 50 human exomes reveals adaptation to high altitude

    DEFF Research Database (Denmark)

    Yi, Xin; Liang, Yu; Huerta-Sanchez, Emilia;

    2010-01-01

    Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which...... represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency...... difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP's association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus...

  4. Is a biomarker-based diagnostic strategy for invasive aspergillosis cost effective in high-risk haematology patients?

    Science.gov (United States)

    Macesic, N; Morrissey, C O; Liew, D; Bohensky, M A; Chen, S C-A; Gilroy, N M; Milliken, S T; Szer, J; Slavin, M A

    2017-01-27

    Empirical antifungal therapy is frequently used in hematology patients at high risk of invasive aspergillosis (IA), with substantial cost and toxicity. Biomarkers for IA aim for earlier and more accurate diagnosis and targeted treatment. However, data on the cost-effectiveness of a biomarker-based diagnostic strategy (BDS) are limited. We evaluated the cost effectiveness of BDS using results from a randomized controlled trial (RCT) and individual patient costing data. Data inputs derived from a published RCT were used to construct a decision-analytic model to compare BDS (Aspergillus galactomannan and PCR on blood) with standard diagnostic strategy (SDS) of culture and histology in terms of total costs, length of stay, IA incidence, mortality, and years of life saved. Costs were estimated for each patient using hospital costing data to day 180 and follow-up for survival was modeled to five years using a Gompertz survival model. Treatment costs were determined for 137 adults undergoing allogeneic hematopoietic stem cell transplant or receiving chemotherapy for acute leukemia in four Australian centers (2005-2009). Median total costs at 180 days were similar between groups (US[Formula: see text] for SDS [IQR US[Formula: see text

  5. Custom database development and biomarker discovery methods for MALDI-TOF mass spectrometry-based identification of high-consequence bacterial pathogens.

    Science.gov (United States)

    Tracz, Dobryan M; Tyler, Andrea D; Cunningham, Ian; Antonation, Kym S; Corbett, Cindi R

    2017-03-01

    A high-quality custom database of MALDI-TOF mass spectral profiles was developed with the goal of improving clinical diagnostic identification of high-consequence bacterial pathogens. A biomarker discovery method is presented for identifying and evaluating MALDI-TOF MS spectra to potentially differentiate biothreat bacteria from less-pathogenic near-neighbour species.

  6. Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies

    Directory of Open Access Journals (Sweden)

    Fedele Vita

    2006-06-01

    Full Text Available Abstract Background Recent studies indicate that microRNAs (miRNAs are mechanistically involved in the development of various human malignancies, suggesting that they represent a promising new class of cancer biomarkers. However, previously reported methods for measuring miRNA expression consume large amounts of tissue, prohibiting high-throughput miRNA profiling from typically small clinical samples such as excision or core needle biopsies of breast or prostate cancer. Here we describe a novel combination of linear amplification and labeling of miRNA for highly sensitive expression microarray profiling requiring only picogram quantities of purified microRNA. Results Comparison of microarray and qRT-PCR measured miRNA levels from two different prostate cancer cell lines showed concordance between the two platforms (Pearson correlation R2 = 0.81; and extension of the amplification, labeling and microarray platform was successfully demonstrated using clinical core and excision biopsy samples from breast and prostate cancer patients. Unsupervised clustering analysis of the prostate biopsy microarrays separated advanced and metastatic prostate cancers from pooled normal prostatic samples and from a non-malignant precursor lesion. Unsupervised clustering of the breast cancer microarrays significantly distinguished ErbB2-positive/ER-negative, ErbB2-positive/ER-positive, and ErbB2-negative/ER-positive breast cancer phenotypes (Fisher exact test, p = 0.03; as well, supervised analysis of these microarray profiles identified distinct miRNA subsets distinguishing ErbB2-positive from ErbB2-negative and ER-positive from ER-negative breast cancers, independent of other clinically important parameters (patient age; tumor size, node status and proliferation index. Conclusion In sum, these findings demonstrate that optimized high-throughput microRNA expression profiling offers novel biomarker identification from typically small clinical samples such as breast

  7. Revealing proton shape fluctuations with incoherent diffraction at high energy

    Science.gov (United States)

    Mäntysaari, Heikki; Schenke, Björn

    2016-08-01

    The differential cross section of exclusive diffractive vector meson production in electron proton collisions carries important information on the geometric structure of the proton. More specifically, the coherent cross section as a function of the transferred transverse momentum is sensitive to the size of the proton, while the incoherent or proton dissociative cross section is sensitive to fluctuations of the gluon distribution in coordinate space. We show that at high energies the experimentally measured coherent and incoherent cross sections for the production of J /Ψ mesons are very well reproduced within the color glass condensate framework when strong geometric fluctuations of the gluon distribution in the proton are included. For ρ meson production, we also find reasonable agreement. We study in detail the dependence of our results on various model parameters, including the average proton shape, analyze the effect of saturation scale and color charge fluctuations and constrain the degree of geometric fluctuations.

  8. Revealing proton shape fluctuations with incoherent diffraction at high energy

    CERN Document Server

    Mäntysaari, Heikki

    2016-01-01

    The differential cross section of exclusive diffractive vector meson production in electron proton collisions carries important information on the geometric structure of the proton. More specifically, the coherent cross section as a function of the transferred transverse momentum is sensitive to the size of the proton, while the incoherent, or proton dissociative cross section is sensitive to fluctuations of the gluon distribution in coordinate space. We show that at high energies the experimentally measured coherent and incoherent cross sections for the production of $J/\\Psi$ mesons are very well reproduced within the color glass condensate framework when strong geometric fluctuations of the gluon distribution in the proton are included. For $\\rho$ meson production we also find reasonable agreement. We study in detail the dependence of our results on various model parameters, including the average proton shape, analyze the effect of saturation scale and color charge fluctuations and constrain the degree of g...

  9. Evaluation and identification of dioxin exposure biomarkers in human urine by high-resolution metabolomics, multivariate analysis and in vitro synthesis.

    Science.gov (United States)

    Jeanneret, Fabienne; Tonoli, David; Hochstrasser, Denis; Saurat, Jean-Hilaire; Sorg, Olivier; Boccard, Julien; Rudaz, Serge

    2016-01-05

    A previous high-resolution metabolomic study pointed out a dysregulation of urinary steroids and bile acids in human cases of acute dioxin exposure. A subset of 24 compounds was highlighted as putative biomarkers. The aim of the current study was (i) to evaluate the 24 biomarkers in an independent human cohort exposed to dioxins released from the incineration fumes of a municipal waste incinerator and; (ii) to identify them by comparison with authentic chemical standards and biosynthesised products obtained with in vitro metabolic reactions. An orthogonal projection to latent structures discriminant analysis built on biomarker profiles measured in the intoxicated cohort and the controls separated both groups with reported values of 93.8%; 100% and 87.5% for global accuracy; sensitivity and specificity; respectively. These results corroborated the 24 compounds as exposure biomarkers; but a definite identification was necessary for a better understanding of dioxin toxicity. Dehydroepiandrosterone 3β-sulfate, androsterone 3α-glucuronide, androsterone 3α-sulfate, pregnanediol 3α-glucuronide and 11-ketoetiocholanolone 3α-glucuronide were identified by authentic standards. Metabolic reactions characterised four biomarkers: glucuronide conjugates of 11β-hydroxyandrosterone; glycochenodeoxycholic acid and glycocholic acid produced in human liver microsomes and glycoursodeoxycholic acid sulfate generated in cytosol fraction. The combination of metabolomics by high-resolution mass spectrometry with in vitro metabolic syntheses confirmed a perturbed profile of steroids and bile acids in human cases of dioxin exposure.

  10. Label-Free LC-MS Profiling of Skeletal Muscle Reveals Heart-Type Fatty Acid Binding Protein as a Candidate Biomarker of Aerobic Capacity

    Directory of Open Access Journals (Sweden)

    Zulezwan A. Malik

    2013-12-01

    .54-fold (p = 0.0064 more abundant in HCR than LCR soleus. This discovery was verified using selective reaction monitoring (SRM of the y5 ion (551.21 m/z of the doubly-charged peptide SLGVGFATR (454.19 m/z of residues 23–31 of FABPH. SRM was conducted on technical replicates of each biological sample and exhibited a coefficient of variation of 20%. The abundance of FABPH measured by SRM was 2.84-fold greater (p = 0.0095 in HCR muscle. In addition, SRM of FABPH was performed in vastus lateralis samples of young and elderly humans with different habitual activity levels (collected during a previous study finding FABPH abundance was 2.23-fold greater (p = 0.0396 in endurance-trained individuals regardless of differences in age. In summary, our findings in HCR/LCR rats provide protein-level confirmation for earlier transcriptome profiling work and show LC-MS is a viable means of profiling the abundance of almost all major metabolic enzymes of skeletal muscle in a highly parallel manner. Moreover, our approach is relatively more time efficient than techniques relying on orthogonal separations, and we demonstrate LC-MS profiling of the HCR/LCR selection model was able to highlight biomarkers that also exhibit differences in trained and untrained human muscle.

  11. Early diagnosis of complex diseases by molecular biomarkers, network biomarkers, and dynamical network biomarkers.

    Science.gov (United States)

    Liu, Rui; Wang, Xiangdong; Aihara, Kazuyuki; Chen, Luonan

    2014-05-01

    Many studies have been carried out for early diagnosis of complex diseases by finding accurate and robust biomarkers specific to respective diseases. In particular, recent rapid advance of high-throughput technologies provides unprecedented rich information to characterize various disease genotypes and phenotypes in a global and also dynamical manner, which significantly accelerates the study of biomarkers from both theoretical and clinical perspectives. Traditionally, molecular biomarkers that distinguish disease samples from normal samples are widely adopted in clinical practices due to their ease of data measurement. However, many of them suffer from low coverage and high false-positive rates or high false-negative rates, which seriously limit their further clinical applications. To overcome those difficulties, network biomarkers (or module biomarkers) attract much attention and also achieve better performance because a network (or subnetwork) is considered to be a more robust form to characterize diseases than individual molecules. But, both molecular biomarkers and network biomarkers mainly distinguish disease samples from normal samples, and they generally cannot ensure to identify predisease samples due to their static nature, thereby lacking ability to early diagnosis. Based on nonlinear dynamical theory and complex network theory, a new concept of dynamical network biomarkers (DNBs, or a dynamical network of biomarkers) has been developed, which is different from traditional static approaches, and the DNB is able to distinguish a predisease state from normal and disease states by even a small number of samples, and therefore has great potential to achieve "real" early diagnosis of complex diseases. In this paper, we comprehensively review the recent advances and developments on molecular biomarkers, network biomarkers, and DNBs in particular, focusing on the biomarkers for early diagnosis of complex diseases considering a small number of samples and high

  12. The Temporal Pattern of Changes in Serum Biomarker Levels Reveal Complex and Dynamically Changing Pathologies after Exposure to a Single Low-intensity Blast in Mice

    Directory of Open Access Journals (Sweden)

    Farid eAhmed

    2015-06-01

    Full Text Available Time dependent changes of protein biomarkers in the serum can help identifying the pathological processes and assessing the severity and progression of the disease in blast induced traumatic brain injury (bTBI. We obtained blood from naïve mice and mice exposed to a single, low-intensity blast at 2 hour, 1 day, 1 week and 1 month post-injury. We then determined the serum levels of biomarkers related to metabolism (4-HNE, HIF-1α, Ceruloplasmin, vascular functions (VEGF, vWF, AQP1, AQP4, FLK-1, cell adhesion (Integrin 6α, TIMP1, TIMP4, Ncad, Connexin-43, inflammation (MMP-8, MIP-1α, CINC1, Fibrinogen, CCR5, CRP, Galectin-1, MCP-1, p38, OX-44, Osteopontin, axonal (NF-H, Tau, neuronal (NSE, CK-BB and glial integrity (GFAP, S100β, MBP and compared the changes among the experimental groups. Our results indicate that in the mouse, exposure to a single, low-intensity blast caused substantial metabolic, vascular and inflammatory responses, altered cell adhesion but only minimal neuronal, axonal and glia injury as indicated by serum proteomics data. Changes in metabolism, vascular functions and inflammation remained elevated at the termination of the experiment while the others were only detectable during the acute post-injury phase. Our findings indicate that exposure to a single; low-intensity blast can induce complex pathological processes with distinct temporal profile. Hence, monitoring serum biomarker levels at various post-injury time points may provide enhanced diagnostics in bTBI.

  13. Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression: Disease and staging biomarkers and new drug targets.

    Science.gov (United States)

    de Farias, Carine Coneglian; Maes, Michael; Bonifácio, Kamila Landucci; Bortolasci, Chiara Cristina; de Souza Nogueira, André; Brinholi, Francis Fregonesi; Matsumoto, Andressa Keiko; do Nascimento, Matheus Amarante; de Melo, Lúcio Baena; Nixdorf, Suzana Lucy; Lavado, Edson Lopes; Moreira, Estefânia Gastaldello; Barbosa, Décio Sabbatini

    2016-03-23

    There is evidence that immune-inflammatory, stress of reactive oxygen and nitrogen species (IO&NS) processes play a role in the neurodegenerative processes observed in Parkinson's disease (PD). The aim of the present study was to investigate peripheral IO&NS biomarkers in PD. We included 56 healthy individuals and 56 PD patients divided in two groups: early PD stage and late PD stage. Plasma lipid hydroperoxides (LOOH), malondialdehyde (MDA), nitric oxide metabolites (NOx), sulfhydryl (SH) groups, catalase (CAT) activity, superoxide dismutase (SOD) activity, paraoxonase (PON)1 activity, total radical trapping antioxidant parameter (TRAP) and C-reactive protein (CRP) were measured. PD is characterized by increased LOOH, MDA and SOD activity and lowered CAT activity. A combination of five O&NS biomarkers highly significantly predicts PD with a sensitivity of 94.5% and a specificity of 86.8% (i.e., MDA, SOD activity, TRAP, SH-groups and CAT activity). The single best biomarker of PD is MDA, while LOOH and SOD activity are significantly associated with late PD stage, but not early PD stage. Antiparkinson drugs did not affect O&NS biomarkers, but levodopa+carbidopa significantly increased CRP. It is suggested that MDA may serve as a disease biomarker, while LOOH and SOD activity are associated with late PD stage characteristic. New treatments for PD should not only target dopamine but also lipid peroxidation.

  14. Urinary (1)H Nuclear Magnetic Resonance Metabolomic Fingerprinting Reveals Biomarkers of Pulse Consumption Related to Energy-Metabolism Modulation in a Subcohort from the PREDIMED study.

    Science.gov (United States)

    Madrid-Gambin, Francisco; Llorach, Rafael; Vázquez-Fresno, Rosa; Urpi-Sarda, Mireia; Almanza-Aguilera, Enrique; Garcia-Aloy, Mar; Estruch, Ramon; Corella, Dolores; Andres-Lacueva, Cristina

    2017-04-07

    Little is known about the metabolome fingerprint of pulse consumption. The study of robust and accurate biomarkers for pulse dietary assessment has great value for nutritional epidemiology regarding health benefits and their mechanisms. To characterize the fingerprinting of dietary pulses (chickpeas, lentils, and beans), spot urine samples from a subcohort from the PREDIMED study were stratified using a validated food frequency questionnaire. Urine samples of nonpulse consumers (≤4 g/day of pulse intake) and habitual pulse consumers (≥25 g/day of pulse intake) were analyzed using a (1)H nuclear magnetic resonance (NMR) metabolomics approach combined with multi- and univariate data analysis. Pulse consumption showed differences through 16 metabolites coming from (i) choline metabolism, (ii) protein-related compounds, and (iii) energy metabolism (including lower urinary glucose). Stepwise logistic regression analysis was applied to design a combined model of pulse exposure, which resulted in glutamine, dimethylamine, and 3-methylhistidine. This model was evaluated by a receiver operating characteristic curve (AUC > 90% in both training and validation sets). The application of NMR-based metabolomics to reported pulse exposure highlighted new candidates for biomarkers of pulse consumption and the impact on energy metabolism, generating new hypotheses on energy modulation. Further intervention studies will confirm these findings.

  15. Network-Based Logistic Classification with an Enhanced L1/2 Solver Reveals Biomarker and Subnetwork Signatures for Diagnosing Lung Cancer

    Directory of Open Access Journals (Sweden)

    Hai-Hui Huang

    2015-01-01

    Full Text Available Identifying biomarker and signaling pathway is a critical step in genomic studies, in which the regularization method is a widely used feature extraction approach. However, most of the regularizers are based on L1-norm and their results are not good enough for sparsity and interpretation and are asymptotically biased, especially in genomic research. Recently, we gained a large amount of molecular interaction information about the disease-related biological processes and gathered them through various databases, which focused on many aspects of biological systems. In this paper, we use an enhanced L1/2 penalized solver to penalize network-constrained logistic regression model called an enhanced L1/2 net, where the predictors are based on gene-expression data with biologic network knowledge. Extensive simulation studies showed that our proposed approach outperforms L1 regularization, the old L1/2 penalized solver, and the Elastic net approaches in terms of classification accuracy and stability. Furthermore, we applied our method for lung cancer data analysis and found that our method achieves higher predictive accuracy than L1 regularization, the old L1/2 penalized solver, and the Elastic net approaches, while fewer but informative biomarkers and pathways are selected.

  16. Preeclampsia, biomarkers, syncytiotrophoblast stress, and placental capacity.

    Science.gov (United States)

    Redman, Christopher W G; Staff, Anne Cathrine

    2015-10-01

    The maternal syndrome of preeclampsia is mediated by dysfunctional syncytiotrophoblast (STB). When this is stressed by uteroplacental malperfusion, its signaling to the mother changes, as part of a highly coordinated stress response. The STB signals are both proinflammatory and dysangiogenic such that the preeclamptic mother has a stronger vascular inflammatory response than normal, with an antiangiogenic bias. Angiogenic factors have limitations as preeclampsia biomarkers, especially for prediction and diagnosis of preeclampsia at term. However, if they are recognized as markers of STB stress, their physiological changes at term demonstrate that STB stress develops in all pregnancies. The biomarkers reveal that the duration of pregnancies is restricted by placental capacity, such that there is increasing placental dysfunction, at and beyond term. This capacity includes limitations imposed by the size of the uterus, the capacity of the uteroplacental circulation and, possibly, the supply of villous progenitor trophoblast cells. Limited placental capacity explains the increasing risks of postmaturity, including preeclampsia. Early-onset preeclampsia is predictable because STB stress and changes in its biomarkers are intrinsic to poor placentation, an early pregnancy pathology. Prediction of preeclampsia at term is not good because there is no early STB pathology. Moreover, biomarkers cannot accurately diagnose term preeclampsia against a background of universal STB dysfunction, which may or may not be clinically revealed before spontaneous or induced delivery. In this sense, postterm pregnancy is, at best, a pseudonormal state. However, the markers may prove useful in screening for women with more severe problems of postmaturity.

  17. Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans.

    Science.gov (United States)

    Butelman, Eduardo R; Mandau, Marek; Tidgewell, Kevin; Prisinzano, Thomas E; Yuferov, Vadim; Kreek, Mary Jeanne

    2007-01-01

    This study focused on the in vivo effects of the kappa-opioid hallucinogen salvinorin A, derived from the plant Salvia divinorum. The effects of salvinorin A (0.0032-0.056 mg/kg i.v.) were studied in a neuroendocrine biomarker assay of the anterior pituitary hormone prolactin in gonadally intact, adult male and female rhesus monkeys (n = 4 each). Salvinorin A produced dose- and time-dependent neuroendocrine effects, similar to the synthetic high-efficacy kappa-agonist U69,593 ((+)-(5alpha,7 alpha,8beta)-N-methyl-N-[7-(1-pyrrolidiniyl)-1-oxaspiro[4.5]dec-8yl]-benzeneacetamide), but of shorter duration than the latter. Salvinorin A was approximately equipotent to U69,593 in this endpoint (salvinorin A ED50, 0.015 mg/kg; U69,593 ED(50), 0.0098 mg/kg). The effects of i.v. salvinorin A were not prevented by a small dose of the opioid antagonist nalmefene (0.01 mg/kg s.c.) but were prevented by a larger dose of nalmefene (0.1 mg/kg); the latter nalmefene dose is sufficient to produce kappa-antagonist effects in this species. In contrast, the 5HT2 receptor antagonist ketanserin (0.1 mg/kg i.m.) did not prevent the effects of salvinorin A. As expected, the neuroendocrine effects of salvinorin A (0.0032 mg/kg i.v.) were more robust in female than in male subjects. Related studies focused on full-length cloning of the coding region of the rhesus monkey kappa-opioid receptor (OPRK1) gene and revealed a high homology of the nonhuman primate OPRK1 gene compared with the human OPRK1 gene, including particular C-terminal residues thought to be involved in receptor desensitization and internalization. The present studies indicate that the hallucinogen salvinorin A acts as a high-efficacy kappa-agonist in nonhuman primates in a translationally viable neuroendocrine biomarker assay.

  18. Biomarker Identification Using Text Mining

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    Hui Li

    2012-01-01

    Full Text Available Identifying molecular biomarkers has become one of the important tasks for scientists to assess the different phenotypic states of cells or organisms correlated to the genotypes of diseases from large-scale biological data. In this paper, we proposed a text-mining-based method to discover biomarkers from PubMed. First, we construct a database based on a dictionary, and then we used a finite state machine to identify the biomarkers. Our method of text mining provides a highly reliable approach to discover the biomarkers in the PubMed database.

  19. Longitudinal micro-CT provides biomarkers of lung disease that can be used to assess the effect of therapy in preclinical mouse models, and reveal compensatory changes in lung volume.

    Science.gov (United States)

    Vande Velde, Greetje; Poelmans, Jennifer; De Langhe, Ellen; Hillen, Amy; Vanoirbeek, Jeroen; Himmelreich, Uwe; Lories, Rik J

    2016-01-01

    In vivo lung micro-computed tomography (micro-CT) is being increasingly embraced in pulmonary research because it provides longitudinal information on dynamic disease processes in a field in which ex vivo assessment of experimental disease models is still the gold standard. To optimize the quantitative monitoring of progression and therapy of lung diseases, we evaluated longitudinal changes in four different micro-CT-derived biomarkers [aerated lung volume, lung tissue (including lesions) volume, total lung volume and mean lung density], describing normal development, lung infections, inflammation, fibrosis and therapy. Free-breathing mice underwent micro-CT before and repeatedly after induction of lung disease (bleomycin-induced fibrosis, invasive pulmonary aspergillosis, pulmonary cryptococcosis) and therapy (imatinib). The four lung biomarkers were quantified. After the last time point, we performed pulmonary function tests and isolated the lungs for histology. None of the biomarkers remained stable during longitudinal follow-up of adult healthy mouse lungs, implying that biomarkers should be compared with age-matched controls upon intervention. Early inflammation and progressive fibrosis led to a substantial increase in total lung volume, which affects the interpretation of aerated lung volume, tissue volume and mean lung density measures. Upon treatment of fibrotic lung disease, the improvement in aerated lung volume and function was not accompanied by a normalization of the increased total lung volume. Significantly enlarged lungs were also present in models of rapidly and slowly progressing lung infections. The data suggest that total lung volume changes could partly reflect a compensatory mechanism that occurs during disease progression in mice. Our findings underscore the importance of quantifying total lung volume in addition to aerated lung or lesion volumes to accurately document growth and potential compensatory mechanisms in mouse models of lung

  20. Biomarkers in Prostate Cancer Epidemiology

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    Mudit Verma

    2011-09-01

    Full Text Available Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high risk for developing prostate cancer. In cancer epidemiology, epigenetic biomarkers offer advantages over other types of biomarkers because they are expressed against a person’s genetic background and environmental exposure, and because abnormal events occur early in cancer development, which includes several epigenetic alterations in cancer cells. This article describes different biomarkers that have potential use in studying the epidemiology of prostate cancer. We also discuss the characteristics of an ideal biomarker for prostate cancer, and technologies utilized for biomarker assays. Among epigenetic biomarkers, most reports indicate GSTP1 hypermethylation as the diagnostic marker for prostate cancer; however, NKX2-5, CLSTN1, SPOCK2, SLC16A12, DPYS, and NSE1 also have been reported to be regulated by methylation mechanisms in prostate cancer. Current challenges in utilization of biomarkers in prostate cancer diagnosis and epidemiologic studies and potential solutions also are discussed.

  1. A Validated High-Let Radiation Specific Biomarker in the Mayak Worker Cohort

    Energy Technology Data Exchange (ETDEWEB)

    David J. Brenner, Ph.D., D.Sc.; Tamara Azizova, M.D.

    2006-12-11

    Our goal (see Project Objectives) is to deliver a dosimetry system which will enable both a Pu body burden of 0.3 kBq, and a 30 cGy {gamma} ray dose, to be separately estimated with a confidence limit of {+-}30%. In terms of the numbers analyzed and the data we have accrued, we have direct quantitative evidence that we are on track to providing such a comprehensive independent dosimetry system for Mayak workers. We had previously demonstrated that intra-chromosomal aberrations measured in peripheral blood lymphocytes can be used as a sensitive long-lived low-background quantitative biomarker of densely-ionizing radiation dose in individuals exposed many years ago. We propose to calibrate the system such that it can be used to estimate both the densely-ionizing internal plutonium exposure and the sparsely-ionizing external exposure in Mayak workers exposed to different combinations of these over a prolonged period, mostly many years ago. Our objective is to deliver a dosimetry system (set of calibration parameters) which will enable both a comparatively low Pu body burden of 0.3 kBq, and a comparatively low 30 cGy {gamma} ray dose (one of these or both of these) to be estimated with a confidence limit of {+-}30% (higher doses will of course be estimated with smaller confidence intervals and still lower doses with larger confidence intervals). (1) Draw blood, make metaphase slides and measure numbers of intra- and inter-chromosome aberrations (using the mBAND and mFISH techniques) in - (A) 255 healthy former Mayak workers who were exposed various combinations of internal and external exposures. The individuals were chosen from the data base of healthy former workers through computer simulation to optimize estimates of the dosimetry parameters. The individuals have both internal and external dose estimates from the SUBI Doses-99 system. (B) 85 healthy non-exposed controls with ages, gender, and smoking status, chosen based on computer simulation to optimize estimates

  2. Eight week exposure to a high sugar high fat diet results in adiposity gain and alterations in metabolic biomarkers in baboons (Papio hamadryas sp.

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    Tejero M Elizabeth

    2010-10-01

    Full Text Available Abstract Background Baboons (Papio hamadryas Sp. develop features of the cardiometabolic syndrome and represent a clinically-relevant animal model in which to study the aetiology of the disorder. To further evaluate the baboon as a model for the study of the cardiometabolic syndrome, we developed a high sugar high fat diet and hypothesized that it could be used to induce adiposity gain and affect associated circulating biomarkers. Methods We developed a diet enriched with monosaccharides and saturated fatty acids that was composed of solid and liquid energy sources. We provided a group of baboons (n = 9 ad libitum access to this diet for 8 weeks. Concurrently, a control group (n = 6 was maintained with ad libitum access to a low sugar low fat baseline diet and normal water for 8 weeks. Body composition was determined by dual-energy X-ray absorptiometry and circulating metabolic biomarkers were measured using standard methodology before and after the 8 week study period. Results Neither body composition nor circulating biomarkers changed in the control group. Following the 8 weeks, the intervention group had a significant increase in fat mass (1.71 ± 0.98 vs. 3.23 ± 1.70 kg, p = 0.004, triglyceride (55 ± 13 vs. 109 ± 67 mg/dL, p = 0.006,, and leptin (1.19 ± 1.40 vs. 3.29 ± 2.32 ng/mL, p = 0.001 and a decline in adiponectin concentrations (33530 ± 9744 vs. 23330 ± 7863 ng/mL, p = 0.002. Percentage haemoglobin A1C (4.0 ± 0.3 vs. 6.0 ± 1.4, p = 0.002 also increased in the intervention group. Conclusions Our findings indicate that when exposed to a high sugar high fat diet, young adult male baboons develop increased body fat and triglyceride concentrations, altered adipokine concentrations, and evidence of altered glucose metabolism. Our findings are in keeping with observations in humans and further demonstrate the potential utility of this highly clinically-relevant animal model for studying diet-induced metabolic dysregulation.

  3. Proteomics tools reveal startlingly high amounts of oxytocin in plasma and serum

    Science.gov (United States)

    Brandtzaeg, Ole Kristian; Johnsen, Elin; Roberg-Larsen, Hanne; Seip, Knut Fredrik; Maclean, Evan L.; Gesquiere, Laurence R.; Leknes, Siri; Lundanes, Elsa; Wilson, Steven Ray

    2016-08-01

    The neuropeptide oxytocin (OT) is associated with a plethora of social behaviors, and is a key topic at the intersection of psychology and biology. However, tools for measuring OT are still not fully developed. We describe a robust nano liquid chromatography-mass spectrometry (nanoLC-MS) platform for measuring the total amount of OT in human plasma/serum. OT binds strongly to plasma proteins, but a reduction/alkylation (R/A) procedure breaks this bond, enabling ample detection of total OT. The method (R/A + robust nanoLC-MS) was used to determine total OT plasma/serum levels to startlingly high concentrations (high pg/mL-ng/mL). Similar results were obtained when combining R/A and ELISA. Compared to measuring free OT, measuring total OT can have advantages in e.g. biomarker studies.

  4. Natural history of high-grade cervical intraepithelial neoplasia : a review of prognostic biomarkers

    NARCIS (Netherlands)

    Koeneman, Margot M.; Kruitwagen, Roy F. P. M.; Nijman, Hans W.; Slangen, Brigitte F. M.; Van Gorp, Toon; Kruse, Arnold-Jan

    2015-01-01

    The natural history of high-grade cervical intraepithelial neoplasia (CIN) is largely unpredictable and current histopathological examination is unable to differentiate between lesions that will regress and those that will not. Therefore, most high-grade lesions are currently treated by surgical exc

  5. Genome-wide methylation profiling identifies hypermethylated biomarkers in high-grade cervical intraepithelial neoplasia

    NARCIS (Netherlands)

    Lendvai, Ágnes; Johannes, Frank; Grimm, Christina; Eijsink, Jasper J H; Wardenaar, René; Volders, Haukeline H; Klip, Harry G; Hollema, Harry; Jansen, Ritsert C; Schuuring, Ed; Wisman, G Bea A; van der Zee, Ate G J

    2012-01-01

    Epigenetic modifications, such as aberrant DNA promoter methylation, are frequently observed in cervical cancer. Identification of hypermethylated regions allowing discrimination between normal cervical epithelium and high-grade cervical intraepithelial neoplasia (CIN2/3), or worse, may improve curr

  6. Biomarkers of inflammation, metabolism, and oxidative stress in blood, liver, and milk reveal a better immunometabolic status in peripartal cows supplemented with Smartamine M or MetaSmart.

    Science.gov (United States)

    Osorio, J S; Trevisi, E; Ji, P; Drackley, J K; Luchini, D; Bertoni, G; Loor, J J

    2014-12-01

    The peripartal dairy cow experiences a state of reduced liver function coupled with increased inflammation and oxidative stress. This study evaluated the effect of supplementing basal diets with rumen-protected Met in the form of MetaSmart (MS) or Smartamine M (SM) (both from Adisseo Inc., Antony, France) during the peripartal period on blood and hepatic biomarkers of liver function, inflammation, and oxidative stress. Thirty-seven multiparous Holstein cows were fed the same basal diet from -50 to -21 d relative to expected calving [1.24 Mcal/kg of dry matter (DM); no Met supplementation]. From -21 d to calving, the cows received diets (1.54 Mcal/kg of DM) with no added Met (control, CON; n=13), CON plus MS (n=11), or CON plus SM (n=13). From calving through 30 d in milk (DIM), the cows received the same postpartal diet (1.75 Mcal/kg of DM; CON), or CON plus MS or CON plus SM. Liver and blood samples were harvested at various time points from -21 to 21 d relative to calving. Preplanned contrasts of CON versus SM + MS during prepartum (-21 and -10 d before calving) and postpartum (7, 14, and 21 d after calving) responses were evaluated. Cows fed MS or SM compared with CON had lower overall concentrations of plasma ceruloplasmin and serum amyloid A (SAA). Compared with CON, Met-supplemented cows had greater overall plasma oxygen radical absorbance capacity. Liver concentrations of glutathione and carnitine also were greater overall with Met supplementation. Milk choline and liver phosphatidylcholine were lower overall in cows fed Met compared with controls. Liver tissue choline concentrations did not differ. Data indicate that supplemental Met enhanced de novo glutathione and carnitine synthesis in liver and, thus, increased antioxidant and β-oxidation capacity. The greater decrease of IL-6 after calving coupled with lower ceruloplasmin and SAA in Met-supplemented cows indicated a reduction in proinflammatory signaling within liver. The lower hepatic

  7. High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging.

    Science.gov (United States)

    Harris, Janna L; Yeh, Hung-Wen; Swerdlow, Russell H; Choi, In-Young; Lee, Phil; Brooks, William M

    2014-07-01

    Altered brain metabolism is likely to be an important contributor to normal cognitive decline and brain pathology in elderly individuals. To characterize the metabolic changes associated with normal brain aging, we used high-field proton magnetic resonance spectroscopy in vivo to quantify 20 neurochemicals in the hippocampus and sensorimotor cortex of young adult and aged rats. We found significant differences in the neurochemical profile of the aged brain when compared with younger adults, including lower aspartate, ascorbate, glutamate, and macromolecules, and higher glucose, myo-inositol, N-acetylaspartylglutamate, total choline, and glutamine. These neurochemical biomarkers point to specific cellular mechanisms that are altered in brain aging, such as bioenergetics, oxidative stress, inflammation, cell membrane turnover, and endogenous neuroprotection. Proton magnetic resonance spectroscopy may be a valuable translational approach for studying mechanisms of brain aging and pathology, and for investigating treatments to preserve or enhance cognitive function in aging.

  8. Proteomics in Discovery of Hepatocellular Carcinoma Biomarkers

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Objective: To discover new proteomic biomarkers of hepatocellular carcinoma. Methods: Surface enhanced laser desorption/ionization time-of-flight (SELDI-TOF) mass spectrometry was used to discover biomarkers for differentiating hepatocellular carcinoma and chronic liver disease. A population of 50 patients with hepatocellular carcinoma and 33 patients with chronic liver disease was studied. Results: Twelve proteomic biomarkers of hepatocellular carcinoma were detected in this study. Three proteomic biomarkers were highly expressed in hepatocellular carcinoma and nine proteomic biomarkers were highly expressed in chronic liver disease. The most valuable proteomic biomarker with m/z=11498 had no similar diagnostic value as α-fetoprotein. Conclusion:Some of the twelve proteomic biomarkers may become new biomarkers of hepatocellular carcinoma.

  9. Glucosylsphingosine is a highly sensitive and specific biomarker for primary diagnostic and follow-up monitoring in Gaucher disease in a non-Jewish, Caucasian cohort of Gaucher disease patients.

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    Arndt Rolfs

    Full Text Available BACKGROUND: Gaucher disease (GD is the most common lysosomal storage disorder (LSD. Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments. METHODOLOGY: Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs. FINDINGS: Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine. INTERPRETATION: In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.

  10. The expression profile of phosphatidylinositol in high spatial resolution imaging mass spectrometry as a potential biomarker for prostate cancer.

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    Takayuki Goto

    Full Text Available High-resolution matrix-assisted laser desorption/ionization imaging mass spectrometry (HR-MALDI-IMS is an emerging application for the comprehensive and detailed analysis of the spatial distribution of ionized molecules in situ on tissue slides. HR-MALDI-IMS in negative mode in a mass range of m/z 500-1000 was performed on optimal cutting temperature (OCT compound-embedded human prostate tissue samples obtained from patients with prostate cancer at the time of radical prostatectomy. HR-MALDI-IMS analysis of the 14 samples in the discovery set identified 26 molecules as highly expressed in the prostate. Tandem mass spectrometry (MS/MS showed that these molecules included 14 phosphatidylinositols (PIs, 3 phosphatidylethanolamines (PEs and 3 phosphatidic acids (PAs. Among the PIs, the expression of PI(18:0/18:1, PI(18:0/20:3 and PI(18:0/20:2 were significantly higher in cancer tissue than in benign epithelium. A biomarker algorithm for prostate cancer was formulated by analyzing the expression profiles of PIs in cancer tissue and benign epithelium of the discovery set using orthogonal partial least squares discriminant analysis (OPLS-DA. The sensitivity and specificity of this algorithm for prostate cancer diagnosis in the 24 validation set samples were 87.5 and 91.7%, respectively. In conclusion, HR-MALDI-IMS identified several PIs as being more highly expressed in prostate cancer than benign prostate epithelium. These differences in PI expression profiles may serve as a novel diagnostic tool for prostate cancer.

  11. Claspin as a biomarker of human papillomavirus-related high grade lesions of uterine cervix

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    Benevolo Maria

    2012-06-01

    Full Text Available Abstract Background Claspin is a nuclear protein involved in DNA replication and damage response and is a key mediator for the S-phase checkpoint. Claspin expression is significantly high in several human solid tumors. Furthermore, high levels of claspin have been found in cervical cancer cell lines. Nevertheless, no data are available regarding claspin expression in cervical tissues. Methods In order to investigate whether claspin immunoreactivity is related to the lesion severity and High-Risk (HR HPV infection, we analyzed claspin expression by immunohistochemistry in a series of cervical biopsies which represent the steps occurring during cervical carcinogenesis (normal tissues, Cervical Intraepithelial Neoplasias 1, 2 and 3, Squamous Cell Carcinomas. All patients also had a cervico-vaginal sample for HPV testing, collected immediately before the colposcopy-guided biopsy. The HR-HPV DNA detection was performed by the HR-HPV Hybrid Capture 2 test. HPV genotyping was performed using the Linear Array HPV Genotyping Test. Results Our results evidenced a constant and significant increase of the rate of claspin positivity from the normal tissues to carcinomas (pχ2trend 2  Conclusions Our findings indicate that in vivo claspin expression is significantly related to HR-HPV infection and lesion grade both in histological and cytological samples. Therefore, the analysis of claspin expression could be clinically relevant in the diagnosis of HPV-related cervical lesions, in particular when applied to cervico-vaginal cytology. Moreover, giving information on the proliferation rate of each lesion, claspin immunostaining may contribute to the evaluation of progression risk, thus being helpful in patient management. Nevertheless, only large prospective studies may clarify the true clinical usefulness of claspin expression in distinguishing lesions with different progression potential.

  12. Rapid and High-Throughput Detection and Quantitation of Radiation Biomarkers in Human and Nonhuman Primates by Differential Mobility Spectrometry-Mass Spectrometry

    Science.gov (United States)

    Chen, Zhidan; Coy, Stephen L.; Pannkuk, Evan L.; Laiakis, Evagelia C.; Hall, Adam B.; Fornace, Albert J.; Vouros, Paul

    2016-10-01

    Radiation exposure is an important public health issue due to a range of accidental and intentional threats. Prompt and effective large-scale screening and appropriate use of medical countermeasures (MCM) to mitigate radiation injury requires rapid methods for determining the radiation dose. In a number of studies, metabolomics has identified small-molecule biomarkers responding to the radiation dose. Differential mobility spectrometry-mass spectrometry (DMS-MS) has been used for similar compounds for high-throughput small-molecule detection and quantitation. In this study, we show that DMS-MS can detect and quantify two radiation biomarkers, trimethyl-L-lysine (TML) and hypoxanthine. Hypoxanthine is a human and nonhuman primate (NHP) radiation biomarker and metabolic intermediate, whereas TML is a radiation biomarker in humans but not in NHP, which is involved in carnitine synthesis. They have been analyzed by DMS-MS from urine samples after a simple strong cation exchange-solid phase extraction (SCX-SPE). The dramatic suppression of background and chemical noise provided by DMS-MS results in an approximately 10-fold reduction in time, including sample pretreatment time, compared with liquid chromatography-mass spectrometry (LC-MS). DMS-MS quantitation accuracy has been verified by validation testing for each biomarker. Human samples are not yet available, but for hypoxanthine, selected NHP urine samples (pre- and 7-d-post 10 Gy exposure) were analyzed, resulting in a mean change in concentration essentially identical to that obtained by LC-MS (fold-change 2.76 versus 2.59). These results confirm the potential of DMS-MS for field or clinical first-level rapid screening for radiation exposure.

  13. Assessment of meat authenticity using bioinformatics, targeted peptide biomarkers and high-resolution mass spectrometry.

    Science.gov (United States)

    Ruiz Orduna, Alberto; Husby, Erik; Yang, Charles T; Ghosh, Dipankar; Beaudry, Francis

    2015-01-01

    In recent years a significant increase of food fraud has been observed, ranging from false label claims to the use of additives and fillers to increase profitability. Recently in 2013 horse and pig DNAs were detected in beef products sold from several retailers. Mass spectrometry (MS) has become the workhorse in protein research, and the detection of marker proteins could serve for both animal species and tissue authentication. Meat species authenticity is performed in this paper using a well-defined proteogenomic annotation, carefully chosen surrogate tryptic peptides and analysis using a hybrid quadrupole-Orbitrap MS. Selected mammalian meat samples were homogenised and proteins were extracted and digested with trypsin. The samples were analysed using a high-resolution MS. Chromatography was achieved using a 30-min linear gradient along with a BioBasic C8 100 × 1 mm column at a flow rate of 75 µl min(-1). The MS was operated in full-scan high resolution and accurate mass. MS/MS spectra were collected for selected proteotypic peptides. Muscular proteins were methodically analysed in silico in order to generate tryptic peptide mass lists and theoretical MS/MS spectra. Following a comprehensive bottom-up proteomic analysis, we detected and identified a proteotypic myoglobin tryptic peptide (120-134) for each species with observed m/z below 1.3 ppm compared with theoretical values. Moreover, proteotypic peptides from myosin-1, myosin-2 and β-haemoglobin were also identified. This targeted method allowed comprehensive meat speciation down to 1% (w/w) of undesired product.

  14. Hypermethylated SFRP2 gene in fecal DNA is a high potential biomarker for colorectal cancer noninvasive screening

    Institute of Scientific and Technical Information of China (English)

    Dao-Rong Wang; Dong Tang

    2008-01-01

    AIM: To investigate the feasibility of detecting hypermethylated secreted frizzled-related protein 2 (SFRP2) gene in fecal DNA as a non-invasive screening tool for colorectal cancer (CRC).METHODS: Fluorescence-based real-time PCR assay (MethyLight) was performed to analyze SFRP2 gene promoter methylation status in a blinded fashion in tumor tissues and in stool samples taken from 69 CRC patients preoperatively and at the 9th postoperative day, 34 patients with adenoma ≥ 1 cm, 26 with hyperplastic polyp, and 30 endoscopically normal subjects. Simultaneously the relationship between hypermethylation of SFRP2 gene and clinicopathological features was analyzed.RESULTS: SFRP2 gene was hypermethylated in 91.3% (63/69) CRC, 79.4% (27/34) and 53.8% (14/26) adenoma and hyperplastic polyp tissues, and in 87.0% (60/69), 61.8% (21/34) and 42.3% (11/26) of corresponding fecal samples, respectively. In contrast, no methylated SFRP2 gene was detected in mucosal tissues of normal controls, while two cases of matched fecal samples from normal controls were detected with hypermethylated SFRP2. A significant decrease (P < 0.001) in the rate of hypermethylated SFRP2 gene was detected in the postoperative (8.7%, 6/69) fecal samples as compared with the preoperative fecal samples (87%, 60/69) of CRC patients. Moreover, no significant associations were observed between SFRP2 hypermethylation and clinicopathological features including sex, age, tumor stage, site, lymph node status and histological grade, etc.CONCLUSION: Hypermethylation of SFRP2 gene infecal DNA is a novel molecular biomarker of CRC and carries a high potential for the remote detection of CRC and premalignant lesions as noninvasive screening method.

  15. Application of a high throughput method of biomarker discovery to improvement of the EarlyCDT(®-Lung Test.

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    Isabel K Macdonald

    Full Text Available BACKGROUND: The National Lung Screening Trial showed that CT screening for lung cancer led to a 20% reduction in mortality. However, CT screening has a number of disadvantages including low specificity. A validated autoantibody assay is available commercially (EarlyCDT®-Lung to aid in the early detection of lung cancer and risk stratification in patients with pulmonary nodules detected by CT. Recent advances in high throughput (HTP cloning and expression methods have been developed into a discovery pipeline to identify biomarkers that detect autoantibodies. The aim of this study was to demonstrate the successful clinical application of this strategy to add to the EarlyCDT-Lung panel in order to improve its sensitivity and specificity (and hence positive predictive value, (PPV. METHODS AND FINDINGS: Serum from two matched independent cohorts of lung cancer patients were used (n = 100 and n = 165. Sixty nine proteins were initially screened on an abridged HTP version of the autoantibody ELISA using protein prepared on small scale by a HTP expression and purification screen. Promising leads were produced in shake flask culture and tested on the full assay. These results were analyzed in combination with those from the EarlyCDT-Lung panel in order to provide a set of re-optimized cut-offs. Five proteins that still displayed cancer/normal differentiation were tested for reproducibility and validation on a second batch of protein and a separate patient cohort. Addition of these proteins resulted in an improvement in the sensitivity and specificity of the test from 38% and 86% to 49% and 93% respectively (PPV improvement from 1 in 16 to 1 in 7. CONCLUSION: This is a practical example of the value of investing resources to develop a HTP technology. Such technology may lead to improvement in the clinical utility of the EarlyCDT--Lung test, and so further aid the early detection of lung cancer.

  16. Protective effect of Garcinia against renal oxidative stress and biomarkers induced by high fat and sucrose diet

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    Abd Eltawab Mohamed A

    2011-01-01

    Full Text Available Abstract Background Obesity became major health problem in the world, the objective of this work was to examine the effect of high sucrose and high fat diet to induce obesity on antioxidant defense system, biochemical changes in blood and tissue of control, non treated and treated groups by administration of Garcinia cambogia, and explore the mechanisms that link obesity with altered renal function Methods Rats were fed a standard control diet for 12 week (wk or a diet containing 65% high sucrose (HSD or 35% fat (HFD for 8 wk and then HFD group divided into two groups for the following 4 wks. One group was given Garcinia+HFD, the second only high fat, Also the HSD divided into two groups, 1st HSD+Garcinia and 2nd HSD. Blood and renal, mesenteric, Perirenal and epididymal adipose tissues were collected for biochemical assays. Results HFD and HSD groups of rats showed a significant increase in feed intake, Body weight (BW and body mass index (BMI. Also there were significant increases in weights of mesenteric, Perirenal and epididymal adipose tissues in HFD and HSD groups. HFD and HSD affect the kidney by increasing serum urea and creatinine levels and decreased level of nitric oxide (NO and increased blood glucose, low density lipoproteins (LDL, triacylglycerol (TG, total cholesterol (TC and malondialdehyde (MDA. Glucose 6-phosphate dehydrogenase (G6PD activities were significantly decreased in HFD while there were significant increases in HSD and HSD+G groups p ≤ 0.05 compared with control. Moreover, renal catalase activities and MDA levels were significantly increased while NO level was lowered. These changes improved by Garcinia that decreased the oxidative stress biomarkers and increased NO level. There were significant positive correlations among BMI, kidney functions (Creatinine and urea, TG and Oxidative markers (renal MDA and catalase. Conclusions Rats fed a diet with HFD or HSD showed, hypertriglyceridemia, increased LDL production

  17. Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a High-throughput Targeted Metabolomics Approach

    Science.gov (United States)

    Yu, Nanyang; Wei, Si; Li, Meiying; Yang, Jingping; Li, Kan; Jin, Ling; Xie, Yuwei; Giesy, John P.; Zhang, Xiaowei; Yu, Hongxia

    2016-04-01

    Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.

  18. Utility of Biomarkers for Early Detection of Malignant Mesothelioma in a High-risk Population — EDRN Public Portal

    Science.gov (United States)

    A prospective study to evaluate the utility of various biomarkers in the context of an MM Early Detection Program. The study cohort will be composed of workers at a company with known asbestos exposure. Historically, a considerable number of workers at this company have developed MM.

  19. Activated Regulatory T Cells Expressing CD4(+)CD25(high)CD45RO(+)CD62L(+) Biomarkers Could Be a Risk Factor in Liver Allograft Rejection.

    Science.gov (United States)

    Boix, F; Millan, O; San Segundo, D; Mancebo, E; Miras, M; Rimola, A; Fábrega, E; Allende, L; Minguela, A; Paz-Artal, E; López-Hoyos, M; Brunet, M; Muro, M

    2015-10-01

    Activated regulatory T cells (aTregs) are nowadays a hot topic in organ transplantation to establish their role during acute rejection (AR) episodes. The aim of this multi-center study was to monitor the frequency of aTregs within the first year after transplantation in a cohort of first-time liver transplant recipients enrolled from 2010 to 2012. aTregs frequency was analyzed by means of flow cytometry. Patients who had AR showed higher levels of aTregs during first year after transplantation in comparison with patients who did not have higher levels. High levels of aTregs in liver recipients might be used as a biomarker of AR; however, further studies must be done to address the potential role of aTregs as biomarkers of AR in liver transplantation.

  20. Biomarkers in Prostate Cancer Epidemiology

    OpenAIRE

    Mudit Verma; Mukesh Verma; Payal Patel

    2011-01-01

    Understanding the etiology of a disease such as prostate cancer may help in identifying populations at high risk, timely intervention of the disease, and proper treatment. Biomarkers, along with exposure history and clinical data, are useful tools to achieve these goals. Individual risk and population incidence of prostate cancer result from the intervention of genetic susceptibility and exposure. Biochemical, epigenetic, genetic, and imaging biomarkers are used to identify people at high ris...

  1. Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers

    Directory of Open Access Journals (Sweden)

    Brian Dean

    2011-01-01

    Full Text Available The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia.

  2. Dissecting the Syndrome of Schizophrenia: Progress toward Clinically Useful Biomarkers.

    Science.gov (United States)

    Dean, Brian

    2011-01-01

    The search for clinically useful biomarkers has been one of the holy grails of schizophrenia research. This paper will outline the evolving notion of biomarkers and then outline outcomes from a variety of biomarkers discovery strategies. In particular, the impact of high-throughput screening technologies on biomarker discovery will be highlighted and how new or improved technologies may allow the discovery of either diagnostic biomarkers for schizophrenia or biomarkers that will be useful in determining appropriate treatments for people with the disorder. History tells those involved in biomarker research that the discovery and validation of useful biomarkers is a long process and current progress must always be viewed in that light. However, the approval of the first biomarker screen with some value in predicting responsiveness to antipsychotic drugs suggests that biomarkers can be identified and that these biomarkers that will be useful in diagnosing and treating people with schizophrenia.

  3. Biomarkers in Barrett's esophagus.

    Science.gov (United States)

    Reid, Brian J; Blount, Patricia L; Rabinovitch, Peter S

    2003-04-01

    future. Biopsy repositories are now readily available for phase 3 studies that can evaluate and compare biomarkers. There are initiatives for multi-institutional Barrett's Centers of Excellence that could provide rapid progress in biomarker evaluation. In addition to new candidate biomarkers, the human genome project has provided high-throughput methodologies and methods for computer analysis of data, which can provide the volume and quality control required for clinically useful biomarkers. Currently, 17p (p53) LOH has progressed the furthest among molecular biomarkers. The authors do not recommend its routine clinical use at the present time, however. Finally, it is likely that clinicians will want to follow the results of clinical treatment-response studies and epidemiologic studies that evaluate relationship between clinical interventions or environmental risk and protective factors and surrogate endpoints, especially if the endpoints are progessing well along the phases of biomarker validation. These studies are likely to be of clinical interest because they may becoming the basis for randomized clinical trials to prevent cancer in BE.

  4. Neuroimaging Biomarkers for Psychosis

    Science.gov (United States)

    Hager, Brandon M.

    2015-01-01

    Background Biomarkers provide clinicians with a predictable model for the diagnosis, treatment and follow-up of medical ailments. Psychiatry has lagged behind other areas of medicine in the identification of biomarkers for clinical diagnosis and treatment. In this review, we investigated the current state of neuroimaging as it pertains to biomarkers for psychosis. Methods We reviewed systematic reviews and meta-analyses of the structural (sMRI), functional (fMRI), diffusion-tensor (DTI), Positron emission tomography (PET) and spectroscopy (MRS) studies of subjects at-risk or those with an established schizophrenic illness. Only articles reporting effect-sizes and confidence intervals were included in an assessment of robustness. Results Out of the identified meta-analyses and systematic reviews, 21 studies met the inclusion criteria for assessment. There were 13 sMRI, 4 PET, 3 MRS, and 1 DTI studies. The search terms included in the current review encompassed familial high risk (FHR), clinical high risk (CHR), First episode (FES), Chronic (CSZ), schizophrenia spectrum disorders (SSD), and healthy controls (HC). Conclusions Currently, few neuroimaging biomarkers can be considered ready for diagnostic use in patients with psychosis. At least in part, this may be related to the challenges inherent in the current symptom-based approach to classifying these disorders. While available studies suggest a possible value of imaging biomarkers for monitoring disease progression, more systematic research is needed. To date, the best value of imaging data in psychoses has been to shed light on questions of disease pathophysiology, especially through the characterization of endophenotypes. PMID:25883891

  5. Imaging-based biomarkers of cognitive performance in older adults constructed via high-dimensional pattern regression applied to MRI and PET.

    Directory of Open Access Journals (Sweden)

    Ying Wang

    Full Text Available In this study, we used high-dimensional pattern regression methods based on structural (gray and white matter; GM and WM and functional (positron emission tomography of regional cerebral blood flow; PET brain data to identify cross-sectional imaging biomarkers of cognitive performance in cognitively normal older adults from the Baltimore Longitudinal Study of Aging (BLSA. We focused on specific components of executive and memory domains known to decline with aging, including manipulation, semantic retrieval, long-term memory (LTM, and short-term memory (STM. For each imaging modality, brain regions associated with each cognitive domain were generated by adaptive regional clustering. A relevance vector machine was adopted to model the nonlinear continuous relationship between brain regions and cognitive performance, with cross-validation to select the most informative brain regions (using recursive feature elimination as imaging biomarkers and optimize model parameters. Predicted cognitive scores using our regression algorithm based on the resulting brain regions correlated well with actual performance. Also, regression models obtained using combined GM, WM, and PET imaging modalities outperformed models based on single modalities. Imaging biomarkers related to memory performance included the orbito-frontal and medial temporal cortical regions with LTM showing stronger correlation with the temporal lobe than STM. Brain regions predicting executive performance included orbito-frontal, and occipito-temporal areas. The PET modality had higher contribution to most cognitive domains except manipulation, which had higher WM contribution from the superior longitudinal fasciculus and the genu of the corpus callosum. These findings based on machine-learning methods demonstrate the importance of combining structural and functional imaging data in understanding complex cognitive mechanisms and also their potential usage as biomarkers that predict cognitive

  6. Molecular profiling reveals diversity of stress signal transduction cascades in highly penetrant Alzheimer's disease human skin fibroblasts.

    Directory of Open Access Journals (Sweden)

    Graziella Mendonsa

    Full Text Available The serious and growing impact of the neurodegenerative disorder Alzheimer's disease (AD as an individual and societal burden raises a number of key questions: Can a blanket test for Alzheimer's disease be devised forecasting long-term risk for acquiring this disorder? Can a unified therapy be devised to forestall the development of AD as well as improve the lot of present sufferers? Inflammatory and oxidative stresses are associated with enhanced risk for AD. Can an AD molecular signature be identified in signaling pathways for communication within and among cells during inflammatory and oxidative stress, suggesting possible biomarkers and therapeutic avenues? We postulated a unique molecular signature of dysfunctional activity profiles in AD-relevant signaling pathways in peripheral tissues, based on a gain of function in G-protein-coupled bradykinin B2 receptor (BKB2R inflammatory stress signaling in skin fibroblasts from AD patients that results in tau protein Ser hyperphosphorylation. Such a signaling profile, routed through both phosphorylation and proteolytic cascades activated by inflammatory and oxidative stresses in highly penetrant familial monogenic forms of AD, could be informative for pathogenesis of the complex multigenic sporadic form of AD. Comparing stimulus-specific cascades of signal transduction revealed a striking diversity of molecular signaling profiles in AD human skin fibroblasts that express endogenous levels of mutant presenilins PS-1 or PS-2 or the Trisomy 21 proteome. AD fibroblasts bearing the PS-1 M146L mutation associated with highly aggressive AD displayed persistent BKB2R signaling plus decreased ERK activation by BK, correctible by gamma-secretase inhibitor Compound E. Lack of these effects in the homologous PS-2 mutant cells indicates specificity of presenilin gamma-secretase catalytic components in BK signaling biology directed toward MAPK activation. Oxidative stress revealed a JNK-dependent survival

  7. Intra-specific diet shift in manila clams (Ruditapes philippinarum) as revealed by carbon and nitrogen stable isotopes and fatty acid biomarker

    Science.gov (United States)

    Suh, Y.; Shin, K.

    2011-12-01

    Manila clams sampled in Seonjae Island, Korea with shell lengths (SL) below 19.76 mm in average showed a significantly depleted carbon and nitrogen isotope values (Pnutrition from both P. tricornutum and aggregated organic matter that consists of dead or decomposed microalgae or other detritus. Bigger size groups (10.92±0.34 mm and 14.81±0.25 mm) obtained most of their energy from P.tricorutum and also from other phytoplankton unlike the biggest size group (21.15±1.02 mm) that feeds mainly on fresh microalgae of all diets fed. This variation in diet reveals that smaller clams mostly inhale dead or decomposed microalgae that sinks on the bottom while the bigger clams uptake more fresh ones that are still alive. This variation in feeding behavior could have been caused by morphological constraints such as limited siphon length. The results suggest that manila clams greater than and below 19.76 mm in average have different feeding behavior and P. tricornutum and I. galbana were the two most preferred diets for manila clams cultured in IFHRI. The result of fatty acid composition of manila clams in relation to size or growth rate suggests that fast growing clams would have rapid metabolism of fatty acids not required by the animals and an accumulation of the essential fatty acids (PUFA). In addition, their higher energy requirement and more active state of development would further diminish lipid reserve of the species.

  8. [Novel biomarkers for diabetic nephropathy].

    Science.gov (United States)

    Araki, Shin-ichi

    2014-02-01

    Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. An early clinical sign of this complication is an increase of urinary albumin excretion, called microalbuminuria, which is not only a predictor of the progression of nephropathy, but also an independent risk factor for cardiovascular disease. Although microalbuminuria is clinically important to assess the prognosis of diabetic patients, it may be insufficient as an early and specific biomarker of diabetic nephropathy because of a large day-to-day variation and lack of a good correlation of microalbuminuria with renal dysfunction and pathohistological changes. Thus, more sensitive and specific biomarkers are needed to improve the diagnostic capability of identifying patients at high risk. The factors involved in renal tubulo-interstitial damage, the production and degradation of extracellular matrix, microinflammation, etc., are investigated as candidate molecules. Despite numerous efforts so far, the assessment of these biomarkers is still a subject of ongoing investigations. Recently, a variety of omics and quantitative techniques in systems biology are rapidly emerging in the field of biomarker discovery, including proteomics, transcriptomics, and metabolomics, and they have been applied to search for novel putative biomarkers of diabetic nephropathy. Novel biomarkers or their combination with microalbuminuria provide a better diagnostic accuracy than microalbuminuria alone, and may be useful for establishing personal medicine. Furthermore, the identification of novel biomarkers may provide insight into the mechanisms underlying diabetic nephropathy.

  9. Dietary biomarkers: advances, limitations and future directions

    Directory of Open Access Journals (Sweden)

    Hedrick Valisa E

    2012-12-01

    Full Text Available Abstract The subjective nature of self-reported dietary intake assessment methods presents numerous challenges to obtaining accurate dietary intake and nutritional status. This limitation can be overcome by the use of dietary biomarkers, which are able to objectively assess dietary consumption (or exposure without the bias of self-reported dietary intake errors. The need for dietary biomarkers was addressed by the Institute of Medicine, who recognized the lack of nutritional biomarkers as a knowledge gap requiring future research. The purpose of this article is to review existing literature on currently available dietary biomarkers, including novel biomarkers of specific foods and dietary components, and assess the validity, reliability and sensitivity of the markers. This review revealed several biomarkers in need of additional validation research; research is also needed to produce sensitive, specific, cost-effective and noninvasive dietary biomarkers. The emerging field of metabolomics may help to advance the development of food/nutrient biomarkers, yet advances in food metabolome databases are needed. The availability of biomarkers that estimate intake of specific foods and dietary components could greatly enhance nutritional research targeting compliance to national recommendations as well as direct associations with disease outcomes. More research is necessary to refine existing biomarkers by accounting for confounding factors, to establish new indicators of specific food intake, and to develop techniques that are cost-effective, noninvasive, rapid and accurate measures of nutritional status.

  10. Dietary biomarkers: advances, limitations and future directions.

    Science.gov (United States)

    Hedrick, Valisa E; Dietrich, Andrea M; Estabrooks, Paul A; Savla, Jyoti; Serrano, Elena; Davy, Brenda M

    2012-12-14

    The subjective nature of self-reported dietary intake assessment methods presents numerous challenges to obtaining accurate dietary intake and nutritional status. This limitation can be overcome by the use of dietary biomarkers, which are able to objectively assess dietary consumption (or exposure) without the bias of self-reported dietary intake errors. The need for dietary biomarkers was addressed by the Institute of Medicine, who recognized the lack of nutritional biomarkers as a knowledge gap requiring future research. The purpose of this article is to review existing literature on currently available dietary biomarkers, including novel biomarkers of specific foods and dietary components, and assess the validity, reliability and sensitivity of the markers. This review revealed several biomarkers in need of additional validation research; research is also needed to produce sensitive, specific, cost-effective and noninvasive dietary biomarkers. The emerging field of metabolomics may help to advance the development of food/nutrient biomarkers, yet advances in food metabolome databases are needed. The availability of biomarkers that estimate intake of specific foods and dietary components could greatly enhance nutritional research targeting compliance to national recommendations as well as direct associations with disease outcomes. More research is necessary to refine existing biomarkers by accounting for confounding factors, to establish new indicators of specific food intake, and to develop techniques that are cost-effective, noninvasive, rapid and accurate measures of nutritional status.

  11. Spatial and temporal variability of biomarkers and microbial diversity reveal metabolic and community flexibility in Streamer Biofilm Communities in the Lower Geyser Basin, Yellowstone National Park.

    Science.gov (United States)

    Schubotz, F; Meyer-Dombard, D R; Bradley, A S; Fredricks, H F; Hinrichs, K-U; Shock, E L; Summons, R E

    2013-11-01

    Detailed analysis of 16S rRNA and intact polar lipids (IPLs) from streamer biofilm communities (SBCs), collected from geochemically similar hot springs in the Lower Geyser Basin, Yellowstone National Park, shows good agreement and affirm that IPLs can be used as reliable markers for the microbial constituents of SBCs. Uncultured Crenarchaea are prominent in SBS, and their IPLs contain both glycosidic and mixed glyco-phospho head groups with tetraether cores, having 0-4 rings. Archaeal IPL contributions increase with increasing temperature and comprise up to one-fourth of the total IPL inventory at >84 °C. At elevated temperatures, bacterial IPLs contain abundant glycosidic glycerol diether lipids. Diether and diacylglycerol (DAG) lipids with aminopentanetetrol and phosphatidylinositol head groups were identified as lipids diagnostic of Aquificales, while DAG glycolipids and glyco-phospholipids containing N-acetylgycosamine as head group were assigned to members of the Thermales. With decreasing temperature and concomitant changes in water chemistry, IPLs typical of phototrophic bacteria, such as mono-, diglycosyl, and sulfoquinovosyl DAG, which are specific for cyanobacteria, increase in abundance, consistent with genomic data from the same samples. Compound-specific stable carbon isotope analysis of IPL breakdown products reveals a large isotopic diversity among SBCs in different hot springs. At two of the hot springs, 'Bison Pool' and Flat Cone, lipids derived from Aquificales are enriched in (13) C relative to biomass and approach values close to dissolved inorganic carbon (DIC) (approximately 0‰), consistent with fractionation during autotrophic carbon fixation via the reversed tricarboxylic acid pathway. At a third site, Octopus Spring, the same Aquificales-diagnostic lipids are 10‰ depleted relative to biomass and resemble stable carbon isotope values of dissolved organic carbon (DOC), indicative of heterotrophy. Other bacterial and archaeal lipids show

  12. Chronic exposure of killifish to a highly polluted environment desensitizes estrogen-responsive reproductive and biomarker genes

    Energy Technology Data Exchange (ETDEWEB)

    Bugel, Sean M., E-mail: Sean.Bugel@oregonstate.edu [Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Bonventre, Josephine A. [Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); White, Lori A. [Department of Biochemistry and Microbiology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901 (United States); Tanguay, Robert L. [Department of Environmental and Molecular Toxicology, Environmental Health Sciences Center, Oregon State University, Corvallis, OR 97331 (United States); Cooper, Keith R. [Department of Biochemistry and Microbiology, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901 (United States)

    2014-07-01

    Highlights: • Reproductive biomarker genes in Newark Bay killifish are desensitized to estrogen. • Gene desensitization indicates pre-transcriptional effects on estrogen signaling. • Desensitization does not have a metabolic or epigenetic basis (gene methylation). • Modulation of vitellogenin and choriogenin genes correlates with reproductive impacts. • Choriogenin L appears less prone to false negatives and may be a sensitive biomarker. - Abstract: Reproductive and endocrine disruption is commonly reported in aquatic species exposed to complex contaminant mixtures. We previously reported that Atlantic killifish (Fundulus heteroclitus) from the chronically contaminated Newark Bay, NJ, exhibit multiple endocrine disrupting effects, including inhibition of vitellogenesis (yolk protein synthesis) in females and false negative vitellogenin biomarker responses in males. Here, we characterized the effects on estrogen signaling and the transcriptional regulation of estrogen-responsive genes in this model population. First, a dose–response study tested the hypothesis that reproductive biomarkers (vtg1, vtg2, chg H, chg Hm, chg L) in Newark Bay killifish are relatively less sensitive to 17β-estradiol at the transcriptional level, relative to a reference (Tuckerton, NJ) population. The second study assessed expression for various metabolism (cyp1a, cyp3a30, mdr) and estrogen receptor (ER α, ER βa, ER βb) genes under basal and estrogen treatment conditions in both populations. Hepatic metabolism of 17β-estradiol was also evaluated in vitro as an integrated endpoint for adverse effects on metabolism. In the third study, gene methylation was evaluated for promoters of vtg1 (8 CpGs) and vtg2 (10 CpGs) in both populations, and vtg1 promoter sequences were examined for single nucleotide polymorphism (SNPs). Overall, these studies show that multi-chemical exposures at Newark Bay have desensitized all reproductive biomarkers tested to estrogen. For example, at 10 ng

  13. High Resolution Discovery Proteomics Reveals Candidate Disease Progression Markers of Alzheimer's Disease in Human Cerebrospinal Fluid.

    Directory of Open Access Journals (Sweden)

    Ronald C Hendrickson

    Full Text Available Disease modifying treatments for Alzheimer's disease (AD constitute a major goal in medicine. Current trends suggest that biomarkers reflective of AD neuropathology and modifiable by treatment would provide supportive evidence for disease modification. Nevertheless, a lack of quantitative tools to assess disease modifying treatment effects remains a major hurdle. Cerebrospinal fluid (CSF biochemical markers such as total tau, p-tau and Ab42 are well established markers of AD; however, global quantitative biochemical changes in CSF in AD disease progression remain largely uncharacterized. Here we applied a high resolution open discovery platform, dMS, to profile a cross-sectional cohort of lumbar CSF from post-mortem diagnosed AD patients versus those from non-AD/non-demented (control patients. Multiple markers were identified to be statistically significant in the cohort tested. We selected two markers SME-1 (p<0.0001 and SME-2 (p = 0.0004 for evaluation in a second independent longitudinal cohort of human CSF from post-mortem diagnosed AD patients and age-matched and case-matched control patients. In cohort-2, SME-1, identified as neuronal secretory protein VGF, and SME-2, identified as neuronal pentraxin receptor-1 (NPTXR, in AD were 21% (p = 0.039 and 17% (p = 0.026 lower, at baseline, respectively, than in controls. Linear mixed model analysis in the longitudinal cohort estimate a decrease in the levels of VGF and NPTXR at the rate of 10.9% and 6.9% per year in the AD patients, whereas both markers increased in controls. Because these markers are detected by mass spectrometry without the need for antibody reagents, targeted MS based assays provide a clear translation path for evaluating selected AD disease-progression markers with high analytical precision in the clinic.

  14. Glycation promoted by dynamic high pressure microfluidisation pretreatment revealed by high resolution mass spectrometry.

    Science.gov (United States)

    Huang, Xiaoqin; Tu, Zongcai; Wang, Hui; Zhang, Qiuting; Hu, Yueming; Zhang, Lan; Niu, Peipei; Shi, Yan; Xiao, Hui

    2013-12-01

    The effect of dynamic high pressure microfluidisation (DHPM) pretreatment on the glycation of bovine serum albumin (BSA) was investigated. A detailed glycation map was obtained from high resolution mass spectrometry. Without DHPM pretreatment, only 7 glycation sites were identified, whereas the numbers were increased to 10, 11 and 11 when BSA-glucose was pretreated with DHPM at 50, 100 and 200 MPa, respectively, suggesting that DHPM pretreatment can significantly promote the Maillard reaction. Average degree of substitution per peptide molecule BSA (DSP) was used to further evaluate the glycation level under various DHPM conditions. All the DHPM pretreated samples exhibited elevated glycation level compared to the un-pretreated sample. With 100 MPa DHPM pretreatment, the protein showed the most significantly enhanced glycation extent. In addition, our results suggest that Maillard-type glycation followed by mass spectrometry analysis can be used to study the conformational changes when proteins are disturbed by external forces.

  15. High rates of hybridisation reveal fragile reproductive barriers between endangered Australian sea snakes

    DEFF Research Database (Denmark)

    Sanders, Kate L; Redsted Rasmussen, Arne; Guinea, Michael L.

    2014-01-01

    The viviparous sea snakes include 62 ecologically diverse species, many of which are of very recent evolutionary origin and have overlapping distributions. Peak sea snake diversity and endemism is recorded from the isolated emergent reefs of the Timor Sea in Northwest Australia. However, nine...... designations, but revealed high frequencies of hybrids on all four reefs and individuals of pure A. fuscus ancestry only at Scott and (historically) Ashmore. Most unexpectedly, 95% of snakes sampled at Hibernia were hybrids that resembled A. laevis in phenotype, revealing a collapse of reproductive barriers...

  16. Saliva: A diagnostic biomarker of periodontal diseases.

    Science.gov (United States)

    Patil, Priti Basgauda; Patil, Basgauda Ramesh

    2011-10-01

    Early detection of disease plays a crucial role in successful therapy. Early diagnosis and management reduces the severity and possible complications of the disease process. To overcome this challenge, medical researchers are devoted to finding molecular disease biomarkers that reveal a hidden lethal threat before the disease becomes complicated. Saliva, an important physiologic fluid, containing a highly complex mixture of substances, is rapidly gaining popularity as a diagnostic tool. Periodontal disease is a chronic disease of the oral cavity comprising a group of inflammatory conditions affecting the supporting structures of the dentition. In the field of periodontology, traditional clinical criteria are often insufficient for determining sites of active disease, for monitoring the response to therapy, or for measuring the degree of susceptibility to future disease progression. Saliva, as a mirror of oral and systemic health, is a valuable source for clinically relevant information because it contains biomarkers specific for the unique physiologic aspects of periodontal diseases. This review highlights the various potentials of saliva as a diagnostic biomarker for periodontal diseases.

  17. Peculiarities of high-overtone transition probabilities in carbon monoxide revealed by high-precision calculation

    Energy Technology Data Exchange (ETDEWEB)

    Medvedev, Emile S., E-mail: esmedved@orc.ru [The Institute of Problems of Chemical Physics, Russian Academy of Sciences, Prospect Akademika Semenova 1, 142432 Chernogolovka (Russian Federation); Meshkov, Vladimir V.; Stolyarov, Andrey V. [Department of Chemistry, Lomonosov Moscow State University, Leninskie gory 1/3, 119991 Moscow (Russian Federation); Gordon, Iouli E. [Atomic and Molecular Physics Division, Harvard-Smithsonian Center for Astrophysics, 60 Garden St, Cambridge, Massachusetts 02138 (United States)

    2015-10-21

    In the recent work devoted to the calculation of the rovibrational line list of the CO molecule [G. Li et al., Astrophys. J., Suppl. Ser. 216, 15 (2015)], rigorous validation of the calculated parameters including intensities was carried out. In particular, the Normal Intensity Distribution Law (NIDL) [E. S. Medvedev, J. Chem. Phys. 137, 174307 (2012)] was employed for the validation purposes, and it was found that, in the original CO line list calculated for large changes of the vibrational quantum number up to Δn = 41, intensities with Δn > 11 were unphysical. Therefore, very high overtone transitions were removed from the published list in Li et al. Here, we show how this type of validation is carried out and prove that the quadruple precision is indispensably required to predict the reliable intensities using the conventional 32-bit computers. Based on these calculations, the NIDL is shown to hold up for the 0 → n transitions till the dissociation limit around n = 83, covering 45 orders of magnitude in the intensity. The low-intensity 0 → n transition predicted in the work of Medvedev [Determination of a new molecular constant for diatomic systems. Normal intensity distribution law for overtone spectra of diatomic and polyatomic molecules and anomalies in overtone absorption spectra of diatomic molecules, Institute of Chemical Physics, Russian Academy of Sciences, Chernogolovka, 1984] at n = 5 is confirmed, and two additional “abnormal” intensities are found at n = 14 and 23. Criteria for the appearance of such “anomalies” are formulated. The results could be useful to revise the high-overtone molecular transition probabilities provided in spectroscopic databases.

  18. Effect of moderate- versus high-intensity exercise on vascular function, biomarkers and quality of life in heart transplant recipients

    DEFF Research Database (Denmark)

    Dall, Christian H; Gustafsson, Finn; Christensen, Stefan B

    2015-01-01

    .001). The physical component score of the 36-item Short Form (SF-36) was increased significantly in HIIT patients (p = 0.02) and borderline increased in CON patients (p = 0.07), whereas there was no significant effect of exercise on the mental component. Depression score decreased significantly in HIIT patients (p...... by a 5-month washout and crossover. Outcomes included endothelial function, arterial stiffness, biomarkers, HRQoL and markers of anxiety and depression. RESULTS: Sixteen HTx recipients (mean age 52 years, 75% male) completed the study. HIIT increased VO2peak more than CON (between-group difference, p

  19. Defining molecular and cellular responses after low and high linear energy transfer radiations to develop biomarkers of carcinogenic risk or therapeutic outcome.

    Science.gov (United States)

    Story, Michael; Ding, Liang-hao; Brock, William A; Ang, K Kian; Alsbeih, Ghazi; Minna, John; Park, Seongmi; Das, Amit

    2012-11-01

    The variability in radiosensitivity across the human population is governed in part by genetic factors. The ability to predict therapeutic response, identify individuals at greatest risk for adverse clinical responses after therapeutic radiation doses, or identify individuals at high risk for carcinogenesis from environmental or medical radiation exposures has a medical and economic impact on both the individual and society at large. As radiotherapy incorporates particles, particularly particles larger than protons, into therapy, the need for such discriminators, (i.e., biomarkers) will become ever more important. Cellular assays for survival, DNA repair, or chromatid/chromosomal analysis have been used to identify at-risk individuals, but they are not clinically applicable. Newer approaches, such as genome-wide analysis of gene expression or single nucleotide polymorphisms and small copy number variations within chromosomes, are examples of technologies being applied to the discovery process. Gene expression analysis of primary or immortalized human cells suggests that there are distinct gene expression patterns associated with radiation exposure to both low and high linear energy transfer radiations and that those most radiosensitive are discernible by their basal gene expression patterns. However, because the genetic alterations that drive radio response may be subtle and cumulative, the need for large sample sizes of specific cell or tissue types is required. A systems biology approach will ultimately be necessary. Potential biomarkers from cell lines or animal models will require validation in a human setting where possible and before being considered as a credible biomarker some understanding of the molecular mechanism is necessary.

  20. New insights into morphology of high performance BHJ photovoltaics revealed by high resolution AFM.

    Science.gov (United States)

    Wang, Dong; Liu, Feng; Yagihashi, Noritoshi; Nakaya, Masafumi; Ferdous, Sunzida; Liang, Xiaobin; Muramatsu, Atsushi; Nakajima, Ken; Russell, Thomas P

    2014-10-08

    Direct imaging of the bulk heterojunction (BHJ) thin film morphology in polymer-based solar cells is essential to understand device function and optimize efficiency. The morphology of the BHJ active layer consists of bicontinuous domains of the donor and acceptor materials, having characteristic length scales of several tens of nanometers, that reduces charge recombination, enhances charge separation, and enables electron and hole transport to their respective electrodes. Direct imaging of the morphology from the molecular to macroscopic level, though, is lacking. Though transmission electron tomography provides a 3D, real-space image of the morphology, quantifying the structure is not possible. Here we used high-resolution atomic force microscopy (AFM) in the tapping and nanomechanical modes to investigate the BHJ active layer morphology that, when combined with Ar(+) etching, provided unique insights with unparalleled spatial resolution. PCBM was seen to form a network that interpenetrated into the fibrillar network of the hole-conducting polymer, both being imbedded in a mixture of the two components. The free surface was found to be enriched with polymer crystals having a "face-on" orientation and the morphology at the anode interface was markedly different.

  1. SERUM LIPIDOMIC BIOMARKERS FROM PATIENTS WITH PROSTATE PATHOLOGY, IDENTIFIED BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY COUPLED WITH MASS SPECTROMETRY

    Directory of Open Access Journals (Sweden)

    Gligor Andrei Lazar

    2016-11-01

    Full Text Available Introduction: Lipidomics can offer an instant picture of the lipophilic metabolites from tissues and biofluids and can indicate the evolution of different pathologies, such as hyperplasia or different types of cancers. Related to these pathologies, Prostate Serum Antigen (PSA, proved to have a low grade prediction for an accurate diagnosis. Meanwhile, untargeted or targeted metabolomics became a useful advanced technology to discover new biomarkers for a better diagnosis. Aims: To  realize an adequate procedure based on liquid chromatography coupled with mass spectrometry (HPLC-MS to determine the profile of lipids from blood serum, followed by adequate biostatistics. Materials and Methods: Blood samples, obtained from healthy men and patients with prostate benign hyperplasia,  post-biopsy cancer and post-surgery cancer were processed for lipid extraction and subjected to HPLC–ESI(+QTOF-MS measurements, followed by the multivariate analysis (PCA and Cluster Analysis with Unscrambler 10.1 software. TofControl 3.2 and Data Analysis 4.2 software (BrukerDaltonics were used for the control of the instrument and data processing. Results: The molecules responsible for such discriminations were identified to be mainly represented by lyso-phospatidylcholines. By Cluster Analysis, the dendograms showed good statistical clustering of samples, especially for cancer patients agains controls and less clustered for hyperplasia. Conclusion: One can consider that molecules belonging to phospholipid family and diacyl /triacylglycerides or ceramides or carnitines can be considered potential biomarkers for hyperplasia and prostate cancer.

  2. Weekly administration of rapamycin improves survival and biomarkers in obese male mice on high-fat diet.

    Science.gov (United States)

    Leontieva, Olga V; Paszkiewicz, Geraldine M; Blagosklonny, Mikhail V

    2014-08-01

    Recent discoveries have revealed the key role of mTOR (target of rapamycin) in aging. Furthermore, rapamycin extends lifespan in mice, especially in female mice. Here, we treated obese male mice on high-fat diet with rapamycin given intermittently: either weekly (once a week) or alternating bi-weekly (three injections every other week). While only marginally reducing obesity, intermittent administration of rapamycin significantly extended lifespan. Significance was achieved for weekly treated group and for the three rapamycin-received groups combined. In weekly treatment group, 100% mice were alive by the age of 2 years, whereas 60% of mice died in untreated group by this age. The effect of weekly treatment on survival was highly significant and cannot be fully explained by partial reduction in obesity. Alternating bi-weekly treatments seem to be less effective than weekly treatment, although effects of additional factors (see ) may not be excluded. After one year of treatment, all survived mice were sacrificed 8 days after the last administration of rapamycin to avoid its direct interference with parameters examined. Fasting levels of cardiac and hepatic p-S6, a marker of mTORC1 activity, were lower in weekly treatment group compared with control mice. In contrast, levels of p-Akt (S473), glucose, triglycerides and insulin were unchanged, whereas leptin and IGF-1 tended to be lower. Thus, weekly treatment with rapamycin may slow down aging in obese male mice on high-fat diet.

  3. Biomarkers of Selenium Status

    Directory of Open Access Journals (Sweden)

    Gerald F. Combs, Jr.

    2015-03-01

    Full Text Available The essential trace element, selenium (Se, has multiple biological activities, which depend on the level of Se intake. Relatively low Se intakes determine the expression of selenoenzymes in which it serves as an essential constituent. Higher intakes have been shown to have anti-tumorigenic potential; and very high Se intakes can produce adverse effects. This hierarchy of biological activities calls for biomarkers informative at different levels of Se exposure. Some Se-biomarkers, such as the selenoproteins and particularly GPX3 and SEPP1, provide information about function directly and are of value in identifying nutritional Se deficiency and tracking responses of deficient individuals to Se-treatment. They are useful under conditions of Se intake within the range of regulated selenoprotein expression, e.g., for humans <55 μg/day and for animals <20 μg/kg diet. Other Se-biomarkers provide information indirectly through inferences based on Se levels of foods, tissues, urine or feces. They can indicate the likelihood of deficiency or adverse effects, but they do not provide direct evidence of either condition. Their value is in providing information about Se status over a wide range of Se intake, particularly from food forms. There is need for additional Se biomarkers particularly for assessing Se status in non-deficient individuals for whom the prospects of cancer risk reduction and adverse effects risk are the primary health considerations. This would include determining whether supranutritional intakes of Se may be required for maximal selenoprotein expression in immune surveillance cells. It would also include developing methods to determine low molecular weight Se-metabolites, i.e., selenoamino acids and methylated Se-metabolites, which to date have not been detectable in biological specimens. Recent analytical advances using tandem liquid chromatography-mass spectrometry suggest prospects for detecting these metabolites.

  4. Analysis of complex-type chromosome exchanges in astronauts' lymphocytes after space flight as a biomarker of high-LET exposure

    Science.gov (United States)

    George, Kerry; Wu, Honglu; Willingham, Veronica; Cucinotta, Francis A.

    2002-01-01

    High-LET radiation is more efficient in producing complex-type chromosome exchanges than sparsely ionizing radiation, and this can potentially be used as a biomarker of radiation quality. To investigate if complex chromosome exchanges are induced by the high-LET component of space radiation exposure, damage was assessed in astronauts' blood lymphocytes before and after long duration missions of 3-4 months. The frequency of simple translocations increased significantly for most of the crewmembers studied. However, there were few complex exchanges detected and only one crewmember had a significant increase after flight. It has been suggested that the yield of complex chromosome damage could be underestimated when analyzing metaphase cells collected at one time point after irradiation, and analysis of chemically-induced PCC may be more accurate since problems with complicated cell-cycle delays are avoided. However, in this case the yields of chromosome damage were similar for metaphase and PCC analysis of astronauts' lymphocytes. It appears that the use of complex-type exchanges as biomarker of radiation quality in vivo after low-dose chronic exposure in mixed radiation fields is hampered by statistical uncertainties.

  5. Circulating Biomarkers for Duchenne Muscular Dystrophy

    Science.gov (United States)

    Aartsma-Rus, Annemieke; Spitali, Pietro

    2015-01-01

    Abstract Duchenne muscular dystrophy is the most common form of muscular dystrophy. Genetic and biochemical research over the years has characterized the cause, pathophysiology and development of the disease providing several potential therapeutic targets and/or biomarkers. High throughput – omic technologies have provided a comprehensive understanding of the changes occurring in dystrophic muscles. Murine and canine animal models have been a valuable source to profile muscles and body fluids, thus providing candidate biomarkers that can be evaluated in patients. This review will illustrate known circulating biomarkers that could track disease progression and response to therapy in patients affected by Duchenne muscular dystrophy. We present an overview of the transcriptomic, proteomic, metabolomics and lipidomic biomarkers described in literature. We show how studies in muscle tissue have led to the identification of serum and urine biomarkers and we highlight the importance of evaluating biomarkers as possible surrogate endpoints to facilitate regulatory processes for new medicinal products. PMID:27858763

  6. Chiral Biomarkers in Meteorites

    Science.gov (United States)

    Hoover, Richard B.

    2010-01-01

    The chirality of organic molecules with the asymmetric location of group radicals was discovered in 1848 by Louis Pasteur during his investigations of the rotation of the plane of polarization of light by crystals of sodium ammonium paratartrate. It is well established that the amino acids in proteins are exclusively Levorotary (L-aminos) and the sugars in DNA and RNA are Dextrorotary (D-sugars). This phenomenon of homochirality of biological polymers is a fundamental property of all life known on Earth. Furthermore, abiotic production mechanisms typically yield recemic mixtures (i.e. equal amounts of the two enantiomers). When amino acids were first detected in carbonaceous meteorites, it was concluded that they were racemates. This conclusion was taken as evidence that they were extraterrestrial and produced by abiologically. Subsequent studies by numerous researchers have revealed that many of the amino acids in carbonaceous meteorites exhibit a significant L-excess. The observed chirality is much greater than that produced by any currently known abiotic processes (e.g. Linearly polarized light from neutron stars; Circularly polarized ultraviolet light from faint stars; optically active quartz powders; inclusion polymerization in clay minerals; Vester-Ulbricht hypothesis of parity violations, etc.). This paper compares the measured chirality detected in the amino acids of carbonaceous meteorites with the effect of these diverse abiotic processes. IT is concluded that the levels observed are inconsistent with post-arrival biological contamination or with any of the currently known abiotic production mechanisms. However, they are consistent with ancient biological processes on the meteorite parent body. This paper will consider these chiral biomarkers in view of the detection of possible microfossils found in the Orgueil and Murchison carbonaceous meteorites. Energy dispersive x-ray spectroscopy (EDS) data obtained on these morphological biomarkers will be

  7. Revealing structural and dynamical properties of high density lipoproteins through molecular simulations

    DEFF Research Database (Denmark)

    Koivuniemi, A.; Vattulainen, I.

    2012-01-01

    The structure and function of high density lipoprotein (HDL) particles have intrigued the scientific community for decades because of their crucial preventive role in coronary heart disease. However, it has been a taunting task to reveal the precise molecular structure and dynamics of HDL. Further......, because of the complex composition of HDL, understanding the impact of its structure and dynamics on the function of HDL in reverse cholesterol transport has also been a major issue. Recent progress in molecular simulation methodology and computing power has made a difference, as it has enabled...... essentially atomistic considerations of HDL particles over microsecond time scales, thereby proving substantial added value to experimental research. In this article, we discuss recent highlights concerning the structure and dynamics of HDL particles as revealed by atomistic and coarse-grained molecular...

  8. Sediment dynamics in paired High Arctic lakes revealed from high-resolution swath bathymetry and acoustic stratigraphy surveys

    Science.gov (United States)

    Normandeau, A.; Lamoureux, S. F.; Lajeunesse, P.; Francus, P.

    2016-09-01

    High Arctic lakes are commonly used for paleoclimatic reconstructions because they are particularly sensitive to climate variability. However, the processes leading to sediment deposition and distribution in these lakes are often poorly understood. Here for the first time in the Canadian High Arctic, we present original data resulting from swath bathymetry and subbottom surveys carried out on two lakes at Cape Bounty, Melville Island. The results reveal the dynamic nature of the lakes, in which mass movement deposits and bedforms on the deltas reflect frequent slope instabilities and hyperpycnal flow activity. The analysis of the mass movement deposits reveals that small blocky debris flows/avalanches, debris flows, and a slide occurred during the Holocene. These mass movements are believed to have been triggered by earthquakes and potentially by permafrost thawing along the shoreline. Altogether, these mass movement deposits cover more than 30% of the lake floors. Additionally, the river deltas on both lakes were mapped and reveal the presence of several gullies and bedforms. The presence of gullies along the delta front indicates that hyperpycnal flows generated at the river mouth can transport sediment in different trajectories downslope, resulting in a different sediment accumulation pattern and record. The dynamic nature of these two lakes suggests that further analysis on sediment transport and distribution within Arctic lakes is required in order to improve paleoclimatic reconstructions.

  9. Cellular Proteases as Cancer Biomarkers: A Review

    Directory of Open Access Journals (Sweden)

    Sarah R. Röthlisberger

    2010-12-01

    Full Text Available Over the past few decades a variety of biomolecules have been proposed as diagnostic biomarkers and predictors of severity for transmissible and nontransmissible diseases. Studies in a range of cancers have revealed many biomarkers with great potential in cancer diagnosis, in establishing tumor stage, progression, and response to therapies; such as the Kallikrein and Metalloproteinase families. Traditionally blood (serum and tissue have been the main biological sources of biomarker discovery, but in the past decade urine has emerged as a promising source of cancer biomarkers. In this review we will focus on two large families, the Kallikrein family of serine proteases discovered in serum, and the Metalloproteinase family of zinc proteases discovered in urine, as potential cancer biomarkers.

  10. High-resolution blood-pool-contrast-enhanced MR angiography in glioblastoma: tumor-associated neovascularization as a biomarker for patient survival. A preliminary study

    Energy Technology Data Exchange (ETDEWEB)

    Puig, Josep; Blasco, Gerard; Remollo, Sebastian; Hernandez, David; Pedraza, Salvador [Hospital Universitari Dr Josep Trueta, Research Unit of Diagnostic Imaging Institute (IDI), Department of Radiology [Girona Biomedical Research Institute] IDIBGI, Girona (Spain); Daunis-i-Estadella, Josep; Mateu, Gloria [University of Girona, Department of Computer Science, Applied Mathematics and Statistics, Girona (Spain); Alberich-Bayarri, Angel [La Fe Polytechnics and University Hospital, Biomedical Imaging Research Group (GIBI230), La Fe Health Research Institute, Valencia (Spain); Essig, Marco [University of Manitoba, Department of Radiology, Winnipeg (Canada); Jain, Rajan [NYU School of Medicine, Division of Neuroradiology, Department of Radiology, New York, NY (United States); Puigdemont, Montserrat [Hospital Universitari Dr Josep Trueta, Catalan Institute of Oncology (ICO), Hospital Cancer Registry, Girona (Spain); Sanchez-Gonzalez, Javier [Philips Healthcare Iberica, Madrid (Spain); Wintermark, Max [Stanford University, Department of Radiology, Neuroradiology Division, Palo Alto, CA (United States)

    2016-01-15

    The objective of the study was to determine whether tumor-associated neovascularization on high-resolution gadofosveset-enhanced magnetic resonance angiography (MRA) is a useful biomarker for predicting survival in patients with newly diagnosed glioblastomas. Before treatment, 35 patients (25 men; mean age, 64 ± 14 years) with glioblastoma underwent MRI including first-pass dynamic susceptibility contrast (DSC) perfusion and post-contrast T1WI sequences with gadobutrol (0.1 mmol/kg) and, 48 h later, high-resolution MRA with gadofosveset (0.03 mmol/kg). Volumes of interest for contrast-enhancing lesion (CEL), non-CEL, and contralateral normal-appearing white matter were obtained, and DSC perfusion and DWI parameters were evaluated. Prognostic factors were assessed by Kaplan-Meier survival and Cox proportional hazards model. Eighteen (51.42 %) glioblastomas were hypervascular on high-resolution MRA. Hypervascular glioblastomas were associated with higher CEL volume and lower Karnofsky score. Median survival rates for patients with hypovascular and hypervascular glioblastomas treated with surgery, radiotherapy, and chemotherapy were 15 and 9.75 months, respectively (P < 0.001). Tumor-associated neovascularization was the best predictor of survival at 5.25 months (AUC = 0.794, 81.2 % sensitivity, 77.8 % specificity, 76.5 % positive predictive value, 82.4 % negative predictive value) and yielded the highest hazard ratio (P < 0.001). Tumor-associated neovascularization detected on high-resolution blood-pool-contrast-enhanced MRA of newly diagnosed glioblastoma seems to be a useful biomarker that correlates with worse survival. (orig.)

  11. Hours of high-frequency stimulations reveal intracellular neuronal trends in vivo

    Science.gov (United States)

    Brama, H.; Goldental, A.; Vardi, R.; Stern, E. A.; Kanter, I.

    2016-11-01

    The neuronal response to controlled stimulations in vivo has been classically estimated using a limited number of events. Here we show that hours of high-frequency stimulations and recordings of neurons in vivo reveal previously unknown response phases of neurons in the intact brain. Results indicate that for stimulation frequencies below a critical neuronal characteristic frequency, f c, response timings are stabilized to tens-of-microseconds accuracy. For stimulation frequencies exceeding f c the firing frequency is saturated and independent of the stimulation frequency, as a result of random neuronal response failures. This neuronal plasticity, previously shown in vitro, supports a robust mechanism for low firing rates on a network level.

  12. Biomarkers in Veterinary Medicine.

    Science.gov (United States)

    Myers, Michael J; Smith, Emily R; Turfle, Phillip G

    2017-02-08

    This article summarizes the relevant definitions related to biomarkers; reviews the general processes related to biomarker discovery and ultimate acceptance and use; and finally summarizes and reviews, to the extent possible, examples of the types of biomarkers used in animal species within veterinary clinical practice and human and veterinary drug development. We highlight opportunities for collaboration and coordination of research within the veterinary community and leveraging of resources from human medicine to support biomarker discovery and validation efforts for veterinary medicine.

  13. Combination of biomarkers

    DEFF Research Database (Denmark)

    Thurfjell, Lennart; Lötjönen, Jyrki; Lundqvist, Roger;

    2012-01-01

    The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury.......The New National Institute on Aging-Alzheimer's Association diagnostic guidelines for Alzheimer's disease (AD) incorporate biomarkers in the diagnostic criteria and suggest division of biomarkers into two categories: Aβ accumulation and neuronal degeneration or injury....

  14. Current and future biomarkers in allergic asthma.

    Science.gov (United States)

    Zissler, U M; Esser-von Bieren, J; Jakwerth, C A; Chaker, A M; Schmidt-Weber, C B

    2016-04-01

    Diagnosis early in life, sensitization, asthma endotypes, monitoring of disease and treatment progression are key motivations for the exploration of biomarkers for allergic rhinitis and allergic asthma. The number of genes related to allergic rhinitis and allergic asthma increases steadily; however, prognostic genes have not yet entered clinical application. We hypothesize that the combination of multiple genes may generate biomarkers with prognostic potential. The current review attempts to group more than 161 different potential biomarkers involved in respiratory inflammation to pave the way for future classifiers. The potential biomarkers are categorized into either epithelial or infiltrate-derived or mixed origin, epithelial biomarkers. Furthermore, surface markers were grouped into cell-type-specific categories. The current literature provides multiple biomarkers for potential asthma endotypes that are related to T-cell phenotypes such as Th1, Th2, Th9, Th17, Th22 and Tregs and their lead cytokines. Eosinophilic and neutrophilic asthma endotypes are also classified by epithelium-derived CCL-26 and osteopontin, respectively. There are currently about 20 epithelium-derived biomarkers exclusively derived from epithelium, which are likely to innovate biomarker panels as they are easy to sample. This article systematically reviews and categorizes genes and collects current evidence that may promote these biomarkers to become part of allergic rhinitis or allergic asthma classifiers with high prognostic value.

  15. Representing high throughput expression profiles via perturbation barcodes reveals compound targets.

    Science.gov (United States)

    Filzen, Tracey M; Kutchukian, Peter S; Hermes, Jeffrey D; Li, Jing; Tudor, Matthew

    2017-02-01

    High throughput mRNA expression profiling can be used to characterize the response of cell culture models to perturbations such as pharmacologic modulators and genetic perturbations. As profiling campaigns expand in scope, it is important to homogenize, summarize, and analyze the resulting data in a manner that captures significant biological signals in spite of various noise sources such as batch effects and stochastic variation. We used the L1000 platform for large-scale profiling of 978 representative genes across thousands of compound treatments. Here, a method is described that uses deep learning techniques to convert the expression changes of the landmark genes into a perturbation barcode that reveals important features of the underlying data, performing better than the raw data in revealing important biological insights. The barcode captures compound structure and target information, and predicts a compound's high throughput screening promiscuity, to a higher degree than the original data measurements, indicating that the approach uncovers underlying factors of the expression data that are otherwise entangled or masked by noise. Furthermore, we demonstrate that visualizations derived from the perturbation barcode can be used to more sensitively assign functions to unknown compounds through a guilt-by-association approach, which we use to predict and experimentally validate the activity of compounds on the MAPK pathway. The demonstrated application of deep metric learning to large-scale chemical genetics projects highlights the utility of this and related approaches to the extraction of insights and testable hypotheses from big, sometimes noisy data.

  16. Representing high throughput expression profiles via perturbation barcodes reveals compound targets

    Science.gov (United States)

    Kutchukian, Peter S.; Li, Jing; Tudor, Matthew

    2017-01-01

    High throughput mRNA expression profiling can be used to characterize the response of cell culture models to perturbations such as pharmacologic modulators and genetic perturbations. As profiling campaigns expand in scope, it is important to homogenize, summarize, and analyze the resulting data in a manner that captures significant biological signals in spite of various noise sources such as batch effects and stochastic variation. We used the L1000 platform for large-scale profiling of 978 representative genes across thousands of compound treatments. Here, a method is described that uses deep learning techniques to convert the expression changes of the landmark genes into a perturbation barcode that reveals important features of the underlying data, performing better than the raw data in revealing important biological insights. The barcode captures compound structure and target information, and predicts a compound’s high throughput screening promiscuity, to a higher degree than the original data measurements, indicating that the approach uncovers underlying factors of the expression data that are otherwise entangled or masked by noise. Furthermore, we demonstrate that visualizations derived from the perturbation barcode can be used to more sensitively assign functions to unknown compounds through a guilt-by-association approach, which we use to predict and experimentally validate the activity of compounds on the MAPK pathway. The demonstrated application of deep metric learning to large-scale chemical genetics projects highlights the utility of this and related approaches to the extraction of insights and testable hypotheses from big, sometimes noisy data. PMID:28182661

  17. High Expression of LAMP3 Is a Novel Biomarker of Poor Prognosis in Patients with Esophageal Squamous Cell Carcinoma

    Directory of Open Access Journals (Sweden)

    Xiaoyu Liao

    2015-07-01

    Full Text Available Lysosomal-associated membrane protein 3 (LAMP3, identified as a molecular marker of mature dendritic cells, is one of the LAMP family members. Its expression was induced by hypoxia, and was associated with hypoxia mediated metastasis in breast and cervical cancers. However, epithelial expression of LAMP3 and its prognostic value in esophageal squamous cell carcinoma (ESCC is still unknown. In the current study, mRNA expression of LAMP3 in 157 ESCC tissues and 50 adjacent normal tissues was detected by quantitative real-time PCR (qRT-PCR. LAMP3 protein expression in 46 paired cancerous and normal tissues was detected by immunohistochemistry (IHC. Then, DNA copy number was examined to observe its potential correlation with mRNA expression. The results showed that both mRNA and protein expression level of LAMP3 was significantly higher in cancerous tissues compared with normal controls (p < 0.001. LAMP3 DNA copy number was amplified in 70% of ESCC tissues and positive correlated with mRNA expression (p = 0.037. Furthermore, patients with higher LAMP3 expression had worse overall survival (HR = 1.90, 95% CI = 1.17–3.09, p = 0.010 and disease-free survival (HR = 1.80, 95% CI = 1.18–2.74, p = 0.006. In conclusion, our results suggest that epithelial LAMP3 expression is an independent prognostic biomarker for ESCC.

  18. Prediction of transition from ultra-high risk to first-episode psychosis using a probabilistic model combining history, clinical assessment and fatty-acid biomarkers

    Science.gov (United States)

    Clark, S R; Baune, B T; Schubert, K O; Lavoie, S; Smesny, S; Rice, S M; Schäfer, M R; Benninger, F; Feucht, M; Klier, C M; McGorry, P D; Amminger, G P

    2016-01-01

    Current criteria identifying patients with ultra-high risk of psychosis (UHR) have low specificity, and less than one-third of UHR cases experience transition to psychosis within 3 years of initial assessment. We explored whether a Bayesian probabilistic multimodal model, combining baseline historical and clinical risk factors with biomarkers (oxidative stress, cell membrane fatty acids, resting quantitative electroencephalography (qEEG)), could improve this specificity. We analyzed data of a UHR cohort (n=40) with a 1-year transition rate of 28%. Positive and negative likelihood ratios were calculated for predictor variables with statistically significant receiver operating characteristic curves (ROCs), which excluded oxidative stress markers and qEEG parameters as significant predictors of transition. We clustered significant variables into historical (history of drug use), clinical (Positive and Negative Symptoms Scale positive, negative and general scores and Global Assessment of Function) and biomarker (total omega-3, nervonic acid) groups, and calculated the post-test probability of transition for each group and for group combinations using the odds ratio form of Bayes' rule. Combination of the three variable groups vastly improved the specificity of prediction (area under ROC=0.919, sensitivity=72.73%, specificity=96.43%). In this sample, our model identified over 70% of UHR patients who transitioned within 1 year, compared with 28% identified by standard UHR criteria. The model classified 77% of cases as very high or low risk (P>0.9, <0.1) based on history and clinical assessment, suggesting that a staged approach could be most efficient, reserving fatty-acid markers for 23% of cases remaining at intermediate probability following bedside interview. PMID:27648919

  19. Pyrosequencing reveals highly diverse and species-specific microbial communities in sponges from the Red Sea

    KAUST Repository

    Lee, Onon

    2010-11-18

    Marine sponges are associated with a remarkable array of microorganisms. Using a tag pyrosequencing technology, this study was the first to investigate in depth the microbial communities associated with three Red Sea sponges, Hyrtios erectus, Stylissa carteri and Xestospongia testudinaria. We revealed highly diverse sponge-associated bacterial communities with up to 1000 microbial operational taxonomic units (OTUs) and richness estimates of up to 2000 species. Altogether, 26 bacterial phyla were detected from the Red Sea sponges, 11 of which were absent from the surrounding sea water and 4 were recorded in sponges for the first time. Up to 100 OTUs with richness estimates of up to 300 archaeal species were revealed from a single sponge species. This is by far the highest archaeal diversity ever recorded for sponges. A non-negligible proportion of unclassified reads was observed in sponges. Our results demonstrated that the sponge-associated microbial communities remained highly consistent in the same sponge species from different locations, although they varied at different degrees among different sponge species. A significant proportion of the tag sequences from the sponges could be assigned to one of the sponge-specific clusters previously defined. In addition, the sponge-associated microbial communities were consistently divergent from those present in the surrounding sea water. Our results suggest that the Red Sea sponges possess highly sponge-specific or even sponge-species-specific microbial communities that are resistant to environmental disturbance, and much of their microbial diversity remains to be explored. © 2011 International Society for Microbial Ecology All rights reserved.

  20. Biomarkers of silicosis: Potential candidates

    Directory of Open Access Journals (Sweden)

    Tiwari R

    2005-01-01

    Full Text Available Silica dust is widely prevalent in the atmosphere and more common than the other types of dust, thus making silicosis the most frequently occurring pneumoconiosis. In India also, studies carried out by National Institute of Occupational Health have shown high prevalence of silicosis in small factories and even in nonoccupational exposed subjects. The postero-anterior chest radiographs remain the key tool in diagnosing and assessing the extent and severity of interstitial lung disease. Although Computed Tomography detects finer anatomical structure than radiography it could not get popularity because of its cost. On the basis of histological features of silicosis many potential biomarkers such as Cytokines, Tumor Necrosis Factor, Interleukin 1, Angiotensin Converting Enzyme, Serum Copper, Fas ligand (FasL, etc. have been tried. However, further studies are needed to establish these potential biomarkers as true biomarker of silicosis.

  1. The effects of the mediterranean diet on biomarkers of vascular wall inflammation and plaque vulnerability in subjects with high risk for cardiovascular disease. A randomized trial.

    Directory of Open Access Journals (Sweden)

    Rosa Casas

    Full Text Available BACKGROUND: Adherence to the Mediterranean diet (MD is associated with reduced morbidity and mortality due to cardiovascular disease. However, how the MD exerts its effects is not fully known. AIM: To assess the 12-month effects of two enhanced MDs compared to a low-fat diet on inflammatory biomarkers related to atherosclerosis and plaque vulnerability in a subcohort of the PREDIMED (Prevención con Dieta Mediterránea study. METHODS: A total of 164 participants at high risk for cardiovascular disease were randomized into three diet groups: MD supplemented with 50mL/d of extra virgin olive oil (MD+EVOO or 30 g/d of nuts (MD+Nuts and a low-fat diet. Changes in classical cardiovascular risk factors, inflammatory biomarkers of atherosclerosis and plaque vulnerability were measured after 12 months of intervention. RESULTS: Compared to participants in the low-fat diet group, those receiving MD+EVOO and MD+Nuts showed a higher decrease in systolic (6mmHg and diastolic (3mmHg blood pressure (P = 0.02; both, as well as a reduction of 10% and 8% in LDL-cholesterol (P = 0.04, respectively. Patients in the MD+Nuts group showed a significant reduction of 34% in CD40 expression on monocyte surface compared to low-fat diet patients (P = 0.03. In addition, inflammatory biomarkers related to plaque instability such as C-reactive protein and interleukin-6 were reduced by 45% and 35% and 95% and 90% in the MD+EVOO and MD+Nuts groups, respectively (P<0.05; all compared to the low-fat diet group. Likewise, sICAM and P-selectin were also reduced by 50% and 27%, respectively in the MD+EVOO group (P = 0.04 and P-selectin by 19% in MD+Nuts group (P = 0.04 compared to the low-fat diet group. CONCLUSIONS: Adherence to the MD is associated with an increase in serum markers of atheroma plaque stability which may explain, at least in part, the protective role of MD against ischemic heart disease. TRIAL REGISTRATION: www.controlled-trials.com ISRCTN

  2. Essay contest reveals misconceptions of high school students in genetics content.

    Science.gov (United States)

    Mills Shaw, Kenna R; Van Horne, Katie; Zhang, Hubert; Boughman, Joann

    2008-03-01

    National educational organizations have called upon scientists to become involved in K-12 education reform. From sporadic interaction with students to more sustained partnerships with teachers, the engagement of scientists takes many forms. In this case, scientists from the American Society of Human Genetics (ASHG), the Genetics Society of America (GSA), and the National Society of Genetic Counselors (NSGC) have partnered to organize an essay contest for high school students as part of the activities surrounding National DNA Day. We describe a systematic analysis of 500 of 2443 total essays submitted in response to this contest over 2 years. Our analysis reveals the nature of student misconceptions in genetics, the possible sources of these misconceptions, and potential ways to galvanize genetics education.

  3. Unusually High Archaeal Diversity in a Crystallizer Pond, Pomorie Salterns, Bulgaria, Revealed by Phylogenetic Analysis

    Directory of Open Access Journals (Sweden)

    Margarita Kambourova

    2016-01-01

    Full Text Available Recent studies on archaeal diversity in few salterns have revealed heterogeneity between sites and unique structures of separate places that hinder drawing of generalized conclusions. Investigations on the archaeal community composition in P18, the biggest crystallizer pond in Pomorie salterns (PS (34% salinity, demonstrated unusually high number of presented taxa in hypersaline environment. Archaeal clones were grouped in 26 different operational taxonomic units (OTUs assigned to 15 different genera from two orders, Halobacteriales and Haloferacales. All retrieved sequences were related to culturable halophiles or unculturable clones from saline (mostly hypersaline niches. New sequences represented 53.9% of archaeal OTUs. Some of them formed separate branches with 90% similarity to the closest neighbor. Present results significantly differed from the previous investigations in regard to the number of presented genera, the domination of some genera not reported before in such extreme niche, and the identification of previously undiscovered 16S rRNA sequences.

  4. Rapid ester biosynthesis screening reveals a high activity alcohol-O-acyltransferase (AATase) from tomato fruit.

    Science.gov (United States)

    Lin, Jyun-Liang; Zhu, Jie; Wheeldon, Ian

    2016-05-01

    Ethyl and acetate esters are naturally produced in various yeasts, plants, and bacteria. The biosynthetic pathways that produce these esters share a common reaction step, the condensation of acetyl/acyl-CoA with an alcohol by alcohol-O-acetyl/acyltransferase (AATase). Recent metabolic engineering efforts exploit AATase activity to produce fatty acid ethyl esters as potential diesel fuel replacements as well as short- and medium-chain volatile esters as fragrance and flavor compounds. These efforts have been limited by the lack of a rapid screen to quantify ester biosynthesis. Enzyme engineering efforts have also been limited by the lack of a high throughput screen for AATase activity. Here, we developed a high throughput assay for AATase activity and used this assay to discover a high activity AATase from tomato fruit, Solanum lycopersicum (Atf-S.l). Atf1-S.l exhibited broad specificity towards acyl-CoAs with chain length from C4 to C10 and was specific towards 1-pentanol. The AATase screen also revealed new acyl-CoA substrate specificities for Atf1, Atf2, Eht1, and Eeb1 from Saccharomyces cerevisiae, and Atf-C.m from melon fruit, Cucumis melo, thus increasing the pool of characterized AATases that can be used in ester biosynthesis of ester-based fragrance and flavor compounds as well as fatty acid ethyl ester biofuels.

  5. Highly selective and automated online SPE LC-MS3 method for determination of cortisol and cortisone in human hair as biomarker for stress related diseases.

    Science.gov (United States)

    Quinete, Natalia; Bertram, Jens; Reska, Marcus; Lang, Jessica; Kraus, Thomas

    2015-03-01

    Hair analysis has been increasingly used to establish long-term biomarkers of exposure to both endogenous and exogenous substances, with a special emphasis on steroidal hormones. Hair cortisol and cortisone have been associated to physiological and psychological strains, anxiety and depression. Hair is a very complex matrix, which might jeopardize analyte detection at low concentrations. A new, highly selective and sensitive method based on fragments of second order, MS(3) (MS/MS/MS), was developed and validated for the analysis of hair cortisol and cortisone. An online solid phase extraction was performed on a C8 restricted access material (RAM) phase following by separation on a reversed-phase C18 column using methanol and 0.02% ammonium hydroxide as mobile phase. The developed method required minimal sample preparation and the injection of only 50 µL of sample leading to a LOQ of 2 pg mg(-1). Good linear responses were observed in the range 2-200 pg mg(-1) (R(2)>0.99) and extraction recoveries ranged between 77-125% and 70-123% for cortisol and cortisone, respectively. Intra- and inter-assay coefficients of variation were between 1.4 and 14%. In order to evaluate the applicability of the method, preliminary tests (N=33) were conducted in 3 cm hair samples (close to scalp) of healthy volunteers with an age range of 4-63. Average concentrations in hair were 12.7±14 pg mg(-1) and 41.6±42 pg mg(-1) for cortisol and cortisone, respectively. Further investigations on cortisol and cortisone as biomarkers for chronic psychological strain will be assessed as a next step.

  6. Unprecedented high-resolution view of bacterial operon architecture revealed by RNA sequencing.

    Science.gov (United States)

    Conway, Tyrrell; Creecy, James P; Maddox, Scott M; Grissom, Joe E; Conkle, Trevor L; Shadid, Tyler M; Teramoto, Jun; San Miguel, Phillip; Shimada, Tomohiro; Ishihama, Akira; Mori, Hirotada; Wanner, Barry L

    2014-07-08

    We analyzed the transcriptome of Escherichia coli K-12 by strand-specific RNA sequencing at single-nucleotide resolution during steady-state (logarithmic-phase) growth and upon entry into stationary phase in glucose minimal medium. To generate high-resolution transcriptome maps, we developed an organizational schema which showed that in practice only three features are required to define operon architecture: the promoter, terminator, and deep RNA sequence read coverage. We precisely annotated 2,122 promoters and 1,774 terminators, defining 1,510 operons with an average of 1.98 genes per operon. Our analyses revealed an unprecedented view of E. coli operon architecture. A large proportion (36%) of operons are complex with internal promoters or terminators that generate multiple transcription units. For 43% of operons, we observed differential expression of polycistronic genes, despite being in the same operons, indicating that E. coli operon architecture allows fine-tuning of gene expression. We found that 276 of 370 convergent operons terminate inefficiently, generating complementary 3' transcript ends which overlap on average by 286 nucleotides, and 136 of 388 divergent operons have promoters arranged such that their 5' ends overlap on average by 168 nucleotides. We found 89 antisense transcripts of 397-nucleotide average length, 7 unannotated transcripts within intergenic regions, and 18 sense transcripts that completely overlap operons on the opposite strand. Of 519 overlapping transcripts, 75% correspond to sequences that are highly conserved in E. coli (>50 genomes). Our data extend recent studies showing unexpected transcriptome complexity in several bacteria and suggest that antisense RNA regulation is widespread. Importance: We precisely mapped the 5' and 3' ends of RNA transcripts across the E. coli K-12 genome by using a single-nucleotide analytical approach. Our resulting high-resolution transcriptome maps show that ca. one-third of E. coli operons are

  7. Migration of Frosts from High-Albedo Regions of Pluto: what New Horizons Reveals

    Science.gov (United States)

    Buratti, Bonnie J.; Stern, S. A.; Weaver, Hal A.; Young, Leslie A.; Olkin, Cathy B.; Ennico, Kimberly; Binzel, Richard P.; Zangari, Amanda; Earle, Alissa M.

    2015-11-01

    With its high eccentricity and obliquity, Pluto should exhibit seasonal volatile transport on its surface. Several lines of evidence support this transport: doubling of Pluto’s atmospheric pressure over the past two decades (Young et al., 2013, Ap. J. 766, L22; Olkin et al., 2015, Icarus 246, 230); changes in its historical rotational light curve, once all variations due to viewing geometry have been modelled (Buratti et al., 2015; Ap. J. 804, L6); and changes in HST albedo maps (Buie et al., 2010, Astron. J. 139, 1128). New Horizons LORRI images reveal that the region of greatest albedo change is not the polar cap(s) of Pluto, but the feature informally named Tombaugh Regio (TR). This feature has a normal reflectance as high as ~0.8 in some places, and it is superposed on older, lower-albedo pre-existing terrain with an albedo of only ~0.10. This contrast is larger than any other body in the Solar System, except for Iapetus. This albedo dichotomy leads to a complicated system of cold-trapping and thermal segregation, beyond the simple picture of seasonal volatile transport. Whatever the origin of TR, it initially acted as a cold trap, as the temperature differential between the high and low albedo regions could be enormous, possibly approaching 20K, based on their albedo differences and assuming their normalized phase curves are similar. This latter assumption will be refined as the full New Horizons data set is returned.Over six decades of ground-based photometry suggest that TR has been decreasing in albedo over the last 25 years. Possible causes include changing insolation angles, or sublimation from the edges where the high-albedo material impinges on a much warmer substrate.Funding by the NASA New Horizons Project acknowledged.

  8. A CLUSTER IN THE MAKING: ALMA REVEALS THE INITIAL CONDITIONS FOR HIGH-MASS CLUSTER FORMATION

    Energy Technology Data Exchange (ETDEWEB)

    Rathborne, J. M.; Contreras, Y. [CSIRO Astronomy and Space Science, P.O. Box 76, Epping NSW, 1710 (Australia); Longmore, S. N.; Bastian, N. [Astrophysics Research Institute, Liverpool John Moores University, 146 Brownlow Hill, Liverpool L3 5RF (United Kingdom); Jackson, J. M. [Institute for Astrophysical Research, Boston University, Boston, MA 02215 (United States); Alves, J. F. [University of Vienna, Türkenschanzstrasse 17, A-1180 Vienna (Austria); Bally, J. [Center for Astrophysics and Space Astronomy, University of Colorado, UCB 389, Boulder, CO 8030 (United States); Foster, J. B. [Department of Astronomy, Yale University, P.O. Box 208101 New Haven, CT 06520-8101 (United States); Garay, G. [Universidad de Chile, Camino El Observatorio1515, Las Condes, Santiago (Chile); Kruijssen, J. M. D. [Max-Planck Institut fur Astrophysik, Karl-Schwarzschild-Strasse 1, D-85748, Garching (Germany); Testi, L. [European Southern Observatory, Karl-Schwarzschild-Str. 2, D-85748 Garching bei Munchen (Germany); Walsh, A. J., E-mail: Jill.Rathborne@csiro.au [International Centre for Radio Astronomy Research, Curtin University, GPO Box U1987, Perth (Australia)

    2015-04-01

    G0.253+0.016 is a molecular clump that appears to be on the verge of forming a high-mass cluster: its extremely low dust temperature, high mass, and high density, combined with its lack of prevalent star formation, make it an excellent candidate for an Arches-like cluster in a very early stage of formation. Here we present new Atacama Large Millimeter/Sub-millimeter Array observations of its small-scale (∼0.07 pc) 3 mm dust continuum and molecular line emission from 17 different species that probe a range of distinct physical and chemical conditions. The data reveal a complex network of emission features with a complicated velocity structure: there is emission on all spatial scales, the morphology of which ranges from small, compact regions to extended, filamentary structures that are seen in both emission and absorption. The dust column density is well traced by molecules with higher excitation energies and critical densities, consistent with a clump that has a denser interior. A statistical analysis supports the idea that turbulence shapes the observed gas structure within G0.253+0.016. We find a clear break in the turbulent power spectrum derived from the optically thin dust continuum emission at a spatial scale of ∼0.1 pc, which may correspond to the spatial scale at which gravity has overcome the thermal pressure. We suggest that G0.253+0.016 is on the verge of forming a cluster from hierarchical, filamentary structures that arise from a highly turbulent medium. Although the stellar distribution within high-mass Arches-like clusters is compact, centrally condensed, and smooth, the observed gas distribution within G0.253+0.016 is extended, with no high-mass central concentration, and has a complex, hierarchical structure. If this clump gives rise to a high-mass cluster and its stars are formed from this initially hierarchical gas structure, then the resulting cluster must evolve into a centrally condensed structure via a dynamical process.

  9. The high resolution structure of tyrocidine A reveals an amphipathic dimer.

    Science.gov (United States)

    Loll, Patrick J; Upton, Elizabeth C; Nahoum, Virginie; Economou, Nicoleta J; Cocklin, Simon

    2014-05-01

    Tyrocidine A, one of the first antibiotics ever to be discovered, is a cyclic decapeptide that binds to membranes of target bacteria, disrupting their integrity. It is active against a broad spectrum of Gram-positive organisms, and has recently engendered interest as a potential scaffold for the development of new drugs to combat antibiotic-resistant pathogens. We present here the X-ray crystal structure of tyrocidine A at a resolution of 0.95Å. The structure reveals that tyrocidine forms an intimate and highly amphipathic homodimer made up of four beta strands that associate into a single, highly curved antiparallel beta sheet. We used surface plasmon resonance and potassium efflux assays to demonstrate that tyrocidine binds tightly to mimetics of bacterial membranes with an apparent dissociation constant (K(D)) of 10 μM, and efficiently permeabilizes bacterial cells at concentrations equal to and below the K(D). Using variant forms of tyrocidine in which the fluorescent probe p-cyano-phenylalanine had been inserted on either the polar or apolar face of the molecule, we performed fluorescence quenching experiments, using both water-soluble and membrane-embedded quenchers. The quenching results, together with the structure, strongly support a membrane association model in which the convex, apolar face of tyrocidine's beta sheet is oriented toward the membrane interior, while the concave, polar face is presented to the aqueous phase.

  10. Single Nucleus Genome Sequencing Reveals High Similarity among Nuclei of an Endomycorrhizal Fungus

    Science.gov (United States)

    Zhang, Zhonghua; Ivanov, Sergey; Saunders, Diane G. O.; Mu, Desheng; Pang, Erli; Cao, Huifen; Cha, Hwangho; Lin, Tao; Zhou, Qian; Shang, Yi; Li, Ying; Sharma, Trupti; van Velzen, Robin; de Ruijter, Norbert; Aanen, Duur K.; Win, Joe; Kamoun, Sophien; Bisseling, Ton; Geurts, René; Huang, Sanwen

    2014-01-01

    Nuclei of arbuscular endomycorrhizal fungi have been described as highly diverse due to their asexual nature and absence of a single cell stage with only one nucleus. This has raised fundamental questions concerning speciation, selection and transmission of the genetic make-up to next generations. Although this concept has become textbook knowledge, it is only based on studying a few loci, including 45S rDNA. To provide a more comprehensive insight into the genetic makeup of arbuscular endomycorrhizal fungi, we applied de novo genome sequencing of individual nuclei of Rhizophagus irregularis. This revealed a surprisingly low level of polymorphism between nuclei. In contrast, within a nucleus, the 45S rDNA repeat unit turned out to be highly diverged. This finding demystifies a long-lasting hypothesis on the complex genetic makeup of arbuscular endomycorrhizal fungi. Subsequent genome assembly resulted in the first draft reference genome sequence of an arbuscular endomycorrhizal fungus. Its length is 141 Mbps, representing over 27,000 protein-coding gene models. We used the genomic sequence to reinvestigate the phylogenetic relationships of Rhizophagus irregularis with other fungal phyla. This unambiguously demonstrated that Glomeromycota are more closely related to Mucoromycotina than to its postulated sister Dikarya. PMID:24415955

  11. DNA Barcoding Reveals High Cryptic Diversity of the Freshwater Halfbeak Genus Hemirhamphodon from Sundaland

    Science.gov (United States)

    Zainal Abidin, Muchlisin; Pulungan, Chaidir Parlindungan

    2016-01-01

    DNA barcoding of the cytochrome oxidase subunit I (COI) gene was utilized to assess the species diversity of the freshwater halfbeak genus Hemirhamphodon. A total of 201 individuals from 46 locations in Peninsular Malaysia, north Borneo (Sarawak) and Sumatra were successfully amplified for 616 base pairs of the COI gene revealing 231 variable and 213 parsimony informative sites. COI gene trees showed that most recognized species form monophyletic clades with high bootstrap support. Pairwise within species comparisons exhibited a wide range of intraspecific diversity from 0.0% to 14.8%, suggesting presence of cryptic diversity. This finding was further supported by barcode gap analysis, ABGD and the constructed COI gene trees. In particular, H. pogonognathus from Kelantan (northeast Peninsular Malaysia) diverged from the other H. pogonognathus groups with distances ranging from 7.8 to 11.8%, exceeding the nearest neighbor taxon. High intraspecific diversity was also observed in H. byssus and H. kuekanthali, but of a lower magnitude. This study also provides insights into endemism and phylogeographic structuring, and limited support for the Paleo-drainage divergence hypothesis as a driver of speciation in the genus Hemirhamphodon. PMID:27657915

  12. Histopathology reveals correlative and unique phenotypes in a high-throughput mouse phenotyping screen.

    Science.gov (United States)

    Adissu, Hibret A; Estabel, Jeanne; Sunter, David; Tuck, Elizabeth; Hooks, Yvette; Carragher, Damian M; Clarke, Kay; Karp, Natasha A; Newbigging, Susan; Jones, Nora; Morikawa, Lily; White, Jacqueline K; McKerlie, Colin

    2014-05-01

    The Mouse Genetics Project (MGP) at the Wellcome Trust Sanger Institute aims to generate and phenotype over 800 genetically modified mouse lines over the next 5 years to gain a better understanding of mammalian gene function and provide an invaluable resource to the scientific community for follow-up studies. Phenotyping includes the generation of a standardized biobank of paraffin-embedded tissues for each mouse line, but histopathology is not routinely performed. In collaboration with the Pathology Core of the Centre for Modeling Human Disease (CMHD) we report the utility of histopathology in a high-throughput primary phenotyping screen. Histopathology was assessed in an unbiased selection of 50 mouse lines with (n=30) or without (n=20) clinical phenotypes detected by the standard MGP primary phenotyping screen. Our findings revealed that histopathology added correlating morphological data in 19 of 30 lines (63.3%) in which the primary screen detected a phenotype. In addition, seven of the 50 lines (14%) presented significant histopathology findings that were not associated with or predicted by the standard primary screen. Three of these seven lines had no clinical phenotype detected by the standard primary screen. Incidental and strain-associated background lesions were present in all mutant lines with good concordance to wild-type controls. These findings demonstrate the complementary and unique contribution of histopathology to high-throughput primary phenotyping of mutant mice.

  13. Histopathology reveals correlative and unique phenotypes in a high-throughput mouse phenotyping screen

    Directory of Open Access Journals (Sweden)

    Hibret A. Adissu

    2014-05-01

    Full Text Available The Mouse Genetics Project (MGP at the Wellcome Trust Sanger Institute aims to generate and phenotype over 800 genetically modified mouse lines over the next 5 years to gain a better understanding of mammalian gene function and provide an invaluable resource to the scientific community for follow-up studies. Phenotyping includes the generation of a standardized biobank of paraffin-embedded tissues for each mouse line, but histopathology is not routinely performed. In collaboration with the Pathology Core of the Centre for Modeling Human Disease (CMHD we report the utility of histopathology in a high-throughput primary phenotyping screen. Histopathology was assessed in an unbiased selection of 50 mouse lines with (n=30 or without (n=20 clinical phenotypes detected by the standard MGP primary phenotyping screen. Our findings revealed that histopathology added correlating morphological data in 19 of 30 lines (63.3% in which the primary screen detected a phenotype. In addition, seven of the 50 lines (14% presented significant histopathology findings that were not associated with or predicted by the standard primary screen. Three of these seven lines had no clinical phenotype detected by the standard primary screen. Incidental and strain-associated background lesions were present in all mutant lines with good concordance to wild-type controls. These findings demonstrate the complementary and unique contribution of histopathology to high-throughput primary phenotyping of mutant mice.

  14. Microsatellite variability reveals high genetic diversity and low genetic differentiation in a critical giant panda population

    Institute of Scientific and Technical Information of China (English)

    Jiandong YANG; Zhihe ZHANG; Fujun SHEN; Xuyu YANG; Liang ZHANG; Limin CHEN; Wenping ZHANG; Qing ZHU; Rong HOU

    2011-01-01

    Understanding present patterns of genetic diversity is critical in order to design effective conservation and management strategies for endangered species.Tangjiahe Nature Reserve (NR) is one of the most important national reserves for giant pandas Ailuropoda melanoleuca in China.Previous studies have shown that giant pandas in Tangjiahe NR may be threatened by population decline and fragmentation.Here we used 10 microsatellite DNA markers to assess the genetic variability in the Tangjiahe population.The results indicate a low level of genetic differentiation between the Hongshihe and Motianling subpopulations in the reserve.Assignment tests using the Bayesian clustering method in STRUCTURE identified one genetic cluster from 42 individuals of the two subpopulations.All individuals from the same subpopulation were assigned to one cluster.This indicates high gene flow between subpopulations.F statistic analyses revealed a low Fls-value of 0.024 in the total population and implies a randomly mating population in Tangjiahe NR.Additionally,our data show a high level of genetic diversity for the Tangjiahe population.Mean allele number (A),Allelic richness (AR) and mean expected heterozygosity (HE) for the Tangiiahe population was 5.9,5.173 and 0.703,respectively.This wild giant panda population can be restored through concerted effort [Current Zoology 57 (6):717-724,2011].

  15. Westerly moisture transport to the middle of Himalayas revealed from the high deuterium excess

    Institute of Scientific and Technical Information of China (English)

    TIAN Lide; YAO Tandong; J.W.C.White; YU Wusheng; WANG Ninglian

    2005-01-01

    Previous studies found extremely high d-excess in both ice core and glacial melt water in Dasuopu glacier, Xixiabangma, middle of Himalayas. These values are much higher than the global average and those measured in southwest monsoon precipitation. The d-excess variation in over one year at Nyalam station will clarify this phenomenon. Studies show that the high d-excess is related to the seasonal variation of moisture transport to this region. The d-excess values are low during the southwest monsoon active periods, when moisture originated from the humid ocean surface. The d-excess values are higher in non-monsoon months, when moisture is derived from westerly transport. Winter and spring precipitation accounts for a substantial portion of the annual precipitation, resulting in higher d-excess in the yearly precipitation in the middle of Himalayas than other parts of the southern Tibetan Plateau. This finding reveals that the precipitation in the middle of Himalayas is not purely from southwest monsoon, but a large portion from the westerly transport, which is very important for ice core study in this area.

  16. Single nucleus genome sequencing reveals high similarity among nuclei of an endomycorrhizal fungus.

    Directory of Open Access Journals (Sweden)

    Kui Lin

    2014-01-01

    Full Text Available Nuclei of arbuscular endomycorrhizal fungi have been described as highly diverse due to their asexual nature and absence of a single cell stage with only one nucleus. This has raised fundamental questions concerning speciation, selection and transmission of the genetic make-up to next generations. Although this concept has become textbook knowledge, it is only based on studying a few loci, including 45S rDNA. To provide a more comprehensive insight into the genetic makeup of arbuscular endomycorrhizal fungi, we applied de novo genome sequencing of individual nuclei of Rhizophagus irregularis. This revealed a surprisingly low level of polymorphism between nuclei. In contrast, within a nucleus, the 45S rDNA repeat unit turned out to be highly diverged. This finding demystifies a long-lasting hypothesis on the complex genetic makeup of arbuscular endomycorrhizal fungi. Subsequent genome assembly resulted in the first draft reference genome sequence of an arbuscular endomycorrhizal fungus. Its length is 141 Mbps, representing over 27,000 protein-coding gene models. We used the genomic sequence to reinvestigate the phylogenetic relationships of Rhizophagus irregularis with other fungal phyla. This unambiguously demonstrated that Glomeromycota are more closely related to Mucoromycotina than to its postulated sister Dikarya.

  17. Zero-expansion glass ceramic ZERODUR: recent developments reveal high potential

    Science.gov (United States)

    Hartmann, Peter; Jedamzik, Ralf; Westerhoff, Thomas

    2012-09-01

    ZERODUR® is a well-established material in astronomy and all fields of applications where temperature gradients might limit extreme precision and stability. Together with its rich heritage come a series of recent developments, which reveal the potential of the material for broader and more demanding applications. The outstanding degree of light-weighting achieved with progress in CNC grinding in the last two years shows its high suitability for space telescope mirrors. This is supported by new data on strength enabling higher mechanical loads. Also ground based telescopes benefit from the improved light-weight processing such as solar telescopes and downstream mirrors of extremely large telescopes. More and better data have been collected demonstrating the unique CTE homogeneity of ZERODUR® and its very high reproducibility a necessary precondition for large series mirror production. Deliveries of more than 250 ZERODUR mirrors of 1.5 m in diameter prove the availability of robust industrial serial production capability inevitable for ELT mirror segment production.

  18. Biomarkers in clinical medicine.

    Science.gov (United States)

    Chen, Xiao-He; Huang, Shuwen; Kerr, David

    2011-01-01

    Biomarkers have been used in clinical medicine for decades. With the rise of genomics and other advances in molecular biology, biomarker studies have entered a whole new era and hold promise for early diagnosis and effective treatment of many diseases. A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention (1). They can be classified into five categories based on their application in different disease stages: 1) antecedent biomarkers to identify the risk of developing an illness, 2) screening biomarkers to screen for subclinical disease, 3) diagnostic biomarkers to recognize overt disease, 4) staging biomarkers to categorise disease severity, and 5) prognostic biomarkers to predict future disease course, including recurrence, response to therapy, and monitoring efficacy of therapy (1). Biomarkers can indicate a variety of health or disease characteristics, including the level or type of exposure to an environmental factor, genetic susceptibility, genetic responses to environmental exposures, markers of subclinical or clinical disease, or indicators of response to therapy. This chapter will focus on how these biomarkers have been used in preventive medicine, diagnostics, therapeutics and prognostics, as well as public health and their current status in clinical practice.

  19. Cytokines as Biomarkers in Rheumatoid Arthritis

    Directory of Open Access Journals (Sweden)

    Agata Burska

    2014-01-01

    Full Text Available RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge’s relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  20. Cytokines as biomarkers in rheumatoid arthritis.

    Science.gov (United States)

    Burska, Agata; Boissinot, Marjorie; Ponchel, Frederique

    2014-01-01

    RA is a complex disease that develops as a series of events often referred to as disease continuum. RA would benefit from novel biomarker development for diagnosis where new biomarkers are still needed (even if progresses have been made with the inclusion of ACPA into the ACR/EULAR 2010 diagnostic criteria) and for prognostic notably in at risk of evolution patients with autoantibody-positive arthralgia. Risk biomarkers for rapid evolution or cardiovascular complications are also highly desirable. Monitoring biomarkers would be useful in predicting relapse. Finally, predictive biomarkers for therapy outcome would allow tailoring therapy to the individual. Increasing numbers of cytokines have been involved in RA pathology. Many have the potential as biomarkers in RA especially as their clinical utility is already established in other diseases and could be easily transferable to rheumatology. We will review the current knowledge's relation to cytokine used as biomarker in RA. However, given the complexity and heterogeneous nature of RA, it is unlikely that a single cytokine may provide sufficient discrimination; therefore multiple biomarker signatures may represent more realistic approach for the future of personalised medicine in RA.

  1. Metagenomic approach reveals variation of microbes with arsenic and antimony metabolism genes from highly contaminated soil.

    Science.gov (United States)

    Luo, Jinming; Bai, Yaohui; Liang, Jinsong; Qu, Jiuhui

    2014-01-01

    Microbes have great potential for arsenic (As) and antimony (Sb) bioremediation in heavily contaminated soil because they have the ability to biotransform As and Sb to species that have less toxicity or are more easily removed. In this study, we integrated a metagenomic method with physicochemical characterization to elucidate the composition of microbial community and functional genes (related to As and Sb) in a high As (range from 34.11 to 821.23 mg kg-1) and Sb (range from 226.67 to 3923.07 mg kg-1) contaminated mine field. Metagenomic analysis revealed that microbes from 18 phyla were present in the 5 samples of soil contaminated with high As and Sb. Moreover, redundancy analysis (RDA) of the relationship between the 18 phyla and the concentration of As and Sb demonstrated that 5 phyla of microbes, i.e. Actinobacteria, Firmicutes, Nitrospirae, Tenericutes and Gemmatimonadetes were positively correlated with As and Sb concentration. The distribution, diversity and abundance of functional genes (including arsC, arrA, aioA, arsB and ACR3) were much higher for the samples containing higher As and Sb concentrations. Based on correlation analysis, the results showed a positive relationship between arsC-like (R2 = 0.871) and aioA-like (R2 = 0.675) gene abundance and As concentration, and indicated that intracellular As(V) reduction and As(III) oxidation could be the dominant As detoxification mechanism enabling the microbes to survive in the environment. This study provides a direct and reliable reference on the diversity of microbial community and functional genes in an extremely high concentration As- and Sb-contaminated environment.

  2. High-throughput sequencing-based analysis of endogenetic fungal communities inhabiting the Chinese Cordyceps reveals unexpectedly high fungal diversity.

    Science.gov (United States)

    Xia, Fei; Chen, Xin; Guo, Meng-Yuan; Bai, Xiao-Hui; Liu, Yan; Shen, Guang-Rong; Li, Yu-Ling; Lin, Juan; Zhou, Xuan-Wei

    2016-09-14

    Chinese Cordyceps, known in Chinese as "DongChong XiaCao", is a parasitic complex of a fungus (Ophiocordyceps sinensis) and a caterpillar. The current study explored the endogenetic fungal communities inhabiting Chinese Cordyceps. Samples were collected from five different geographical regions of Qinghai and Tibet, and the nuclear ribosomal internal transcribed spacer-1 sequences from each sample were obtained using Illumina high-throughput sequencing. The results showed that Ascomycota was the dominant fungal phylum in Chinese Cordyceps and its soil microhabitat from different sampling regions. Among the Ascomycota, 65 genera were identified, and the abundant operational taxonomic units showed the strongest sequence similarity to Ophiocordyceps, Verticillium, Pseudallescheria, Candida and Ilyonectria Not surprisingly, the genus Ophiocordyceps was the largest among the fungal communities identified in the fruiting bodies and external mycelial cortices of Chinese Cordyceps. In addition, fungal communities in the soil microhabitats were clustered separately from the external mycelial cortices and fruiting bodies of Chinese Cordyceps from different sampling regions. There was no significant structural difference in the fungal communities between the fruiting bodies and external mycelial cortices of Chinese Cordyceps. This study revealed an unexpectedly high diversity of fungal communities inhabiting the Chinese Cordyceps and its microhabitats.

  3. Copper Chaperone for Cu/Zn Superoxide Dismutase is a sensitive biomarker of mild copper deficiency induced by moderately high intakes of zinc

    Directory of Open Access Journals (Sweden)

    L'Abbé Mary R

    2005-11-01

    Full Text Available Abstract Background Small increases in zinc (Zn consumption above recommended amounts have been shown to reduce copper (Cu status in experimental animals and humans. Recently, we have reported that copper chaperone for Cu/Zn superoxide dismutase (CCS protein level is increased in tissues of overtly Cu-deficient rats and proposed CCS as a novel biomarker of Cu status. Methods Weanling male Wistar rats were fed one of four diets normal in Cu and containing normal (30 mg Zn/kg diet or moderately high (60, 120 or 240 mg Zn/kg diet amounts of Zn for 5 weeks. To begin to examine the clinical relevance of CCS, we compared the sensitivity of CCS to mild Cu deficiency, induced by moderately high intakes of Zn, with conventional indices of Cu status. Results Liver and erythrocyte CCS expression was significantly (P P Conclusion Collectively, these data show that CCS is a sensitive measure of Zn-induced mild Cu deficiency and demonstrate a dose-dependent biphasic response for reduced Cu status by moderately high intakes of Zn.

  4. Biomarkers of environmental benzene exposure

    Energy Technology Data Exchange (ETDEWEB)

    Weisel, C.; Yu, R.; Roy, A.; Georgopoulos, P. [Environmental and Occupational Health Sciences Institute, Piscataway, NJ (United States)

    1996-12-01

    Environmental exposures to benzene result in increases in body burden that are reflected in various biomarkers of exposure, including benzene in exhaled breath, benzene in blood and urinary trans-trans-muconic acid and S-phenylmercapturic acid. A review of the literature indicates that these biomarkers can be used to distinguish populations with different levels of exposure (such as smokers from nonsmokers and occupationally exposed from environmentally exposed populations) and to determine differences in metabolism. Biomarkers in humans have shown that the percentage of benzene metabolized by the ring-opening pathway is greater at environmental exposures than that at higher occupational exposures, a trend similar to that found in animal studies. This suggests that the dose-response curve is nonlinear; that potential different metabolic mechanisms exist at high and low doses; and that the validity of a linear extrapolation of adverse effects measured at high doses to a population exposed to lower, environmental levels of benzene is uncertain. Time-series measurements of the biomarker, exhaled breath, were used to evaluate a physiologically based pharmacokinetic (PBPK) model. Biases were identified between the PBPK model predictions and experimental data that were adequately described using an empirical compartmental model. It is suggested that a mapping of the PBPK model to a compartmental model can be done to optimize the parameters in the PBPK model to provide a future framework for developing a population physiologically based pharmacokinetic model. 44 refs., 3 figs., 1 tab.

  5. Combination of hand mapping and automatic mapping to reveal the Miocene high elevation Pyrenean peneplain

    Science.gov (United States)

    Bosch, Gemma V.; Babault, Julien; Van Den Driessche, Jean

    2016-04-01

    A striking feature of the morphology of the Pyrenees is the occurrence of high-elevation, low-relief surfaces, which are interpreted as remnants of a single Miocene planation surface. Whether the original surface was uplifted or developed at high altitude is debated. This "Miocene Pyrenean peneplain" has been dissected by fluvial and glacial erosion during the Quaternary. Reworking by glacial erosion also provides new smooth surfaces such as glacial cirque floors that must not be confused with the remnants of the original planation surface. The later are convex-up landforms whereas glacial cirque floors are concave-up landforms. To reveal the Miocene high-elevation Pyrenean peneplain, we combined hand mapping and automatic mapping at the scale of the whole chain. From previous mapping in literature and from our own field work, we first perform a map of both the Miocene planation surface remnants and the Quaternary glacial cirque floors. Using Digital Elevation Models, numerical parameters were extracted from this map to characterize the two types of smooth surfaces. The slope is the parameter that helps to delimitate and differentiate the smooth surfaces from the rest of the Pyrenean topography. To distinguish between the two types of smooth surfaces we used the Topographic Index (TPI). This parameter is the difference between the elevation of a point and the mean elevation. Choosing the pertinent radius according to the scale of the landform to map, and the pertinent values interval, we can differentiate the planation surface (convex-up) from the glacial cirque floors (concave-up). A sensitivity test was performed to determine the best radius and the best interval for TPI and slope values to distinguish between the two types of smooth surfaces. Finally, we used a combination of slope values, TPI values and radius to determine automatically the high-elevation, low-relief surfaces in the entire Pyrenees. We verified in the field the presence of the newly mapped high

  6. Biomarkers for Parkinson's disease.

    Science.gov (United States)

    Sherer, Todd B

    2011-04-20

    Biomarkers for detecting the early stages of Parkinson's disease (PD) could accelerate development of new treatments. Such biomarkers could be used to identify individuals at risk for developing PD, to improve early diagnosis, to track disease progression with precision, and to test the efficacy of new treatments. Although some progress has been made, there are many challenges associated with developing biomarkers for detecting PD in its earliest stages.

  7. In situ Expression of Functional Genes Reveals Nitrogen Cycling at High Temperatures in Terrestrial Hydrothermal Systems

    Science.gov (United States)

    Loiacono, S. T.; Meyer-Dombard, D. R.

    2011-12-01

    An essential element for life, nitrogen occurs in all living organisms and is critical for the synthesis of amino acids, proteins, nucleic acids, and other forms of biomass. Thus, nitrogen cycling likely plays a vital role in microbial metabolic processes as well as nutrient availability. For microorganisms in "extreme" environments, this means developing adaptations that allow them to survive in harsh conditions and still perform the metabolisms essential to sustain life. Recent studies have screened biofilms and thermal sediments of Yellowstone National Park (YNP) thermal features for the presence of nifH genes, which code for a key enzyme in the nitrogen fixation process [1-4]. Furthermore, analysis of nitrogen isotopes in biofilms across a temperature and chemical gradient revealed that nitrogen fixation likely varies across the chemosynthetic/photosynthetic ecotone [5]. Although research has evaluated and confirmed the presence of nifH genes in various thermophilic microbial communities, the existence of a gene in the DNA of an organism does not verify its use. Instead, other methods, such as culturing, isotope tracer assays, and gene expression studies are required to provide direct evidence of biological nitrogen fixation. Culturing and isotope tracer approaches have successfully revealed high-temperature biological nitrogen fixation in both marine hydrothermal vent microbial communities [6] and in acidic, terrestrial hydrothermal sediment [3]. Transcriptomics-based techniques (using mRNA extracted from samples to confirm in situ expression of targeted genes) have been much more limited in number, and only a few studies have, to date, investigated in situ expression of the nifH gene in thermophilic microbial communities [2, 7]. This study explores the presence and expression of nifH genes in several features of the Lower Geyser Basin (LGB) of YNP. Nucleic acids from chemosynthetic and photosynthetic microbial communities were extracted and then amplified

  8. Bayesian coalescent inference reveals high evolutionary rates and diversification of Zika virus populations.

    Science.gov (United States)

    Fajardo, Alvaro; Soñora, Martín; Moreno, Pilar; Moratorio, Gonzalo; Cristina, Juan

    2016-10-01

    Zika virus (ZIKV) is a member of the family Flaviviridae. In 2015, ZIKV triggered an epidemic in Brazil and spread across Latin America. By May of 2016, the World Health Organization warns over spread of ZIKV beyond this region. Detailed studies on the mode of evolution of ZIKV strains are extremely important for our understanding of the emergence and spread of ZIKV populations. In order to gain insight into these matters, a Bayesian coalescent Markov Chain Monte Carlo analysis of complete genome sequences of recently isolated ZIKV strains was performed. The results of these studies revealed a mean rate of evolution of 1.20 × 10(-3) nucleotide substitutions per site per year (s/s/y) for ZIKV strains enrolled in this study. Several variants isolated in China are grouped together with all strains isolated in Latin America. Another genetic group composed exclusively by Chinese strains were also observed, suggesting the co-circulation of different genetic lineages in China. These findings indicate a high level of diversification of ZIKV populations. Strains isolated from microcephaly cases do not share amino acid substitutions, suggesting that other factors besides viral genetic differences may play a role for the proposed pathogenesis caused by ZIKV infection. J. Med. Virol. 88:1672-1676, 2016. © 2016 Wiley Periodicals, Inc.

  9. Dengue virus surveillance in Singapore reveals high viral diversity through multiple introductions and in situ evolution.

    Science.gov (United States)

    Lee, Kim-Sung; Lo, Sharon; Tan, Sharon Siok-Yin; Chua, Rachel; Tan, Li-Kiang; Xu, Helen; Ng, Lee-Ching

    2012-01-01

    Dengue fever, a vector-borne disease, has caused tremendous burden to countries in the tropics and sub tropics. Over the past 20 years, dengue epidemics have become more widespread, severe and frequent. This study aims to understand the dynamics of dengue viruses in cosmopolitan Singapore. Envelope protein gene sequences of all four dengue serotypes (DENV-1-DENV-4) obtained from human sera in Singapore (2008-2010) revealed that constant viral introductions and in situ evolution contribute to viral diversity in Singapore and play important roles in shaping the epidemiology of dengue in the island state. The diversity of dengue viruses reported here could be a reflection of the on-going dengue situation in the region given Singapore's location in a dengue hyperendemic region and its role as the regional hub for travels and trade. Though cosmopolitan genotype of DENV-2 has remained as the predominant strain circulating in Singapore, we uncovered evidence of in situ evolution which could possibly result in viruses with improved fitness. While we have previously shown that a switch in the predominant dengue serotype could serve as a warning for an impending outbreak, our current data shows that a replacement of a predominant viral clade, even in the absence of a switch in predominant serotype, could signal a possible increase in dengue transmission. The circulating dengue viruses in Singapore are highly diverse, a situation which could offer ample opportunities for selection of strains of higher fitness, thus increasing the risk of outbreaks despite a low Aedes population.

  10. Revealing the beneficial effect of protease supplementation to high gravity beer fermentations using "-omics" techniques

    Directory of Open Access Journals (Sweden)

    Workman Chris

    2011-04-01

    Full Text Available Abstract Background Addition of sugar syrups to the basic wort is a popular technique to achieve higher gravity in beer fermentations, but it results in dilution of the free amino nitrogen (FAN content in the medium. The multicomponent protease enzyme Flavourzyme has beneficial effect on the brewer's yeast fermentation performance during high gravity fermentations as it increases the initial FAN value and results in higher FAN uptake, higher specific growth rate, higher ethanol yield and improved flavour profile. Results In the present study, transcriptome and metabolome analysis were used to elucidate the effect on the addition of the multicomponent protease enzyme Flavourzyme and its influence on the metabolism of the brewer's yeast strain Weihenstephan 34/70. The study underlines the importance of sufficient nitrogen availability during the course of beer fermentation. The applied metabolome and transcriptome analysis allowed mapping the effect of the wort sugar composition on the nitrogen uptake. Conclusion Both the transcriptome and the metabolome analysis revealed that there is a significantly higher impact of protease addition for maltose syrup supplemented fermentations, while addition of glucose syrup to increase the gravity in the wort resulted in increased glucose repression that lead to inhibition of amino acid uptake and hereby inhibited the effect of the protease addition.

  11. Sarcomere dynamics in single myocardial cells as revealed by high-resolution light diffractometry.

    Science.gov (United States)

    Leung, A F

    1983-08-01

    A specially designed diffractometer with a high spatial and temporal resolution recorded the diffraction of a laser beam by single enzymatically isolated myocardial cells. The fine structures within the first-order diffraction were resolved and each structure was interpreted as the diffraction from a group of sarcomeres of nearly equal length. During activation of the cell dynamics of each discrete group of sarcomeres was uniform and independent of the other groups. However, a small nonuniform component in the sarcomere dynamics was observed and attributed to the coupling between the shortening tension and the radial stress resulting from the expansion of the myofibrillar cross-section. The time-course of the diffraction fine structures during contractile activity revealed (1) the period of the contraction-relaxation cycle, (2) the latent period, (3) the shortening and relengthening speeds and (4) the variation in the line width and intensity of the fine structure. Measurements showed that the latent period was dependent on the free Ca2+ of the cell's bathing solution while the initial shortening speed was not. The diffraction line width and intensity of the shortening cell were explained by the grating model.

  12. Production of individualized V gene databases reveals high levels of immunoglobulin genetic diversity

    Science.gov (United States)

    Corcoran, Martin M.; Phad, Ganesh E.; Bernat, Néstor Vázquez; Stahl-Hennig, Christiane; Sumida, Noriyuki; Persson, Mats A. A.; Martin, Marcel; Hedestam, Gunilla B. Karlsson

    2016-12-01

    Comprehensive knowledge of immunoglobulin genetics is required to advance our understanding of B cell biology. Validated immunoglobulin variable (V) gene databases are close to completion only for human and mouse. We present a novel computational approach, IgDiscover, that identifies germline V genes from expressed repertoires to a specificity of 100%. IgDiscover uses a cluster identification process to produce candidate sequences that, once filtered, results in individualized germline V gene databases. IgDiscover was tested in multiple species, validated by genomic cloning and cross library comparisons and produces comprehensive gene databases even where limited genomic sequence is available. IgDiscover analysis of the allelic content of the Indian and Chinese-origin rhesus macaques reveals high levels of immunoglobulin gene diversity in this species. Further, we describe a novel human IGHV3-21 allele and confirm significant gene differences between Balb/c and C57BL6 mouse strains, demonstrating the power of IgDiscover as a germline V gene discovery tool.

  13. Highly distinct chromosomal structures in cowpea (Vigna unguiculata), as revealed by molecular cytogenetic analysis.

    Science.gov (United States)

    Iwata-Otsubo, Aiko; Lin, Jer-Young; Gill, Navdeep; Jackson, Scott A

    2016-05-01

    Cowpea (Vigna unguiculata (L.) Walp) is an important legume, particularly in developing countries. However, little is known about its genome or chromosome structure. We used molecular cytogenetics to characterize the structure of pachytene chromosomes to advance our knowledge of chromosome and genome organization of cowpea. Our data showed that cowpea has highly distinct chromosomal structures that are cytologically visible as brightly DAPI-stained heterochromatic regions. Analysis of the repetitive fraction of the cowpea genome present at centromeric and pericentromeric regions confirmed that two retrotransposons are major components of pericentromeric regions and that a 455-bp tandem repeat is found at seven out of 11 centromere pairs in cowpea. These repeats likely evolved after the divergence of cowpea from common bean and form chromosomal structure unique to cowpea. The integration of cowpea genetic and physical chromosome maps reveals potential regions of suppressed recombination due to condensed heterochromatin and a lack of pairing in a few chromosomal termini. This study provides fundamental knowledge on cowpea chromosome structure and molecular cytogenetics tools for further chromosome studies.

  14. Metagenomes from high-temperature chemotrophic systems reveal geochemical controls on microbial community structure and function

    Energy Technology Data Exchange (ETDEWEB)

    Frank Roberto

    2010-03-01

    The Yellowstone caldera contains the most numerous and diverse geothermal systems on Earth, yielding an extensive array of unique high-temperature environments that host numerous deeply-rooted and understudied Archaea, Bacteria and Eukarya. The combination of extreme temperature and chemical conditions encountered in geothermal environments often results in considerably less microbial diversity than other terrestrial habitats and offers a tremendous opportunity for studying the structure and function of indigenous microbial communities and for establishing linkages between putative metabolisms and element cycling. Metagenome sequence (14-15,000 Sanger reads per site) was obtained for five high-temperature (> 65 oC) chemotrophic microbial communities sampled from geothermal springs (or pools) in Yellowstone National Park (YNP) that exhibit a wide range in geochemistry including pH, dissolved sulfide, dissolved O2 and ferrous Fe. Metagenome data revealed significant differences in the predominant phyla associated with each of these geochemical environments. Novel members of the Sulfolobales are dominant in low pH environments, while other Crenarchaeota including distantly-related Thermoproteales and Desulfurococcales populations dominate in suboxic sulfidic sediments. Several novel archaeal groups are well represented in an acidic (pH 3) Fe-oxyhydroxide mat, where a higher O2 influx is accompanied with an increase in archaeal diversity. The presence or absence of genes and pathways important in S oxidation-reduction, H2-oxidation, and aerobic respiration (terminal oxidation) provide insight regarding the metabolic strategies of indigenous organisms present in geothermal systems. Multiple-pathway and protein-specific functional analysis of metagenome sequence data corroborated results from phylogenetic analyses and clearly demonstrate major differences in metabolic potential across sites. The distribution of functional genes involved in electron transport is

  15. Metagenomes from high-temperature chemotrophic systems reveal geochemical controls on microbial community structure and function.

    Directory of Open Access Journals (Sweden)

    William P Inskeep

    Full Text Available The Yellowstone caldera contains the most numerous and diverse geothermal systems on Earth, yielding an extensive array of unique high-temperature environments that host a variety of deeply-rooted and understudied Archaea, Bacteria and Eukarya. The combination of extreme temperature and chemical conditions encountered in geothermal environments often results in considerably less microbial diversity than other terrestrial habitats and offers a tremendous opportunity for studying the structure and function of indigenous microbial communities and for establishing linkages between putative metabolisms and element cycling. Metagenome sequence (14-15,000 Sanger reads per site was obtained for five high-temperature (>65 degrees C chemotrophic microbial communities sampled from geothermal springs (or pools in Yellowstone National Park (YNP that exhibit a wide range in geochemistry including pH, dissolved sulfide, dissolved oxygen and ferrous iron. Metagenome data revealed significant differences in the predominant phyla associated with each of these geochemical environments. Novel members of the Sulfolobales are dominant in low pH environments, while other Crenarchaeota including distantly-related Thermoproteales and Desulfurococcales populations dominate in suboxic sulfidic sediments. Several novel archaeal groups are well represented in an acidic (pH 3 Fe-oxyhydroxide mat, where a higher O2 influx is accompanied with an increase in archaeal diversity. The presence or absence of genes and pathways important in S oxidation-reduction, H2-oxidation, and aerobic respiration (terminal oxidation provide insight regarding the metabolic strategies of indigenous organisms present in geothermal systems. Multiple-pathway and protein-specific functional analysis of metagenome sequence data corroborated results from phylogenetic analyses and clearly demonstrate major differences in metabolic potential across sites. The distribution of functional genes involved in

  16. Ratiometric high-resolution imaging of JC-1 fluorescence reveals the subcellular heterogeneity of astrocytic mitochondria.

    Science.gov (United States)

    Keil, Vera C; Funke, Frank; Zeug, Andre; Schild, Detlev; Müller, Michael

    2011-11-01

    Using the mitochondrial potential (ΔΨ(m)) marker JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide) and high-resolution imaging, we functionally analyzed mitochondria in cultured rat hippocampal astrocytes. Ratiometric detection of JC-1 fluorescence identified mitochondria with high and low ΔΨ(m). Mitochondrial density was highest in the perinuclear region, whereas ΔΨ(m) tended to be higher in peripheral mitochondria. Spontaneous ΔΨ(m) fluctuations, representing episodes of increased energization, appeared in individual mitochondria or synchronized in mitochondrial clusters. They continued upon withdrawal of extracellular Ca(2+), but were antagonized by dantrolene or 2-aminoethoxydiphenylborate (2-APB). Fluo-3 imaging revealed local cytosolic Ca(2+) transients with similar kinetics that also were depressed by dantrolene and 2-APB. Massive cellular Ca(2+) load or metabolic impairment abolished ΔΨ(m) fluctuations, occasionally evoking heterogeneous mitochondrial depolarizations. The detected diversity and ΔΨ(m) heterogeneity of mitochondria confirms that even in less structurally polarized cells, such as astrocytes, specialized mitochondrial subpopulations coexist. We conclude that ΔΨ(m) fluctuations are an indication of mitochondrial viability and are triggered by local Ca(2+) release from the endoplasmic reticulum. This spatially confined organelle crosstalk contributes to the functional heterogeneity of mitochondria and may serve to adapt the metabolism of glial cells to the activity and metabolic demand of complex neuronal networks. The established ratiometric JC-1 imaging-especially combined with two-photon microscopy-enables quantitative functional analyses of individual mitochondria as well as the comparison of mitochondrial heterogeneity in different preparations and/or treatment conditions.

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

    Directory of Open Access Journals (Sweden)

    Chiao-Ling Lo

    2016-08-01

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

  18. Motor agency: a new and highly sensitive measure to reveal agency disturbances in early psychosis.

    Directory of Open Access Journals (Sweden)

    Hélène Wilquin

    Full Text Available BACKGROUND: Early diagnosis of young adults at risk of schizophrenia is essential for preventive approaches of the illness. Nevertheless, classic screening instruments are difficult to use because of the non-specific nature of the signs at this pre-onset phase of illness. The objective of the present contribution was to propose an innovating test that can probe the more specific symptom of psychosis, i.e., the sense of agency, which is defined as being the immediate experience of oneself as the cause of an action. More specifically, we tested whether motor agency is abnormal in early psychosis. METHODS: Thirty-two young symptomatic patients and their age-matched controls participated in the study. 15 of these patients were at ultra high-risk for developing psychosis (UHR, and 17 patients were suffering from first-episode psychosis (FEP. Patients' neurocognitive capacities were assessed through the use of seven neuropsychological tests. A motor agency task was also introduced to obtain an objective indicator of the degree of sense of agency, by contrasting force levels applied during other and self-produced collisions between a hand-held objet and a pendulum. RESULTS: As reported in the literature for adult controls, healthy adolescents used more efficient force levels in self than in other-imposed collisions. For both UHR and FEP patients, abnormally high levels of grip force were used for self-produced collisions, leading to an absence of difference between self and other. The normalized results revealed that motor agency differentiated patients from controls with a higher level of sensitivity than the more classic neuropsychological test battery. CONCLUSIONS: This study is in favour of the existence of an abnormal sense of agency early in the psychotic illness. Because it is quick and none verbal, motor agency may be a valuable tool to use in complement to classic interviews, especially when investigating complex ineffable experiences that are

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

    Science.gov (United States)

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

    2016-08-01

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

  20. Metagenomes from high-temperature chemotrophic systems reveal geochemical controls on microbial community structure and function.

    Science.gov (United States)

    Inskeep, William P; Rusch, Douglas B; Jay, Zackary J; Herrgard, Markus J; Kozubal, Mark A; Richardson, Toby H; Macur, Richard E; Hamamura, Natsuko; Jennings, Ryan deM; Fouke, Bruce W; Reysenbach, Anna-Louise; Roberto, Frank; Young, Mark; Schwartz, Ariel; Boyd, Eric S; Badger, Jonathan H; Mathur, Eric J; Ortmann, Alice C; Bateson, Mary; Geesey, Gill; Frazier, Marvin

    2010-03-19

    The Yellowstone caldera contains the most numerous and diverse geothermal systems on Earth, yielding an extensive array of unique high-temperature environments that host a variety of deeply-rooted and understudied Archaea, Bacteria and Eukarya. The combination of extreme temperature and chemical conditions encountered in geothermal environments often results in considerably less microbial diversity than other terrestrial habitats and offers a tremendous opportunity for studying the structure and function of indigenous microbial communities and for establishing linkages between putative metabolisms and element cycling. Metagenome sequence (14-15,000 Sanger reads per site) was obtained for five high-temperature (>65 degrees C) chemotrophic microbial communities sampled from geothermal springs (or pools) in Yellowstone National Park (YNP) that exhibit a wide range in geochemistry including pH, dissolved sulfide, dissolved oxygen and ferrous iron. Metagenome data revealed significant differences in the predominant phyla associated with each of these geochemical environments. Novel members of the Sulfolobales are dominant in low pH environments, while other Crenarchaeota including distantly-related Thermoproteales and Desulfurococcales populations dominate in suboxic sulfidic sediments. Several novel archaeal groups are well represented in an acidic (pH 3) Fe-oxyhydroxide mat, where a higher O2 influx is accompanied with an increase in archaeal diversity. The presence or absence of genes and pathways important in S oxidation-reduction, H2-oxidation, and aerobic respiration (terminal oxidation) provide insight regarding the metabolic strategies of indigenous organisms present in geothermal systems. Multiple-pathway and protein-specific functional analysis of metagenome sequence data corroborated results from phylogenetic analyses and clearly demonstrate major differences in metabolic potential across sites. The distribution of functional genes involved in electron

  1. Direct label-free electrical immunodetection of transplant rejection protein biomarker in physiological buffer using floating gate AlGaN/GaN high electron mobility transistors.

    Science.gov (United States)

    Tulip, Fahmida S; Eteshola, Edward; Desai, Suchita; Mostafa, Salwa; Roopa, Subramanian; Evans, Boyd; Islam, Syed Kamrul

    2014-06-01

    Monokine induced by interferon gamma (MIG/CXCL9) is used as an immune biomarker for early monitoring of transplant or allograft rejection. This paper demonstrates a direct electrical, label-free detection method of recombinant human MIG with anti-MIG IgG molecules in physiologically relevant buffer environment. The sensor platform used is a biologically modified GaN-based high electron mobility transistor (HEMT) device. Biomolecular recognition capability was provided by using high affinity anti-MIG monoclonal antibody to form molecular affinity interface receptors on short N-hydroxysuccinimide-ester functionalized disulphide (DSP) self-assembled monolayers (SAMs) on the gold sensing gate of the HEMT device. A floating gate configuration has been adopted to eliminate the influences of external gate voltage. Preliminary test results with the proposed chemically treated GaN HEMT biosensor show that MIG can be detected for a wide range of concentration varying from 5 ng/mL to 500 ng/mL.

  2. Biomarkers for lymphoma

    Science.gov (United States)

    Zangar, Richard C.; Varnum, Susan M.

    2014-09-02

    A biomarker, method, test kit, and diagnostic system for detecting the presence of lymphoma in a person are disclosed. The lymphoma may be Hodgkin's lymphoma or non-Hodgkin's lymphoma. The person may be a high-risk subject. In one embodiment, a plasma sample from a person is obtained. The level of at least one protein listed in Table S3 in the plasma sample is measured. The level of at least one protein in the plasma sample is compared with the level in a normal or healthy subject. The lymphoma is diagnosed based upon the level of the at least one protein in the plasma sample in comparison to the normal or healthy level.

  3. Urinary excretion of total isothiocyanates from cruciferous vegetables shows high dose-response relationship and may be a useful biomarker for isothiocyanate exposure

    DEFF Research Database (Denmark)

    Kristensen, Mette; Krogholm, Kirstine Suszkiewicz; Frederiksen, Hanne

    2007-01-01

    Background Isothiocyanates (ITCs), hydrolysis products from glucosinolates, are a family of biologically active compounds originating from cruciferous vegetables. Many ITCs are assumed to have cancer preventive effects and to further evaluate these potential health effects, reliable biomarkers of...

  4. Atypical category processing and hemispheric asymmetries in high-functioning children with autism: revealed through high-density EEG mapping.

    Science.gov (United States)

    Fiebelkorn, Ian C; Foxe, John J; McCourt, Mark E; Dumas, Kristina N; Molholm, Sophie

    2013-05-01

    Behavioral evidence for an impaired ability to group objects based on similar physical or semantic properties in autism spectrum disorders (ASD) has been mixed. Here, we recorded brain activity from high-functioning children with ASD as they completed a visual-target detection task. We then assessed the extent to which object-based selective attention automatically generalized from targets to non-target exemplars from the same well-known object class (e.g., dogs). Our results provide clear electrophysiological evidence that children with ASD (N=17, aged 8-13 years) process the similarity between targets (e.g., a specific dog) and same-category non-targets (SCNT) (e.g., another dog) to a lesser extent than do their typically developing (TD) peers (N=21). A closer examination of the data revealed striking hemispheric asymmetries that were specific to the ASD group. These findings align with mounting evidence in the autism literature of anatomic underconnectivity between the cerebral hemispheres. Years of research in individuals with TD have demonstrated that the left hemisphere (LH) is specialized toward processing local (or featural) stimulus properties and the right hemisphere (RH) toward processing global (or configural) stimulus properties. We therefore propose a model where a lack of communication between the hemispheres in ASD, combined with typical hemispheric specialization, is a root cause for impaired categorization and the oft-observed bias to process local over global stimulus properties.

  5. High heregulin expression is associated with activated HER3 and may define an actionable biomarker in patients with squamous cell carcinomas of the head and neck.

    Directory of Open Access Journals (Sweden)

    David S Shames

    Full Text Available PURPOSE: Tumors with oncogenic dependencies on the HER family of receptor tyrosine kinases (RTKs often respond well to targeted inhibition. Our previous work suggested that many cell lines derived from squamous cell carcinomas of the head and neck (SCCHNs depend on autocrine signaling driven by HER2/3 dimerization and high-level co-expression of HRG. Additionally, results from a Phase I trial of MEHD7495A, a dual-action antibody that blocks ligand binding to EGFR and HER3, suggest that high-level HRG expression was associated with clinical response in SCCHN patients. Here we explore the hypothesis that high-level HRG expression defines a subpopulation of SCCHNs with activated HER3. EXPERIMENTAL DESIGN: qRT-PCR expression profiling was performed on >750 tumors of diverse origin, including >150 therapy-naïve, primary, and recurrent SCCHNs. Activated HER3, defined by immunoprecipitation of phospho-HER3, was compared to HRG expression in SCCHN samples. Paracrine versus autocrine expression was evaluated using RNA-in situ hybridization. RESULTS: SCCHN tumors express the highest levels of HRG compared to a diverse collection of other tumor types. We show that high HRG expression is associated with activated HER3, whereas low HRG expression is associated with low HER3 activation in SCCHN tumors. Furthermore, HRG expression is higher in recurrent SCCHN compared to patient-matched therapy naïve specimens. CONCLUSIONS: HRG expression levels define a biologically distinct subset of SCCHN patients. We propose that high-level expression of HRG is associated with constitutive activation of HER3 in SCCHN and thus defines an actionable biomarker for interventions targeting HER3.

  6. A multilocus assay reveals high nucleotide diversity and limited differentiation among Scandinavian willow grouse (Lagopus lagopus

    Directory of Open Access Journals (Sweden)

    Quintela Maria

    2008-12-01

    Full Text Available Abstract Background There is so far very little data on autosomal nucleotide diversity in birds, except for data from the domesticated chicken and some passerines species. Estimates of nucleotide diversity reported so far in birds have been high (~10-3 and a likely explanation for this is the generally higher effective population sizes compared to mammals. In this study, the level of nucleotide diversity has been examined in the willow grouse, a non-domesticated bird species from the order Galliformes, which also holds the chicken. The willow grouse (Lagopus lagopus has an almost circumpolar distribution but is absent from Greenland and the north Atlantic islands. It primarily inhabits tundra, forest edge habitats and sub-alpine vegetation. Willow grouse are hunted throughout its range, and regionally it is a game bird of great cultural and economical importance. Results We sequenced 18 autosomal protein coding loci from approximately 15–18 individuals per population. We found a total of 127 SNP's, which corresponds to 1 SNP every 51 bp. 26 SNP's were amino acid replacement substitutions. Total nucleotide diversity (πt was between 1.30 × 10-4 and 7.66 × 10-3 (average πt = 2.72 × 10-3 ± 2.06 × 10-3 and silent nucleotide diversity varied between 4.20 × 10-4and 2.76 × 10-2 (average πS = 9.22 × 10-3 ± 7.43 × 10-4. The synonymous diversity is approximately 20 times higher than in humans and two times higher than in chicken. Non-synonymous diversity was on average 18 times lower than the synonymous diversity and varied between 0 and 4.90 × 10-3 (average πa = 5.08 × 10-4 ± 7.43 × 103, which suggest that purifying selection is strong in these genes. FST values based on synonymous SNP's varied between -5.60 × 10-4 and 0.20 among loci and revealed low levels of differentiation among the four localities, with an overall value of FST = 0.03 (95% CI: 0.006 – 0.057 over 60 unlinked loci. Non-synonymous SNP's gave similar results. Low

  7. High-content screening of natural products reveals novel nuclear export inhibitors.

    Science.gov (United States)

    Cautain, Bastien; de Pedro, Nuria; Murillo Garzón, Virginia; Muñoz de Escalona, María; González Menéndez, Victor; Tormo, José R; Martin, Jesús; El Aouad, Noureddine; Reyes, Fernando; Asensio, Francisco; Genilloud, Olga; Vicente, Francisca; Link, Wolfgang

    2014-01-01

    Natural products are considered an extremely valuable source for the discovery of new drugs against diverse pathologies. As yet, we have only explored a fraction of the diversity of bioactive compounds, and opportunities for discovering new natural products leading to new drugs are huge. In the present study, U2nesRELOC, a previously established cell-based imaging assay, was employed to screen a collection of extracts of microbial origin for nuclear export inhibition activity. The fluorescent signal of untreated U2nesRELOC cells localizes predominantly to the cytoplasm. Upon treatment with the nuclear export inhibitor leptomycin B, the fluorescent-tagged reporter proteins appear as speckles in the nucleus. A proprietary collection of extracts from fungi, actinomycetes, and unicellular bacteria that covers an uncommonly broad chemical space was used to interrogate this nuclear export assay system. A two-step image-based analysis allowed us to identify 12 extracts with biological activities that are not associated with previously known active metabolites. The fractionation and structural elucidation of active compounds revealed several chemical structures with nuclear export inhibition activity. Here we show that substrates of the nuclear export receptor CRM1, such as Rev, FOXO3a and NF-κB, accumulate in the nucleus in the presence of the fungal metabolite MDN-0105 with an IC50 value of 3.4 µM. Many important processes in tumor formation and progression, as well as in many viral infections, critically depend on the nucleocytoplasmic trafficking of proteins and RNA molecules. Therefore, the disruption of nuclear export is emerging as a novel therapeutic approach with enormous clinical potential. Our work highlights the potential of applying high-throughput phenotypic imaging on natural product extracts to identify novel nuclear export inhibitors.

  8. Barcoded pyrosequencing reveals that consumption of galactooligosaccharides results in a highly specific bifidogenic response in humans.

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    Lauren M G Davis

    Full Text Available Prebiotics are selectively fermented ingredients that allow specific changes in the gastrointestinal microbiota that confer health benefits to the host. However, the effects of prebiotics on the human gut microbiota are incomplete as most studies have relied on methods that fail to cover the breadth of the bacterial community. The goal of this research was to use high throughput multiplex community sequencing of 16S rDNA tags to gain a community wide perspective of the impact of prebiotic galactooligosaccharide (GOS on the fecal microbiota of healthy human subjects. Fecal samples from eighteen healthy adults were previously obtained during a feeding trial in which each subject consumed a GOS-containing product for twelve weeks, with four increasing dosages (0, 2.5, 5, and 10 gram of GOS. Multiplex sequencing of the 16S rDNA tags revealed that GOS induced significant compositional alterations in the fecal microbiota, principally by increasing the abundance of organisms within the Actinobacteria. Specifically, several distinct lineages of Bifidobacterium were enriched. Consumption of GOS led to five- to ten-fold increases in bifidobacteria in half of the subjects. Increases in Firmicutes were also observed, however, these changes were detectable in only a few individuals. The enrichment of bifidobacteria was generally at the expense of one group of bacteria, the Bacteroides. The responses to GOS and the magnitude of the response varied between individuals, were reversible, and were in accordance with dosage. The bifidobacteria were the only bacteria that were consistently and significantly enriched by GOS, although this substrate supported the growth of diverse colonic bacteria in mono-culture experiments. These results suggest that GOS can be used to enrich bifidobacteria in the human gastrointestinal tract with remarkable specificity, and that the bifidogenic properties of GOS that occur in vivo are caused by selective fermentation as well as by

  9. High Dietary Iron and Radiation Exposure Increase Biomarkers of Oxidative Stress in Blood and Liver of Rats

    Science.gov (United States)

    Morgan, Jennifer L. L.; Theriot, Corey A.; Wu, Honglu; Smith, Scott M.; Zwart, Sara R.

    2012-01-01

    Radiation exposure and increased iron (Fe) status independently cause oxidative damage that can result in protein, lipid, and DNA oxidation. During space flight astronauts are exposed to both increased radiation and increased Fe stores. Increased body Fe results from a decrease in red blood cell mass and the typically high Fe content of the food system. In this study we investigated the combined effects of radiation exposure (0.375 Gy of Cs-137 every other day for 16 days for a total of 3 Gy) and high dietary Fe (650 mg Fe/kg diet compared to 45 mg Fe/kg for controls) in Sprague-Dawley rats (n=8/group). Liver and serum Fe were significantly increased in the high dietary Fe groups. Likewise, radiation treatment increased serum ferritin and Fe concentrations. These data indicate that total body Fe stores increase with both radiation exposure and excess dietary Fe. Hematocrit decreased in the group exposed to radiation, providing a possible mechanism for the shift in Fe indices after radiation exposure. Markers of oxidative stress were also affected by both radiation and high dietary Fe, evidenced by increased liver glutathione peroxidase (GPX) and serum catalase as well as decreased serum GPX. We thus found preliminary indications of synergistic effects of radiation exposure and increased dietary Fe, warranting further study. This study was funded by the NASA Human Research Project.

  10. Role of Topoisomerases in Pediatric High Grade Osteosarcomas: TOP2A Gene Is One of the Unique Molecular Biomarkers of Chemoresponse

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    Natacha Entz-Werle

    2013-06-01

    Full Text Available Currently, the treatment of pediatric high-grade osteosarcomas systematically includes one topoisomerase IIα inhibitor. This chemotherapy is usually adapted to the response to the neo-adjuvant therapy after surgery. The current and unique marker of chemoresponsiveness is the percentage of viable residual cells in the surgical resection. This late patient management marker has to be evaluated earlier in the therapeutic history of the patients on initial biopsy. Therefore, new biomarkers, especially those involved in the topoisomerase IIα inhibitor response might be good candidates. Therefore, our study was designed to target TOP1, TOP2A and TOP2B genes in 105 fresh-frozen diagnostic biopsies by allelotyping and real-time quantitative PCR. Our analyses in those pediatric osteosarcomas, homogeneously treated, highlighted the frequent involvement of topo-isomerase genes. The main and most important observation was the statistical link between the presence of TOP2A amplification and the good response to neo-adjuvant chemotherapy. Compared to adult cancers, the 17q21 amplicon, including TOP2A and ERBB2 genes, seems to be differentially implicated in the osteosarcoma chemoresponsiveness. Surprisingly, there is no ERBB2 gene co-amplification and the patients harboring TOP2A amplification tend to show a worse survival, so TOP2A analyses remain a preliminary, but a good molecular approach for the evaluation at diagnosis of pediatric osteosarcoma chemoresponsiveness.

  11. Role of Topoisomerases in Pediatric High Grade Osteosarcomas: TOP2A Gene Is One of the Unique Molecular Biomarkers of Chemoresponse

    Energy Technology Data Exchange (ETDEWEB)

    Nguyen, Aurelia; Lasthaus, Christelle; Guerin, Eric [Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hautepierre, Avenue Molière, Strasbourg Cedex 67098 (France); EA4438, Groupe Marqueurs Moléculaires de Progression Tumorale et de Sensibilisation aux Drogues Anti-Cancéreuses, University of Strasbourg, 3 Avenue Molière, Strasbourg 67000 (France); Marcellin, Luc [Laboratoire d’Anatomie Pathologique, CHRU Hautepierre, Avenue Molière, Strasbourg Cedex 67098 (France); Pencreach, Erwan; Gaub, Marie-Pierre [Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hautepierre, Avenue Molière, Strasbourg Cedex 67098 (France); EA4438, Groupe Marqueurs Moléculaires de Progression Tumorale et de Sensibilisation aux Drogues Anti-Cancéreuses, University of Strasbourg, 3 Avenue Molière, Strasbourg 67000 (France); Guenot, Dominique [Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hautepierre, Avenue Molière, Strasbourg Cedex 67098 (France); Entz-Werle, Natacha, E-mail: Natacha.entz-werle@chru-strasbourg.fr [Laboratoire de Biochimie et Biologie Moléculaire, CHRU Hautepierre, Avenue Molière, Strasbourg Cedex 67098 (France); Service de Pédiatrie Onco-Hématologie, CHRU Hautepierre, Avenue Molière, Strasbourg Cedex 67098 (France)

    2013-06-04

    Currently, the treatment of pediatric high-grade osteosarcomas systematically includes one topoisomerase IIα inhibitor. This chemotherapy is usually adapted to the response to the neo-adjuvant therapy after surgery. The current and unique marker of chemoresponsiveness is the percentage of viable residual cells in the surgical resection. This late patient management marker has to be evaluated earlier in the therapeutic history of the patients on initial biopsy. Therefore, new biomarkers, especially those involved in the topoisomerase IIα inhibitor response might be good candidates. Therefore, our study was designed to target TOP1, TOP2A and TOP2B genes in 105 fresh-frozen diagnostic biopsies by allelotyping and real-time quantitative PCR. Our analyses in those pediatric osteosarcomas, homogeneously treated, highlighted the frequent involvement of topo-isomerase genes. The main and most important observation was the statistical link between the presence of TOP2A amplification and the good response to neo-adjuvant chemotherapy. Compared to adult cancers, the 17q21 amplicon, including TOP2A and ERBB2 genes, seems to be differentially implicated in the osteosarcoma chemoresponsiveness. Surprisingly, there is no ERBB2 gene co-amplification and the patients harboring TOP2A amplification tend to show a worse survival, so TOP2A analyses remain a preliminary, but a good molecular approach for the evaluation at diagnosis of pediatric osteosarcoma chemoresponsiveness.

  12. High sensitive troponin T and heart fatty acid binding protein: Novel biomarker in heart failure with normal ejection fraction?: A cross-sectional study

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    Barroso Michael

    2011-07-01

    Full Text Available Abstract Background High sensitive troponin T (hsTnT and heart fatty acid binding protein (hFABP are both markers of myocardial injury and predict adverse outcome in patients with systolic heart failure (SHF. We tested whether hsTnT and hFABP plasma levels are elevated in patients with heart failure with normal ejection fraction (HFnEF. Methods We analyzed hsTnT, hFABP and N-terminal brain natriuretic peptide in 130 patients comprising 49 HFnEF patients, 51 patients with asymptomatic left ventricular diastolic dysfunction (LVDD, and 30 controls with normal diastolic function. Patients were classified to have HFnEF when the diagnostic criteria as recommended by the European Society of Cardiology were met. Results Levels of hs TnT and hFABP were significantly higher in patients with asymptomatic LVDD and HFnEF (both p Conclusion In HFnEF patients, hsTnT and hFABP are elevated independent of coronary artery disease, suggesting that ongoing myocardial damage plays a critical role in the pathophysiology. A combination of biomarkers and echocardiographic parameters might improve diagnostic accuracy and risk stratification of patients with HFnEF.

  13. Biomarkers in Alzheimer's Disease-Recent Update.

    Science.gov (United States)

    Sharma, Sushil; Lipincott, Walter

    2017-02-20

    Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized by loss of memory and cognitive function. It is the common cause of dementia in elderly and is a global health concern as the population of people aged 85 and older, is growing alarmingly. Although pharmacotherapy for the treatment of AD has improved, lot of work remains to treat this devastating disease. AD pathology begins even before the onset of clinical symptoms. Because therapies could be more effective if implemented early in the disease progression, it is highly prudent to discover reliable biomarkers, to detect its exact pathophysiology during pre-symptomatic stage. Biomarker(s) with high sensitivity and specificity would facilitate AD diagnosis at early stages. Currently, CSF amyloid β 1-42, total tau, and phosphorylated tau181 are used as AD biomarkers. This report describes conventional and potential in-vitro and in-vivo biomarkers of AD. Particularly, in-vitro transcriptomic, proteomic, lipidomic, and metabolomic; body fluid biomarkers (C-reactive proteins, homocysteine, α-sunuclein index, and dehydroepiandrosterone sulphate) from blood, serum, plasma, CSF, and saliva; and neuronal, platelets, and lymphocyte microRNA, mtDNA, and Charnoly body are detected. In-vivo physiological and neurobehavioral biomarkers are evaluated by analyzing computerized EEG, event-related potentials, circadian rhythm, and multimodality fusion imaging including: CT, MRI, SPECT, and PET. More specifically, PET imaging biomarkers representing reduced fronto-temporal 18FdG uptake, increased 11C or 18F-PIB uptake, 11C-PBR28 to measure 18 kDa translocator protein (TSPO), a biomarker for inflammation; and 3-D MRI (ventriculomegaly)/MRS are performed for early and effective clinical management of AD.

  14. On consensus biomarker selection

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    Gambin Anna

    2007-05-01

    Full Text Available Abstract Background Recent development of mass spectrometry technology enabled the analysis of complex peptide mixtures. A lot of effort is currently devoted to the identification of biomarkers in human body fluids like serum or plasma, based on which new diagnostic tests for different diseases could be constructed. Various biomarker selection procedures have been exploited in recent studies. It has been noted that they often lead to different biomarker lists and as a consequence, the patient classification may also vary. Results Here we propose a new approach to the biomarker selection problem: to apply several competing feature ranking procedures and compute a consensus list of features based on their outcomes. We validate our methods on two proteomic datasets for the diagnosis of ovarian and prostate cancer. Conclusion The proposed methodology can improve the classification results and at the same time provide a unified biomarker list for further biological examinations and interpretation.

  15. Biomarkers of Reflux Disease.

    Science.gov (United States)

    Kia, Leila; Pandolfino, John E; Kahrilas, Peter J

    2016-06-01

    Gastroesophageal reflux disease (GERD) encompasses an array of disorders unified by the reflux of gastric contents. Because there are many potential disease manifestations, esophageal and extraesophageal, there is no single biomarker of the entire disease spectrum; a set of GERD biomarkers that each quantifies specific aspects of GERD-related pathology might be needed. We review recent reports of biomarkers of GERD, specifically in relation to endoscopically negative esophageal disease and excluding conventional pH-impedance monitoring. We consider histopathologic biomarkers, baseline impedance, and serologic assays to determine that most markers are based on manifestations of impaired esophageal mucosal integrity, which is based on increased ionic and molecular permeability, and/or destruction of tight junctions. Impaired mucosal integrity quantified by baseline mucosal impedance, proteolytic fragments of junctional proteins, or histopathologic features has emerged as a promising GERD biomarker.

  16. Biomarkers in Parkinson's disease.

    Science.gov (United States)

    Morgan, John C; Mehta, Shyamal H; Sethi, Kapil D

    2010-11-01

    Biomarkers are objectively measured characteristics that are indicators of normal biological processes, pathogenic processes, or responses to therapeutic interventions. To date, clinical assessment remains the gold standard in the diagnosis of Parkinson's disease (PD) and clinical rating scales are well established as the gold standard for tracking progression of PD. Researchers have identified numerous potential biomarkers that may aid in the differential diagnosis of PD and/or tracking disease progression. Clinical, genetic, blood and cerebrospinal fluid (proteomics, transcriptomics, metabolomics), and neuroimaging biomarkers may provide useful tools in the diagnosis of PD and in measuring disease progression and response to therapies. Some potential biomarkers are inexpensive and do not require much technical expertise, whereas others are expensive or require specialized equipment and technical skills. Many potential biomarkers in PD show great promise; however, they need to be assessed for their sensitivity and specificity over time in large and varied samples of patients with and without PD.

  17. Mass Spectrometry-Based Proteomic Study Makes High-Density Lipoprotein a Biomarker for Atherosclerotic Vascular Disease

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    Chiz-Tzung Chang

    2015-01-01

    Full Text Available High-density lipoprotein (HDL is a lipid and protein complex that consists of apolipoproteins and lower level HDL-associated enzymes. HDL dysfunction is a factor in atherosclerosis and decreases patient survival. Mass spectrometry- (MS- based proteomics provides a high throughput approach for analyzing the composition and modifications of complex HDL proteins in diseases. HDL can be separated according to size, surface charge, electronegativity, or apoprotein composition. MS-based proteomics on subfractionated HDL then allows investigation of lipoprotein roles in diseases. Herein, we review recent developments in MS-based quantitative proteomic techniques, HDL proteomics and lipoprotein modifications in diseases, and HDL subfractionation studies. We also discuss future directions and perspectives in MS-based proteomics on HDL.

  18. Biomarkers of Aging: From Function to Molecular Biology.

    Science.gov (United States)

    Wagner, Karl-Heinz; Cameron-Smith, David; Wessner, Barbara; Franzke, Bernhard

    2016-06-02

    Aging is a major risk factor for most chronic diseases and functional impairments. Within a homogeneous age sample there is a considerable variation in the extent of disease and functional impairment risk, revealing a need for valid biomarkers to aid in characterizing the complex aging processes. The identification of biomarkers is further complicated by the diversity of biological living situations, lifestyle activities and medical treatments. Thus, there has been no identification of a single biomarker or gold standard tool that can monitor successful or healthy aging. Within this short review the current knowledge of putative biomarkers is presented, focusing on their application to the major physiological mechanisms affected by the aging process including physical capability, nutritional status, body composition, endocrine and immune function. This review emphasizes molecular and DNA-based biomarkers, as well as recent advances in other biomarkers such as microRNAs, bilirubin or advanced glycation end products.

  19. Novel oligonucleotide primers reveal a high diversity of microbes which drive phosphorous turnover in soil.

    Science.gov (United States)

    Bergkemper, Fabian; Kublik, Susanne; Lang, Friederike; Krüger, Jaane; Vestergaard, Gisle; Schloter, Michael; Schulz, Stefanie

    2016-06-01

    Phosphorus (P) is of central importance for cellular life but likewise a limiting macronutrient in numerous environments. Certainly microorganisms have proven their ability to increase the phosphorus bioavailability by mineralization of organic-P and solubilization of inorganic-P. On the other hand they efficiently take up P and compete with other biota for phosphorus. However the actual microbial community that is associated to the turnover of this crucial macronutrient in different ecosystems remains largely anonymous especially taking effects of seasonality and spatial heterogeneity into account. In this study seven oligonucleotide primers are presented which target genes coding for microbial acid and alkaline phosphatases (phoN, phoD), phytases (appA), phosphonatases (phnX) as well as the quinoprotein glucose dehydrogenase (gcd) and different P transporters (pitA, pstS). Illumina amplicon sequencing of soil genomic DNA underlined the high rate of primer specificity towards the respective target gene which usually ranged between 98% and 100% (phoN: 87%). As expected the primers amplified genes from a broad diversity of distinct microorganisms. Using DNA from a beech dominated forest soil, the highest microbial diversity was detected for the alkaline phosphatase (phoD) gene which was amplified from 15 distinct phyla respectively 81 families. Noteworthy the primers also allowed amplification of phoD from 6 fungal orders. The genes coding for acid phosphatase (phoN) and the quinoprotein glucose dehydrogenase (gcd) were amplified from 20 respectively 17 different microbial orders. In comparison the phytase and phosphonatase (appA, phnX) primers covered 13 bacterial orders from 2 different phyla respectively. Although the amplified microbial diversity was apparently limited both primers reliably detected all orders that contributed to the P turnover in the investigated soil as revealed by a previous metagenomic approach. Genes that code for microbial P transporter

  20. Biomarkers in DILI: one more step forward

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    Mercedes Robles-Díaz

    2016-08-01

    Full Text Available Despite being relatively rare, drug-induced liver injury (DILI is a serious condition, both for the individual patient due to the risk of acute liver failure, and for the drug development industry and regulatory agencies due to associations with drug development attritions, black box warnings and postmarketing withdrawals. A major limitation in DILI diagnosis and prediction is the current lack of specific biomarkers. Despite refined usage of traditional liver biomarkers in DILI, reliable disease outcome predictions are still difficult to make. These limitations have driven the growing interest in developing new more sensitive and specific DILI biomarkers, which can improve early DILI prediction, diagnosis and course of action. Several promising DILI biomarker candidates have been discovered to date, including mechanistic-based biomarker candidates such as glutamate dehydrogenase, high-mobility group box 1 protein and keratin-18, which can also provide information on the injury mechanism of different causative agents. Furthermore, microRNAs have received much attention lately as potential non-invasive DILI biomarker candidates, in particular miR-122. Advances in omics technologies offer a new approach for biomarker exploration studies. The ability to screen a large number of molecules (for example metabolites, proteins or DNA simultaneously enables the identification of ‘toxicity signatures’, which may be used to enhance preclinical safety assessments and disease diagnostics. Omics-based studies can also provide information on the underlying mechanisms of distinct forms of DILI that may further facilitate the identification of early diagnostic biomarkers and safer implementation of personalized medicine. In this review we summarize recent advances in the area of DILI biomarker studies.

  1. Biomarkers in DILI: One More Step Forward

    Science.gov (United States)

    Robles-Díaz, Mercedes; Medina-Caliz, Inmaculada; Stephens, Camilla; Andrade, Raúl J.; Lucena, M. Isabel

    2016-01-01

    Despite being relatively rare, drug-induced liver injury (DILI) is a serious condition, both for the individual patient due to the risk of acute liver failure, and for the drug development industry and regulatory agencies due to associations with drug development attritions, black box warnings, and postmarketing withdrawals. A major limitation in DILI diagnosis and prediction is the current lack of specific biomarkers. Despite refined usage of traditional liver biomarkers in DILI, reliable disease outcome predictions are still difficult to make. These limitations have driven the growing interest in developing new more sensitive and specific DILI biomarkers, which can improve early DILI prediction, diagnosis, and course of action. Several promising DILI biomarker candidates have been discovered to date, including mechanistic-based biomarker candidates such as glutamate dehydrogenase, high-mobility group box 1 protein and keratin-18, which can also provide information on the injury mechanism of different causative agents. Furthermore, microRNAs have received much attention lately as potential non-invasive DILI biomarker candidates, in particular miR-122. Advances in “omics” technologies offer a new approach for biomarker exploration studies. The ability to screen a large number of molecules (e.g., metabolites, proteins, or DNA) simultaneously enables the identification of ‘toxicity signatures,’ which may be used to enhance preclinical safety assessments and disease diagnostics. Omics-based studies can also provide information on the underlying mechanisms of distinct forms of DILI that may further facilitate the identification of early diagnostic biomarkers and safer implementation of personalized medicine. In this review, we summarize recent advances in the area of DILI biomarker studies. PMID:27597831

  2. High-Resolution AUV Mapping Reveals Structural Details of Submarine Inflated Lava Flows

    Science.gov (United States)

    Paduan, J.; Clague, D. A.; Caress, D. W.; Thomas, H.; Thompson, D.; Conlin, D.

    2009-12-01

    The MBARI mapping AUV D. Allan B. has now been used to map volcanic terrain at mid-ocean ridges, back-arc spreading centers, and seamounts. These include the summit caldera and upper south rift zone at Axial Volcano, the summit of Davidson Seamount, the Endeavour hydrothermal fields, the Northeast Lau Spreading Center and West Mata Volcano, and, most recently, the CoAxial, North Cleft and North Gorda historic eruption sites on the Juan de Fuca and Gorda Ridges. ROV and submersible dives at most of these sites have provided groundtruth for the textures and features revealed in the roughly 1-m resolution maps. A prominent feature in the maps from four of the sites are inflated flows that did not deflate or drain. These resemble subaerial tumuli but differ in being located on level terrain, apparently atop or very near eruptive vents instead of being in the distal portions of flows. The largest inflated flow at Axial Volcano is on the caldera floor. The main part is 500 by 300 m, and up to 30 m high, with a lobe that extends another 750 m in a sinuous path. It and two nearby, medium-sized inflated flows were first described from sidescan imagery and a submersible dive by Appelgate and Embley (Bull. Volcanol., 54, 447-458, 1992). The AUV maps show clearly the smooth, gently domed relief of the large inflated flow and its sinuous shape on the seafloor, the medium-sized nearby inflated flows, and several additional smaller ones. Particularly striking is a network of 4 to 10 m deep cracks along the crest of each inflation. The cracks occur 30 to 50 m from the margins on all sides of the wider parts of the inflated flows, and become medial cracks along the entire length of the narrow parts, which are nearly triangular in cross-section. An inflation pit 35 m in diameter has a depth equal to the surrounding lava fields. ROV Doc Ricketts dove on these flows in August 2009 and photographed the deeply cracked, uplifted, once flat-lying lineated and ropy sheet flows that form

  3. High throughput HPLC-ESI(-)-MS/MS methodology for mercapturic acid metabolites of 1,3-butadiene: Biomarkers of exposure and bioactivation.

    Science.gov (United States)

    Kotapati, Srikanth; Esades, Amanda; Matter, Brock; Le, Chap; Tretyakova, Natalia

    2015-11-05

    1,3-Butadiene (BD) is an important industrial and environmental carcinogen present in cigarette smoke, automobile exhaust, and urban air. The major urinary metabolites of BD in humans are 2-(N-acetyl-L-cystein-S-yl)-1-hydroxybut-3-ene/1-(N-acetyl-L-cystein-S-yl)-2-hydroxybut-3-ene (MHBMA), 4-(N-acetyl-L-cystein-S-yl)-1,2-dihydroxybutane (DHBMA), and 4-(N-acetyl-L-cystein-S-yl)-1,2,3-trihydroxybutyl mercapturic acid (THBMA), which are formed from the electrophilic metabolites of BD, 3,4-epoxy-1-butene (EB), hydroxymethyl vinyl ketone (HMVK), and 3,4-epoxy-1,2-diol (EBD), respectively. In the present work, a sensitive high-throughput HPLC-ESI(-)-MS/MS method was developed for simultaneous quantification of MHBMA and DHBMA in small volumes of human urine (200 μl). The method employs a 96 well Oasis HLB SPE enrichment step, followed by isotope dilution HPLC-ESI(-)-MS/MS analysis on a triple quadrupole mass spectrometer. The validated method was used to quantify MHBMA and DHBMA in urine of workers from a BD monomer and styrene-butadiene rubber production facility (40 controls and 32 occupationally exposed to BD). Urinary THBMA concentrations were also determined in the same samples. The concentrations of all three BD-mercapturic acids and the metabolic ratio (MHBMA/(MHBMA+DHBMA+THBMA)) were significantly higher in the occupationally exposed group as compared to controls and correlated with BD exposure, with each other, and with BD-hemoglobin biomarkers. This improved high throughput methodology for MHBMA and DHBMA will be useful for future epidemiological studies in smokers and occupationally exposed workers.

  4. Human semen as an early, sensitive biomarker of highly polluted living environment in healthy men: A pilot biomonitoring study on trace elements in blood and semen and their relationship with sperm quality and RedOx status.

    Science.gov (United States)

    Bergamo, Paolo; Volpe, Maria Grazia; Lorenzetti, Stefano; Mantovani, Alberto; Notari, Tiziana; Cocca, Ennio; Cerullo, Stefano; Di Stasio, Michele; Cerino, Pellegrino; Montano, Luigi

    2016-12-01

    The Campania region in Italy is facing an environmental crisis due to the illegal disposal of toxic waste. Herein, a pilot study (EcoFoodFertility initiative) was conducted to investigate the use of human semen as an early biomarker of pollution on 110 healthy males living in various areas of Campania with either high or low environmental impact. The semen from the "high impact" group showed higher zinc, copper, chromium and reduced iron levels, as well as reduced sperm motility and higher sperm DNA Fragmentation Index (DFI). Redox biomarkers (total antioxidant capacity, TAC, and glutathione, GSH) and the activity of antioxidant enzymes in semen were lower in the "high impact" group. The percentage of immotile spermatozoa showed a significant inverse correlation with TAC and GSH. Overall, several semen parameters (reduced sperm quality and antioxidant defenses, altered chemical element pattern), which were associated with residence in a high polluted environment, could be used in a further larger scale study, as early biomarkers of environmental pollution.

  5. [Biomarkers in Alzheimer's disease].

    Science.gov (United States)

    García-Ribas, G; López-Sendón Moreno, J L; García-Caldentey, J

    2014-04-01

    The new diagnostic criteria for Alzheimer's disease (AD) include brain imaging and cerebrospinal fluid (CSF) biomarkers, with the aim of increasing the certainty of whether a patient has an ongoing AD neuropathologic process or not. Three CSF biomarkers, Aß42, total tau, and phosphorylated tau, reflect the core pathological features of AD. It is already known that these pathological processes of AD starts decades before the first symptoms, so these biomarkers may provide means of early disease detection. At least three stages of AD could be identified: preclinical AD, mild cognitive impairment due to AD, and dementia due to AD. In this review, we aim to summarize the CSF biomarker data available for each of these stages. We also review the actual research on blood-based biomarkers. Recent studies on healthy elderly subjects and on carriers of dominantly inherited AD mutations have also found biomarker changes that allow separate groups in these preclinical stages. These studies may aid for segregate populations in clinical trials and objectively evaluate if there are changes over the pathological processes of AD. Limits to widespread use of CSF biomarkers, apart from the invasive nature of the process itself, is the higher coefficient of variation for the analyses between centres. It requires strict pre-analytical and analytical procedures that may make feasible multi-centre studies and global cut-off points for the different stages of AD.

  6. Identification of protein biomarkers for cervical cancer using human cervicovaginal fluid.

    Directory of Open Access Journals (Sweden)

    Geert A A Van Raemdonck

    Full Text Available OBJECTIVES: Cervicovaginal fluid (CVF can be considered as a potential source of biomarkers for diseases of the lower female reproductive tract. The fluid can easily be collected, thereby offering new opportunities such as the development of self tests. Our objective was to identify a CVF protein biomarker for cervical cancer or its precancerous state. METHODS: A differential proteomics study was set up using CVF samples from healthy and precancerous women. Label-free spectral counting was applied to quantify protein abundances. RESULTS: The proteome analysis revealed 16 candidate biomarkers of which alpha-actinin-4 (p = 0.001 and pyruvate kinase isozyme M1/M2 (p = 0.014 were most promising. Verification of alpha-actinin-4 by ELISA (n = 28 showed that this candidate biomarker discriminated between samples from healthy and both low-risk and high-risk HPV-infected women (p = 0.009. Additional analysis of longitudinal samples (n = 29 showed that alpha-actinin-4 levels correlated with virus persistence and clearing, with a discrimination of approximately 18 pg/ml. CONCLUSIONS: Our results show that CVF is an excellent source of protein biomarkers for detection of lower female genital tract pathologies and that alpha-actinin-4 derived from CVF is a promising candidate biomarker for the precancerous state of cervical cancer. Further studies regarding sensitivity and specificity of this biomarker will demonstrate its utility for improving current screening programs and/or its use for a cervical cancer self-diagnosis test.

  7. Selection of DNA Aptamers for Ovarian Cancer Biomarker CA125 Using One-Pot SELEX and High-Throughput Sequencing

    Directory of Open Access Journals (Sweden)

    Delia J. Scoville

    2017-01-01

    Full Text Available CA125 is a mucin glycoprotein whose concentration in serum correlates with a woman’s risk of developing ovarian cancer and also indicates response to therapy in diagnosed patients. Accurate detection of this large, complex protein in patient samples is of great clinical relevance. We suggest that powerful new diagnostic tools may be enabled by the development of nucleic acid aptamers with affinity for CA125. Here, we report on our use of One-Pot SELEX to isolate single-stranded DNA aptamers with affinity for CA125, followed by high-throughput sequencing of the selected oligonucleotides. This data-rich approach, combined with bioinformatics tools, enabled the entire selection process to be characterized. Using fluorescence anisotropy and affinity probe capillary electrophoresis, the binding affinities of four aptamer candidates were evaluated. Two aptamers, CA125_1 and CA125_12, both without primers, were found to bind to clinically relevant concentrations of the protein target. Binding was differently influenced by the presence of Mg2+ ions, being required for binding of CA125_1 and abrogating binding of CA125_12. In conclusion, One-Pot SELEX was found to be a promising selection method that yielded DNA aptamers to a clinically important protein target.

  8. Apoptosis and biochemical biomarkers of stress in spiders from industrially polluted areas exposed to high temperature and dimethoate.

    Science.gov (United States)

    Wilczek, Grazyna

    2005-06-01

    The aim of this study was to evaluate the relations between apoptosis and the activity of antioxidant enzymes (superoxide dismutase; catalase) and quantitative changes in stress protein positive cells (Hsp70; metallothionein) in midgut glands of funnel web spiders Agelena labyrinthica (Agelenidae) and wolf spiders Pardosa lugubris (Lycosidae) exposed to high temperature and pesticide under laboratory conditions. The spiders were collected from two meadow ecosystems differently polluted with metals (Olkusz and Pilica, southern Poland). Under stress conditions, P. lugubris had fewer apoptotic cells in the midgut glands than A. labyrinthica. In P. lugubris from both sites, the observed increase in the percentage of metallothionein and Hsp70-positive cells, simultaneous with intensification of superoxide dismutase and catalase activity, suggests an anti-apoptotic function of those proteins in representatives of wandering spiders. In the midgut glands of A. labyrinthica, heat shock and dimethoate increased the number of Annexin V-positive cells as well as the amounts of mitochondria with low transmembrane potential (DeltaPsi(m)) versus the control. The changes in the percentage of MT- and Hsp70-positive cells in funnel web spiders were less than in wolf spiders. The absence of change in SOD and CAT activity in A. labyrinthica shows that the participation of those enzymes in antioxidant reactions is minimal in this species.

  9. Sex-specific serum biomarker patterns in adults with Asperger's syndrome.

    Science.gov (United States)

    Schwarz, E; Guest, P C; Rahmoune, H; Wang, L; Levin, Y; Ingudomnukul, E; Ruta, L; Kent, L; Spain, M; Baron-Cohen, S; Bahn, S

    2011-12-01

    Autism spectrum conditions have been hypothesized to be an exaggeration of normal male low-empathizing and high-systemizing behaviors. We tested this hypothesis at the molecular level by performing comprehensive multi-analyte profiling of blood serum from adult subjects with Asperger's syndrome (AS) compared with controls. This led to identification of distinct sex-specific biomarker fingerprints for male and female subjects. Males with AS showed altered levels of 24 biomarkers including increased levels of cytokines and other inflammatory molecules. Multivariate statistical classification of males using this panel of 24 biomarkers revealed a marked separation between AS and controls with a sensitivity of 0.86 and specificity of 0.88. Testing this same panel in females did not result in a separation between the AS and control groups. In contrast, AS females showed altered levels of 17 biomarkers including growth factors and hormones such as androgens, growth hormone and insulin-related molecules. Classification of females using this biomarker panel resulted in a separation between AS and controls with sensitivities and specificities of 0.96 and 0.83, respectively, and testing this same panel in the male group did not result in a separation between the AS and control groups. The finding of elevated testosterone in AS females confirmed predictions from the 'extreme male brain' and androgen theories of autism spectrum conditions. We conclude that to understand the etiology and development of autism spectrum conditions, stratification by sex is essential.

  10. Metabolic products as biomarkers

    Science.gov (United States)

    Melancon, M.J.; Alscher, R.; Benson, W.; Kruzynski, G.; Lee, R.F.; Sikka, H.C.; Spies, R.B.; Huggett, Robert J.; Kimerle, Richard A.; Mehrle, Paul M.=; Bergman, Harold L.

    1992-01-01

    Ideally, endogenous biomarkers would indicate both exposure and environmental effects of toxic chemicals; however, such comprehensive biochemical and physiological indices are currently being developed and, at the present time, are unavailable for use in environmental monitoring programs. Continued work is required to validate the use of biochemical and physiological stress indices as useful components of monitoring programs. Of the compounds discussed only phytochelatins and porphyrins are currently in biomarkers in a useful state; however, glutathione,metallothioneins, stress ethylene, and polyamines are promising as biomarkers in environmental monitoring.

  11. Commentary: statistics for biomarkers.

    Science.gov (United States)

    Lovell, David P

    2012-05-01

    This short commentary discusses Biomarkers' requirements for the reporting of statistical analyses in submitted papers. It is expected that submitters will follow the general instructions of the journal, the more detailed guidance given by the International Committee of Medical Journal Editors, the specific guidelines developed by the EQUATOR network, and those of various specialist groups. Biomarkers expects that the study design and subsequent statistical analyses are clearly reported and that the data reported can be made available for independent assessment. The journal recognizes that there is continuing debate about different approaches to statistical science. Biomarkers appreciates that the field continues to develop rapidly and encourages the use of new methodologies.

  12. High temperature garnet growth in New England: regional temperature-time trends revealed

    Science.gov (United States)

    Sullivan, N.; Ostwald, C.; Chu, X.; Baxter, E. F.; Ague, J. J.; Eckert, J. O.

    2013-12-01

    A series of localized ultrahigh-temperature (UHT)/high-temperature (HT) granulite facies regions have been identified within the regional amphibolite facies metamorphic zone of the Central Maine Terrane stretching from north-central New Hampshire, through central Massachusetts, and into northeastern Connecticut. Here, we aim to constrain the age and peak temperature of metamorphism at three localities within this region: Bristol, NH, Phillipston, MA and Willington, CT. Garnet-forming reactions are linked directly to peak metamorphic temperatures through thermodynamic modeling and/or Zr-in-rutile thermometry. Precise garnet geochronology allows us to identify the timing of these peak temperatures, as well as the duration of garnet growth. Geochronologic and thermodynamic work was done on 12 samples collected throughout a ~5 km2 metamorphic 'hotspot' previously identified in Bristol, NH (Chamberlain and Rumble, 1988; Journal of Petrology). The highest temperature assemblage within this hotspot is characterized by the presence of garnet + sillimanite + K-feldspar + cordierite and reached temperatures >820οC. The lowest temperature periphery of the hotspot is characterized by sillimanite + muscovite + K-feldspar + minor garnet and reached a maximum temperature of 650οC. Bulk garnet ages from samples within the hotspot range significantly from at least 400.0 × 2.5 Ma to 352.7 × 1.8 Ma with the youngest ages associated with the lower temperature samples. This collection of ages indicates a prolonged period (~50 Ma) of >650οC temperatures interspersed by period(s) of garnet growth. Zoned garnet geochronology will help reveal whether garnet growth and related heating was continuous or episodic. Further south, in Phillipston, MA, zoned garnet geochronology performed on a 2.5 cm diameter garnet porphyroblast indicates garnet growth spanning 389 - 363 Ma, reaching peak temperatures at the end of that time span of 920-940οC, followed by a younger event recorded in

  13. Cardiorenal biomarkers in acute heart failure

    Institute of Scientific and Technical Information of China (English)

    Rajiv Choudhary; Dipika Gopal; Ben A. Kipper; Alejandro De La Parra Landa; Hermineh Aramin

    2012-01-01

    Managing patients with heart failure (HF) is a challenging task within itself, but the presence of associated worsening renal function can greatly increase mortality and morbidity. Early diagnosis and treatment is the key to prevent re-hospitalizations and reduce healthcare costs. Biomarkers have long been established as highly sensitive and specific tools in diagnosing and prognosticating patients with HF. Reflecting distinct pathophysiological events and ongoing cellular insult, biomarkers have been proven superior to conventional laboratory tests. Availability of better assays and rapid analysis has allowed the use of biomarkers as point-of-care tests in the emergency department and at the patient's bed-side. Acute HF patients often go on to develop worsening renal function, termed as acute cardiorenal syndrome. The growing breadth of studies has shown the implications of combining multiple biomarkers to better chart outcomes and produce desirable results in such patients.

  14. Genetic biomarkers in hypertrophic cardiomyopathy.

    Science.gov (United States)

    Coats, Caroline J; Elliott, Perry M

    2013-08-01

    Hypertrophic cardiomyopathy is a common inherited heart muscle disorder associated with sudden cardiac death, arrhythmias and heart failure. Genetic mutations can be identified in approximately 60% of patients; these are commonest in genes that encode proteins of the cardiac sarcomere. Similar to other Mendelian diseases these mutations are characterized by incomplete penetrance and variable clinical expression. Our knowledge of this genetic diversity is rapidly evolving as high-throughput DNA sequencing technology is now used to characterize an individual patient's disease. In addition, the genomic basis of several multisystem diseases associated with a hypertrophic cardiomyopathy phenotype has been elucidated. Genetic biomarkers can be helpful in making an accurate diagnosis and in identifying relatives at risk of developing the condition. In the clinical setting, genetic testing and genetic screening should be used pragmatically with appropriate counseling. Here we review the current role of genetic biomarkers in hypertrophic cardiomyopathy, highlight recent progress in the field and discuss future challenges.

  15. Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia.

    Science.gov (United States)

    Covell, David G

    2015-01-01

    Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE) and Sanger Cancer Genome Project (CGP). The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a) evaluate drug responses of compounds with similar mechanism of action (MOA), b) examine measures of gene expression (GE), copy number (CN) and mutation status (MUT) biomarkers, combined with gene set enrichment analysis (GSEA), for hypothesizing biological processes important for drug response, c) conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d) assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.

  16. Data Mining Approaches for Genomic Biomarker Development: Applications Using Drug Screening Data from the Cancer Genome Project and the Cancer Cell Line Encyclopedia.

    Directory of Open Access Journals (Sweden)

    David G Covell

    Full Text Available Developing reliable biomarkers of tumor cell drug sensitivity and resistance can guide hypothesis-driven basic science research and influence pre-therapy clinical decisions. A popular strategy for developing biomarkers uses characterizations of human tumor samples against a range of cancer drug responses that correlate with genomic change; developed largely from the efforts of the Cancer Cell Line Encyclopedia (CCLE and Sanger Cancer Genome Project (CGP. The purpose of this study is to provide an independent analysis of this data that aims to vet existing and add novel perspectives to biomarker discoveries and applications. Existing and alternative data mining and statistical methods will be used to a evaluate drug responses of compounds with similar mechanism of action (MOA, b examine measures of gene expression (GE, copy number (CN and mutation status (MUT biomarkers, combined with gene set enrichment analysis (GSEA, for hypothesizing biological processes important for drug response, c conduct global comparisons of GE, CN and MUT as biomarkers across all drugs screened in the CGP dataset, and d assess the positive predictive power of CGP-derived GE biomarkers as predictors of drug response in CCLE tumor cells. The perspectives derived from individual and global examinations of GEs, MUTs and CNs confirm existing and reveal unique and shared roles for these biomarkers in tumor cell drug sensitivity and resistance. Applications of CGP-derived genomic biomarkers to predict the drug response of CCLE tumor cells finds a highly significant ROC, with a positive predictive power of 0.78. The results of this study expand the available data mining and analysis methods for genomic biomarker development and provide additional support for using biomarkers to guide hypothesis-driven basic science research and pre-therapy clinical decisions.

  17. Nonnegative spline regression of incomplete tracing data reveals high resolution neural connectivity

    CERN Document Server

    Harris, Kameron Decker; Shea-Brown, Eric

    2016-01-01

    Whole-brain neural connectivity data are now available from viral tracing experiments, which reveal the connections between a source injection site and elsewhere in the brain. These hold the promise of revealing spatial patterns of connectivity throughout the mammalian brain. To achieve this goal, we seek to fit a weighted, nonnegative adjacency matrix among 100 {\\mu}m brain "voxels" using viral tracer data. Despite a multi-year experimental effort, the problem remains severely underdetermined: Injection sites provide incomplete coverage, and the number of voxels is orders of magnitude larger than the number of injections. Furthermore, projection data are missing within the injection site because local connections there are not separable from the injection signal. We use a novel machine-learning algorithm to meet these challenges and develop a spatially explicit, voxel-scale connectivity map of the mouse visual system. Our method combines three features: a matrix completion loss for missing data, a smoothing ...

  18. Identification of serum protein biomarkers for utrophin based DMD therapy

    Science.gov (United States)

    Guiraud, Simon; Edwards, Benjamin; Squire, Sarah E.; Babbs, Arran; Shah, Nandini; Berg, Adam; Chen, Huijia; Davies, Kay E.

    2017-01-01

    Despite promising therapeutic avenues, there is currently no effective treatment for Duchenne muscular dystrophy (DMD), a lethal monogenic disorder caused by the loss of the large cytoskeletal protein, dystrophin. A highly promising approach to therapy, applicable to all DMD patients irrespective to their genetic defect, is to modulate utrophin, a functional paralogue of dystrophin, able to compensate for the primary defects of DMD restoring sarcolemmal stability. One of the major difficulties in assessing the effectiveness of therapeutic strategies is to define appropriate outcome measures. In the present study, we utilised an aptamer based proteomics approach to profile 1,310 proteins in plasma of wild-type, mdx and Fiona (mdx overexpressing utrophin) mice. Comparison of the C57 and mdx sera revealed 83 proteins with statistically significant >2 fold changes in dystrophic serum abundance. A large majority of previously described biomarkers (ANP32B, THBS4, CAMK2A/B/D, CYCS, CAPNI) were normalised towards wild-type levels in Fiona animals. This work also identified potential mdx markers specific to increased utrophin (DUS3, TPI1) and highlights novel mdx biomarkers (GITR, MYBPC1, HSP60, SIRT2, SMAD3, CNTN1). We define a panel of putative protein mdx biomarkers to evaluate utrophin based strategies which may help to accelerate their translation to the clinic. PMID:28252048

  19. [Proteomic biomarkers in Parkinson's disease].

    Science.gov (United States)

    Bandrés, Sara; Durán, Raquel; Barrero, Francisco; Ramírez, Manuel; Vives, Francisco

    2014-02-16

    Parkinson's disease (PD) is a neurodegenerative disorder that affects movement and is caused by the death of the dopaminergic neurons in the compact part of the substantia nigra. Its diagnosis is essentially clinical, but although the signs and symptoms of PD are well known, the rate of diagnostic error is relatively high. It is estimated that 10-30% of patients initially diagnosed with PD are later reclassified. This disease has a high prevalence beyond the age of 60, and one of its biggest problems is that it is diagnosed when the degenerative process is already at a very advanced stage. Therefore, it is necessary to look for other biomarkers that make it possible to carry out an early diagnosis of PD, follow up its development, distinguish it from other related pathologies (parkinsonisms) and help monitor the effect of novel therapies. The fact that there are mutations that lead to PD, as well as polygenetic combinations that can act as risk factors, suggests the possibility of measuring the proteins resulting from the expression of these genes in peripheral tissues. And once their sensitivity and specificity have been proved they could be used as biomarkers for PD, even in the early phases of the disease. The aim of this work is to focus on a detailed review of the main candidate proteomic biomarkers researched to date by discussing the most recent literature.

  20. Poor efficacy of the phosphorylated high-molecular-weight neurofilament heavy subunit serum level, a biomarker of axonal damage, as a marker of chemotherapy-induced peripheral neuropathy

    Science.gov (United States)

    SUMITANI, MASAHIKO; OGATA, TORU; NATORI, AKINA; HOZUMI, JUN; SHIMOJO, NOBUTAKE; KIDA, KUMIKO; YAMAUCHI, HIDEKO; YAMAUCHI, TERUO

    2016-01-01

    The phosphorylated form of the high-molecular-weight neurofilament heavy subunit (pNF-H) is a major structural protein in axons. The pNF-H level is elevated in the serum of certain patients with central nervous disorders, including chemotherapy-induced cognitive impairment. The present study was conducted to elucidate the potential role of pNF-H as a marker of chemotherapy-induced peripheral neuropathy (CIPN). A total of 71 patients with early breast cancer in various stages of treatment (following 1, 3 or 7 cycles of chemotherapy, or a previous history of breast cancer chemotherapy) were assessed with a self-administered PainDETECT questionnaire [pain location, pain intensity on an 11-point numeric rating scale (NRS), and various pain qualities] and a single serum pNF-H measurement. Patients were divided into two groups based on the presence or absence of bilateral symmetric pain in the distal portions of the extremities [CIPN(+) or CIPN(−)]. The χ2 and Mann-Whitney tests were used for statistical analyses. Among the participants, only 8 patients complained of CIPN. Their pain intensity was 3.5±1.9 (mean ± standard deviation) compared with 1.5±1.8 in the CIPN(−) group (P<0.01). The NRS of numbness in the CIPN(+) group was significantly higher (2.4±1.4) than that of the CIPN(−) group (1.0±1.0). Increased pNF-H levels were observed in 37.5% of the CIPN(+) patients and in 23.8% of CIPN(−) patients (P=0.40). In conclusion, CIPN is observed in the most distal portions of the peripheral nerves that are composed of dendrites but not axons. Although serum pNF-H is a biomarker of axonal damage, it is not useful as a marker of CIPN. PMID:27284419

  1. Stress Biomarkers, Mood States, and Sleep during a Major Competition: “Success” and “Failure” Athlete's Profile of High-Level Swimmers

    Science.gov (United States)

    Chennaoui, Mounir; Bougard, Clément; Drogou, Catherine; Langrume, Christophe; Miller, Christian; Gomez-Merino, Danielle; Vergnoux, Frédéric

    2016-01-01

    The aim of this study was to evaluate stress markers, mood states, and sleep indicators in high-level swimmers during a major 7-days competition according to the outcomes. Nine swimmers [six men and three women (age: 22 ± 2 and 22 ± 4 years, respectively)] were examined. Before (PRE) and after (POST) each race (series, semi-finals, and finals), salivary concentrations of cortisol, α-amylase (sAA), and chromogranin-A (CgA) were determined. Mood states were assessed by the profile of mood state (POMS) questionnaire completed before and after the 7-days, and self-reported sleep diaries were completed daily. In the “failure” group, cortisol and sAA significantly increased between PRE-POST measurements (p < 0.05), while sCgA was not changed. Significant overall decrease of cortisol (-52.6%) and increase of sAA (+68.7%) was shown in the “failure group.” In this group, fatigue, confusion and depression scores, and sleep duration before the finals increased. The results in the “success” group show tendencies for increased cortisol and sCgA concentrations in response to competition, while sAA was not changed. Cortisol levels before the semi-finals and finals and sCgA levels before the finals were positively correlated to the fatigue score in the “failure” group only (r = 0.89). sAA levels before and after the semi-finals were negatively correlated to sleep duration measured in the subsequent night (r = −0.90). In conclusion, the stress of the competition could trigger a negative mood profile and sleep disturbance which correspond to different responses of biomarkers related to the hypothalamo-pituitary-adrenal axis and the sympathetic nervous system (SNS) activity, cortisol, sAA, and CgA. PMID:27014092

  2. Stress biomarkers, mood states and sleep during a major competition: success and failure athlete’s profile of high-level swimmers.

    Directory of Open Access Journals (Sweden)

    MOUNIR eCHENNAOUI

    2016-03-01

    Full Text Available The aim of this study was to evaluate stress markers, mood states and sleep indicators in high-level swimmers during a major 7-days competition according to the outcomes. Nine swimmers (6 men and 3 women (age: 22 ± 2 years and 22 ± 4 years, respectively were examined. Before (PRE and after (POST each race (series, semi-finals and finals, salivary concentrations of cortisol, α-amylase (sAA and chromogranin-A (CgA were determined. Mood states were assessed by the profile of mood state (POMS questionnaire completed before and after the 7-days, and self-reported sleep diaries were completed daily. In the failure group, cortisol and sAA significantly increased between PRE-POST measurements (p<0.05, while sCgA was not changed. Significant overall decrease of cortisol (-52.6% and increase of sAA (+68.7% was shown in the failure group. In this group, fatigue, confusion and depression scores and sleep duration before the finals increased. The results in the success group show tendencies for increased cortisol and sCgA concentrations in response to competition, while sAA was not changed. Cortisol levels before the semi-finals and finals and sCgA levels before the finals were positively correlated to the fatigue score in the failure group only (r=0.89. sAA levels before and after the semi-finals were negatively correlated to sleep duration measured in the subsequent night (r=-0.90. In conclusion, the stress of the competition could trigger a negative mood profile and sleep disturbance which correspond to different responses of biomarkers related to the hypothalamo-pituitary-adrenal axis and the sympathetic nervous system activity, cortisol, sAA and CgA.

  3. Validation of New Cancer Biomarkers

    DEFF Research Database (Denmark)

    Duffy, Michael J; Sturgeon, Catherine M; Söletormos, Georg;

    2015-01-01

    BACKGROUND: Biomarkers are playing increasingly important roles in the detection and management of patients with cancer. Despite an enormous number of publications on cancer biomarkers, few of these biomarkers are in widespread clinical use. CONTENT: In this review, we discuss the key steps...... in advancing a newly discovered cancer candidate biomarker from pilot studies to clinical application. Four main steps are necessary for a biomarker to reach the clinic: analytical validation of the biomarker assay, clinical validation of the biomarker test, demonstration of clinical value from performance...... of the biomarker test, and regulatory approval. In addition to these 4 steps, all biomarker studies should be reported in a detailed and transparent manner, using previously published checklists and guidelines. Finally, all biomarker studies relating to demonstration of clinical value should be registered before...

  4. Biomarker time out.

    Science.gov (United States)

    Petzold, Axel; Bowser, Robert; Calabresi, Paolo; Zetterberg, Henrik; Uitdehaag, Bernard M J

    2014-10-01

    The advancement of knowledge relies on scientific investigations. The timing between asking a question and data collection defines if a study is prospective or retrospective. Prospective studies look forward from a point in time, are less prone to bias and are considered superior to retrospective studies. This conceptual framework conflicts with the nature of biomarker research. New candidate biomarkers are discovered in a retrospective manner. There are neither resources nor time for prospective testing in all cases. Relevant sources for bias are not covered. Ethical questions arise through the time penalty of an overly dogmatic concept. The timing of sample collection can be separated from testing biomarkers. Therefore the moment of formulating a hypothesis may be after sample collection was completed. A conceptual framework permissive to asking research questions without the obligation to bow to the human concept of calendar time would simplify biomarker research, but will require new safeguards against bias.

  5. Biomarkers in Airway Diseases

    Directory of Open Access Journals (Sweden)

    Janice M Leung

    2013-01-01

    Full Text Available The inherent limitations of spirometry and clinical history have prompted clinicians and scientists to search for surrogate markers of airway diseases. Although few biomarkers have been widely accepted into the clinical armamentarium, the authors explore three sources of biomarkers that have shown promise as indicators of disease severity and treatment response. In asthma, exhaled nitric oxide measurements can predict steroid responsiveness and sputum eosinophil counts have been used to titrate anti-inflammatory therapies. In chronic obstructive pulmonary disease, inflammatory plasma biomarkers, such as fibrinogen, club cell secretory protein-16 and surfactant protein D, can denote greater severity and predict the risk of exacerbations. While the multitude of disease phenotypes in respiratory medicine make biomarker development especially challenging, these three may soon play key roles in the diagnosis and management of airway diseases.

  6. Lung Cancer Signature Biomarkers: tissue specific semantic similarity based clustering of Digital Differential Display (DDD data

    Directory of Open Access Journals (Sweden)

    Srivastava Mousami

    2012-11-01

    Full Text Available Abstract Background The tissue-specific Unigene Sets derived from more than one million expressed sequence tags (ESTs in the NCBI, GenBank database offers a platform for identifying significantly and differentially expressed tissue-specific genes by in-silico methods. Digital differential display (DDD rapidly creates transcription profiles based on EST comparisons and numerically calculates, as a fraction of the pool of ESTs, the relative sequence abundance of known and novel genes. However, the process of identifying the most likely tissue for a specific disease in which to search for candidate genes from the pool of differentially expressed genes remains difficult. Therefore, we have used ‘Gene Ontology semantic similarity score’ to measure the GO similarity between gene products of lung tissue-specific candidate genes from control (normal and disease (cancer sets. This semantic similarity score matrix based on hierarchical clustering represents in the form of a dendrogram. The dendrogram cluster stability was assessed by multiple bootstrapping. Multiple bootstrapping also computes a p-value for each cluster and corrects the bias of the bootstrap probability. Results Subsequent hierarchical clustering by the multiple bootstrapping method (α = 0.95 identified seven clusters. The comparative, as well as subtractive, approach revealed a set of 38 biomarkers comprising four distinct lung cancer signature biomarker clusters (panel 1–4. Further gene enrichment analysis of the four panels revealed that each panel represents a set of lung cancer linked metastasis diagnostic biomarkers (panel 1, chemotherapy/drug resistance biomarkers (panel 2, hypoxia regulated biomarkers (panel 3 and lung extra cellular matrix biomarkers (panel 4. Conclusions Expression analysis reveals that hypoxia induced lung cancer related biomarkers (panel 3, HIF and its modulating proteins (TGM2, CSNK1A1, CTNNA1, NAMPT/Visfatin, TNFRSF1A, ETS1, SRC-1, FN1, APLP2, DMBT1

  7. Biomarkers for neuromyelitis optica.

    Science.gov (United States)

    Chang, Kuo-Hsuan; Ro, Long-Sun; Lyu, Rong-Kuo; Chen, Chiung-Mei

    2015-02-02

    Neuromyelitis optica (NMO) is an acquired, heterogeneous inflammatory disorder, which is characterized by recurrent optic neuritis and longitudinally extensive spinal cord lesions. The discovery of the serum autoantibody marker, anti-aquaporin 4 (anti-AQP4) antibody, revolutionizes our understanding of pathogenesis of NMO. In addition to anti-AQP4 antibody, other biomarkers for NMO are also reported. These candidate biomarkers are particularly involved in T helper (Th)17 and astrocytic damages, which play a critical role in the development of NMO lesions. Among them, IL-6 in the peripheral blood is associated with anti-AQP4 antibody production. Glial fibrillary acidic protein (GFAP) in CSF demonstrates good correlations with clinical severity of NMO relapses. Detecting these useful biomarkers may be useful in the diagnosis and evaluation of disease activity of NMO. Development of compounds targeting these biomarkers may provide novel therapeutic strategies for NMO. This article will review the related biomarker studies in NMO and discuss the potential therapeutics targeting these biomarkers.

  8. Incremental Prognostic Power of Novel Biomarkers (Growth-Differentiation Factor-15, High-Sensitivity C-Reactive Protein, Galectin-3, and High-Sensitivity Troponin-T) in Patients With Advanced Chronic Heart Failure

    NARCIS (Netherlands)

    Lok, Dirk J.; Klip, IJsbrand T.; Lok, Sjoukje I.; de la Porte, Pieta W. Bruggink-Andre; Badings, Erik; van Wijngaarden, Jan; Voors, Adriaan A.; de Boer, Rudolf A.; van Veldhuisen, Dirk J.; van der Meer, Peter

    2013-01-01

    Elevated natriuretic peptides provide strong prognostic information in patients with heart failure (HF). The role of novel biomarkers in HF needs to be established. Our objective was to evaluate the prognostic power of novel biomarkers, incremental to the N-terminal portion of the natriuretic peptid

  9. Identifying Modular Flows on Multilayer Networks Reveals Highly Overlapping Organization in Interconnected Systems

    Science.gov (United States)

    De Domenico, Manlio; Lancichinetti, Andrea; Arenas, Alex; Rosvall, Martin

    2015-01-01

    To comprehend interconnected systems across the social and natural sciences, researchers have developed many powerful methods to identify functional modules. For example, with interaction data aggregated into a single network layer, flow-based methods have proven useful for identifying modular dynamics in weighted and directed networks that capture constraints on flow processes. However, many interconnected systems consist of agents or components that exhibit multiple layers of interactions, possibly from several different processes. Inevitably, representing this intricate network of networks as a single aggregated network leads to information loss and may obscure the actual organization. Here, we propose a method based on a compression of network flows that can identify modular flows both within and across layers in nonaggregated multilayer networks. Our numerical experiments on synthetic multilayer networks, with some layers originating from the same interaction process, show that the analysis fails in aggregated networks or when treating the layers separately, whereas the multilayer method can accurately identify modules across layers that originate from the same interaction process. We capitalize on our findings and reveal the community structure of two multilayer collaboration networks with topics as layers: scientists affiliated with the Pierre Auger Observatory and scientists publishing works on networks on the arXiv. Compared to conventional aggregated methods, the multilayer method uncovers connected topics and reveals smaller modules with more overlap that better capture the actual organization.

  10. Multilocus sequence analysis of nectar pseudomonads reveals high genetic diversity and contrasting recombination patterns.

    Directory of Open Access Journals (Sweden)

    Sergio Alvarez-Pérez

    Full Text Available The genetic and evolutionary relationships among floral nectar-dwelling Pseudomonas 'sensu stricto' isolates associated to South African and Mediterranean plants were investigated by multilocus sequence analysis (MLSA of four core housekeeping genes (rrs, gyrB, rpoB and rpoD. A total of 35 different sequence types were found for the 38 nectar bacterial isolates characterised. Phylogenetic analyses resulted in the identification of three main clades [nectar groups (NGs 1, 2 and 3] of nectar pseudomonads, which were closely related to five intrageneric groups: Pseudomonas oryzihabitans (NG 1; P. fluorescens, P. lutea and P. syringae (NG 2; and P. rhizosphaerae (NG 3. Linkage disequilibrium analysis pointed to a mostly clonal population structure, even when the analysis was restricted to isolates from the same floristic region or belonging to the same NG. Nevertheless, signatures of recombination were observed for NG 3, which exclusively included isolates retrieved from the floral nectar of insect-pollinated Mediterranean plants. In contrast, the other two NGs comprised both South African and Mediterranean isolates. Analyses relating diversification to floristic region and pollinator type revealed that there has been more unique evolution of the nectar pseudomonads within the Mediterranean region than would be expected by chance. This is the first work analysing the sequence of multiple loci to reveal geno- and ecotypes of nectar bacteria.

  11. Advances in biomarkers of major depressive disorder.

    Science.gov (United States)

    Huang, Tiao-Lai; Lin, Chin-Chuen

    2015-01-01

    Major depressive disorder (MDD) is characterized by mood, vegetative, cognitive, and even psychotic symptoms and signs that can cause substantial impairments in quality of life and functioning. Biomarkers are measurable indicators that could help diagnosing MDD or predicting treatment response. In this chapter, lipid profiles, immune/inflammation, and neurotrophic factor pathways that have long been implicated in the pathogenesis of MDD are discussed. Then, pharmacogenetics and epigenetics of serotonin transport and its metabolism pathway, brain-derived neurotrophic factor, and abnormality of hypothalamo-pituitary-adrenocortical axis also revealed new biomarkers. Lastly, new techniques, such as proteomics and metabolomics, which allow researchers to approach the studying of MDD with new directions and make new discoveries are addressed. In the future, more data are needed regarding pathophysiology of MDD, including protein levels, single nucleotide polymorphism, epigenetic regulation, and clinical data in order to better identify reliable and consistent biomarkers for diagnosis, treatment choice, and outcome prediction.

  12. The donor of Aquila X-1 revealed by high angular resolution near-infrared spectroscopy

    CERN Document Server

    Sánchez, D Mata; Casares, J; Jiménez-Ibarra, F

    2016-01-01

    The low mass X-ray binary Aquila X-1 is one of the most active neutron star X-ray transients. Despite it has a relatively bright quiescent optical counterpart, the detection of its companion has been hampered by the presence of a nearby interloper star. Using the infrared integral field spectrograph SINFONI on the VLT-8.2m telescope, we unambiguously single out Aquila X-1 from the interloper. Phase-resolved near infrared spectroscopy reveals absorption features from a K4 +- 2 companion star moving at a projected velocity of K_2= 139 +- 4 km/s. We here present the first dynamical solution and associated fundamental parameters of Aquila X-1, imposing new constraints to the orbital inclination (36 deg < i < 49 deg) and the distance (d = 6 +- 2 kpc) to this prototypical neutron star transient.

  13. The donor of Aquila X-1 revealed by high-angular resolution near-infrared spectroscopy

    Science.gov (United States)

    Mata Sánchez, D.; Muñoz-Darias, T.; Casares, J.; Jiménez-Ibarra, F.

    2017-01-01

    The low-mass X-ray binary Aquila X-1 is one of the most active neutron star X-ray transients. Despite its relatively bright quiescent optical counterpart, the detection of its companion has been hampered by the presence of a nearby interloper star. Using the Spectrograph for INtegral Field Observations in the Near Infrared (SINFONI) on the Very Large Telescope-8.2m telescope, we unambiguously single out Aquila X-1 from the interloper. Phase-resolved near-infrared spectroscopy reveals absorption features from a K4 ± 2 companion star moving at a projected velocity of K2 = 136 ± 4 km s- 1. We here present the first dynamical solution and associated fundamental parameters of Aquila X-1, imposing new constraints on the orbital inclination (36° star transient.

  14. High-Resolution Mapping of Protein Concentration Reveals Principles of Proteome Architecture and Adaptation

    Directory of Open Access Journals (Sweden)

    Emmanuel D. Levy

    2014-05-01

    Full Text Available A single yeast cell contains a hundred million protein molecules. How these proteins are organized to orchestrate living processes is a central question in biology. To probe this organization in vivo, we measured the local concentration of proteins based on the strength of their nonspecific interactions with a neutral reporter protein. We first used a cytosolic reporter and measured local concentrations for ∼2,000 proteins in S. cerevisiae, with accuracy comparable to that of mass spectrometry. Localizing the reporter to membranes specifically increased the local concentration measured for membrane proteins. Comparing the concentrations measured by both reporters revealed that encounter frequencies between proteins are primarily dictated by their abundances. However, to change these encounter frequencies and restructure the proteome, as in adaptation, we find that changes in localization have more impact than changes in abundance. These results highlight how protein abundance and localization contribute to proteome organization and reorganization.

  15. The complete primary structure of Cw*1701 reveals a highly divergent HLA class I molecule.

    Science.gov (United States)

    Herrero, M J; Vilches, C; de Pablo, R; Puente, S; Kreisler, M

    1997-03-01

    Genotyping of the HLA-C locus by PCR-SSP has previously shown 100% association of B41 and B42 with a new allelic variant. Partial sequencing studies (exons 2-4) demonstrated that this PCR-SSP variant corresponded to the new allele Cw*1701. In this study we have characterized the whole coding region of Cw*1701 from a Bubi individual of Equatorial Guinea. Our results partially confirm the previously reported sequence and reveal that Cw*1701 has many new polymorphisms at several exons, including a 18-bp insertion in exon 5. Cw*1701 is thus a most unusual HLA-C molecule defining a third allelic lineage of this locus.

  16. Antileishmanial High-Throughput Drug Screening Reveals Drug Candidates with New Scaffolds

    OpenAIRE

    Siqueira-Neto, Jair L; Ok-Ryul Song; Hyunrim Oh; Jeong-Hun Sohn; Gyongseon Yang; Jiyoun Nam; Jiyeon Jang; Jonathan Cechetto; Chang Bok Lee; Seunghyun Moon; Auguste Genovesio; Eric Chatelain; Thierry Christophe; Freitas-Junior, Lucio H.

    2010-01-01

    International audience; Drugs currently available for leishmaniasis treatment often show parasite resistance, highly toxic side effects and prohibitive costs commonly incompatible with patients from the tropical endemic countries. In this sense, there is an urgent need for new drugs as a treatment solution for this neglected disease. Here we show the development and implementation of an automated high-throughput viability screening assay for the discovery of new drugs against Leishmania. Assa...

  17. A highly-ionized region surrounding SN Refsdal revealed by MUSE

    CERN Document Server

    Karman, W; Balestra, I; Rosati, P; Caputi, K I; Di Teodoro, E; Fraternali, F; Gavazzi, R; Mercurio, A; Prochaska, J X; Rodney, S; Treu, T

    2016-01-01

    Supernova (SN) Refsdal is the first multiply-imaged, highly-magnified, and spatially-resolved SN ever observed. The SN exploded in a highly-magnified spiral galaxy at z=1.49 behind the Frontier Fields Cluster MACS1149, and provides a unique opportunity to study the environment of SNe at high z. We exploit the time delay between multiple images to determine the properties of the SN and its environment, before, during, and after the SN exploded. We use the integral-field spectrograph MUSE on the VLT to simultaneously target all observed and model-predicted positions of SN Refsdal. We find MgII emission at all positions of SN Refsdal, accompanied by weak FeII* emission at two positions. The measured ratios of [OII] to MgII emission of 10-20 indicate a high degree of ionization with low metallicity. Because the same high degree of ionization is found in all images, it cannot be caused by SN Refsdal, but rather by previous SNe or a young and hot stellar population. We find no variability of the [OII] line over a p...

  18. Suppression subtractive hybridization reveals differential gene expression in sunflower grown in high P.

    Science.gov (United States)

    Padmanabhan, Priya; Sahi, Shivendra V

    2011-06-01

    Sunflower (Helianthus annuus L.) is a commercially important oilseed crop. Previous studies proved that this crop is a promising plant species for phytoextraction of excess soil phosphorus (P) because of its superior P accumulating characteristics. Suppression subtractive hybridization (SSH) strategy was employed to isolate and characterize genes that are induced in response to high P in this crop. SSH library was prepared using cDNA generated from plants treated with high P as the 'tester'. Based on the results of dot blot analysis, 360 positive cDNA clones were selected from the SSH library for sequencing. A total of 89 non-redundant expressed sequence tags (ESTs) were identified as high P-responsive genes and they were classified into 6 functional groups. Several genes involved in metabolism showed markedly preferential expression in the library. For further confirmation, thirteen of the representative ESTs were selected from all categories for RT-PCR analysis and the results showed up-regulation of these genes in response to high P-treatment. The gene expression data derived from this study suggested that several of the up-regulated genes identified under high P-treatment might be involved in P-accumulation and tolerance in this plant.

  19. Penicillium arizonense, a new, genome sequenced fungal species, reveals a high chemical diversity in secreted metabolites

    DEFF Research Database (Denmark)

    Grijseels, Sietske; Nielsen, Jens Christian; Randelovic, Milica;

    2016-01-01

    confirmed the grouping of P. arizonense within section Canescentia. Compared to related species, P. arizonense proved to encode a high number of proteins involved in carbohydrate metabolism, in particular hemicellulases. Mining the genome for genes involved in secondary metabolite biosynthesis resulted...... of biosynthetic gene clusters in P. arizonense responsible for the synthesis of all detected compounds except curvulinic acid. The capacity to produce biomass degrading enzymes and the identification of a high chemical diversity in secreted bioactive secondary metabolites, offers a broad range of potential...

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

    Science.gov (United States)

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

    2016-04-01

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

  1. Revealing The Assembly History Of Discs In Galaxies Through High-Order Stellar Kinematics With Sami

    Science.gov (United States)

    van de Sande, Jesse

    2016-09-01

    Fast-rotating galaxies which host stellar discs show a strong anti-correlation between the higher-order Gauss-Hermite spectral moment h3 (skewness of the line) and the anisotropy parameter v/sigma. Recent cosmological hydrodynamical simulations suggest that these discs could only have formed through gas-rich mergers (Naab et al. 2014); in gas-poor mergers no discs are formed due to the absence of a dissipative gas component. With integral field spectrographs such as SAMI it is now possible to assess these results by classifying galaxies based on their higher-order stellar kinematics signatures alone. In this talk, I will present the stellar kinematic measurements from the SAMI galaxy survey and a first observational attempt to connect the higher-order stellar kinematic moments in galaxies to their cosmological assembly history.I will show the higher-order kinematic classes that we find within the SAMI galaxy survey, and compare how our new classes correlate with other global galaxy properties. Finally, I will show that our new way of classifying galaxies from their higher-order stellar kinematics signatures shows great potential for revealing possible hidden discs and bars in galaxies.

  2. Phylum-specific environmental DNA analysis reveals remarkably high global biodiversity of Cercozoa (Protozoa).

    Science.gov (United States)

    Bass, David; Cavalier-Smith, Thomas

    2004-11-01

    This study presents the first 18S rRNA multi-library environmental PCR survey of a single protozoan phylum, Cercozoa Cavalier-Smith 1998, from a range of different habitats. Phylogenetic analysis reveals at least nine novel clades within the phylum, several possibly at the level of order or above. Further experiments are described to ascertain the true ecological and geographical distributions of some clades that might be inferred from the tree to be restricted in either or both ways. These results suggest that the diversity of cercozoan taxa may run into thousands of lineages, making it comparable in diversity to the largest better-characterized protozoan phyla, e.g. Ciliophora (ciliates and suctorians) and Foraminifera. New sequences of cultured Spongomonas, Metromonas and Metopion are also presented. In the light of these additions, and the increased taxon sampling from the environmental libraries, some revisions of cercozoan classification are made: the transfer of Spongomonadea from Reticulofilosa to Monadofilosa; the removal of Metopiida from Sarcomonadea; and the creation of the new order Metromonadida, currently containing the single genus Metromonas. Although Metromonas groups with weak to moderate support with Chlorarachnea, it is here placed in superclass Monadofilosa, to which it is morphologically more similar.

  3. Off like a shot: scaling of ballistic tongue projection reveals extremely high performance in small chameleons.

    Science.gov (United States)

    Anderson, Christopher V

    2016-01-04

    Stretching elastic tissues and using their recoil to power movement allows organisms to release energy more rapidly than by muscle contraction directly, thus amplifying power output. Chameleons employ such a mechanism to ballistically project their tongue up to two body lengths, achieving power outputs nearly three times greater than those possible via muscle contraction. Additionally, small organisms tend to be capable of greater performance than larger species performing similar movements. To test the hypothesis that small chameleon species outperform larger species during ballistic tongue projection, performance was examined during feeding among 20 chameleon species in nine genera. This revealed that small species project their tongues proportionately further than large species, achieving projection distances of 2.5 body lengths. Furthermore, feedings with peak accelerations of 2,590 m s(-2), or 264 g, and peak power output values of 14,040 W kg(-1) are reported. These values represent the highest accelerations and power outputs reported for any amniote movement, highlighting the previously underestimated performance capability of the family. These findings show that examining movements in smaller animals may expose movements harbouring cryptic power amplification mechanisms and illustrate how varying metabolic demands may help drive morphological evolution.

  4. The sources of sodium escaping from Io revealed by spectral high definition imaging.

    Science.gov (United States)

    Mendillo, Michael; Laurent, Sophie; Wilson, Jody; Baumgardner, Jeffrey; Konrad, Janusz; Karl, W Clem

    2007-07-19

    On Jupiter's moon Io, volcanic plumes and evaporating lava flows provide hot gases to form an atmosphere that is subsequently ionized. Some of Io's plasma is captured by the planet's strong magnetic field to form a co-rotating torus at Io's distance; the remaining ions and electrons form Io's ionosphere. The torus and ionosphere are also depleted by three time-variable processes that produce a banana-shaped cloud orbiting with Io, a giant nebula extending out to about 500 Jupiter radii, and a jet close to Io. No spatial constraints exist for the sources of the first two; they have been inferred only from modelling the patterns seen in the trace gas sodium observed far from Io. Here we report observations that reveal a spatially confined stream that ejects sodium only from the wake of the Io-torus interaction, together with a visually distinct, spherically symmetrical outflow region arising from atmospheric sputtering. The spatial extent of the ionospheric wake that feeds the stream is more than twice that observed by the Galileo spacecraft and modelled successfully. This implies considerable variability, and therefore the need for additional modelling of volcanically-driven, episodic states of the great jovian nebula.

  5. Sequence characteristics of T4-like bacteriophage IME08 benome termini revealed by high throughput sequencing

    Directory of Open Access Journals (Sweden)

    An Xiaoping

    2011-04-01

    Full Text Available Abstract Background T4 phage is a model species that has contributed broadly to our understanding of molecular biology. T4 DNA replication and packaging share various mechanisms with human double-stranded DNA viruses such as herpes virus. The literature indicates that T4-like phage genomes have permuted terminal sequences, and are generated by a DNA terminase in a sequence-independent manner; Methods genomic DNA of T4-like bacteriophage IME08 was subjected to high throughput sequencing, and the read sequences with extraordinarily high occurrences were analyzed; Results we demonstrate that both the 5' and 3' termini of the IME08 genome starts with base G or A. The presence of a consensus sequence TTGGA|G around the breakpoint of the high frequency read sequences suggests that the terminase cuts the branched pre-genome in a sequence-preferred manner. Our analysis also shows that terminal cleavage is asymmetric, with one end cut at a consensus sequence, and the other end generated randomly. The sequence-preferred cleavage may produce sticky-ends, but with each end being packaged with different efficiencies; Conclusions this study illustrates how high throughput sequencing can be used to probe replication and packaging mechanisms in bacteriophages and/or viruses.

  6. Revealing the Hidden Wave: Using the Very Small Radio Telescope to Teach High School Physics

    Science.gov (United States)

    Doherty, Michael; Fish, Vincent L.; Needles, Madeleine

    2011-01-01

    Scientists and teachers have worked together to produce teaching materials for the Very Small Radio Telescope (VSRT), an easy-to-use, low-cost apparatus that can be used in multiple laboratory experiments in high school and university physics and astronomy classes. In this article, we describe the motivation for the VSRT and several of the…

  7. Genetic analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

    DEFF Research Database (Denmark)

    Feitosa, Mary F; Wojczynski, Mary K; Straka, Robert

    2014-01-01

    The plasma levels of high-density lipoprotein cholesterol (HDL) have an inverse relationship to the risks of atherosclerosis and cardiovascular disease (CVD), and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights...

  8. Sustained high basal motion of the Greenland ice sheet revealed by borehole deformation

    DEFF Research Database (Denmark)

    Ryser, Claudia; Luethi, Martin P.; Andrews, Lauren C.;

    2014-01-01

    Ice deformation and basal motion characterize the dynamical behavior of the Greenland ice sheet (GrIS). We evaluate the contribution of basal motion from ice deformation measurements in boreholes drilled to the bed at two sites in the western marginal zone of the GrIS. We find a sustained high am...

  9. Genetic analysis of Phytophthora infestans populations in the Nordic European countries reveals high genetic variability

    DEFF Research Database (Denmark)

    Brurberg, May Bente; Elameen, Abdelhameed; Le, Ving Hong

    2011-01-01

    Late blight, caused by the oomycete Phytophthora infestans, is the most important disease of potato (Solanum tuberosum). The pathogen is highly adaptable and to get an overview of the genetic variation in the Nordic countries, Denmark, Finland, Norway and Sweden we have analyzed 200 isolates from...

  10. Single nucleus genome sequencing reveals high similarity among nuclei of an endomycorrhizal fungus

    NARCIS (Netherlands)

    Lin, K.; Limpens, E.H.M.; Zhang, Z.; Ivanov, S.; Saunders, D.G.O.; Mu, D.; Pang, E.; Cao, H.; Cha, H.; Lin, T.; Zhou, Q.; Shang, Y.; Li, Y.; Sharma, T.C.; Velzen, van R.; Ruijter, de N.C.A.; Aanen, D.K.; Win, J.; Kamoun, S.; Bisseling, T.; Geurts, R.; Huang, S.W.

    2014-01-01

    Nuclei of arbuscular endomycorrhizal fungi have been described as highly diverse due to their asexual nature and absence of a single cell stage with only one nucleus. This has raised fundamental questions concerning speciation, selection and transmission of the genetic make-up to next generations. A

  11. Bacillus pumilus reveals a remarkably high resistance to hydrogen peroxide provoked oxidative stress

    NARCIS (Netherlands)

    Handtke, S.; Schroeter, R.; Jurgen, B.; Methling, K.; Schluter, R.; Albrecht, D.; Hijum, S.A.F.T. van; Bongaerts, J.; Maurer, K.H.; Lalk, M.; Schweder, T.; Hecker, M.; Voigt, B.

    2014-01-01

    Bacillus pumilus is characterized by a higher oxidative stress resistance than other comparable industrially relevant Bacilli such as B. subtilis or B. licheniformis. In this study the response of B. pumilus to oxidative stress was investigated during a treatment with high concentrations of hydrogen

  12. A review on airway biomarkers: exposure, effect and susceptibility.

    Science.gov (United States)

    Corradi, Massimo; Goldoni, Matteo; Mutti, Antonio

    2015-04-01

    Current research in pulmonology requires the use of biomarkers to investigate airway exposure and diseases, for both diagnostic and prognostic purposes. The traditional approach based on invasive approaches (lung lavages and biopsies) can now be replaced, at least in part, through the use of non invasively collected specimens (sputum and breath), in which biomarkers of exposure, effect and susceptibility can be searched. The discovery of specific lung-related proteins, which can spill over in blood or excreted in urine, further enhanced the spectrum of airway specific biomarkers to be studied. The recent introduction of high-performance 'omic' technologies - genomics, proteomics and metabolomics, and the rate at which biomarker candidates are being discovered, will permit the use of a combination of biomarkers for a more precise selection of patient with different outcomes and responses to therapies. The aim of this review is to critically evaluate the use of airway biomarkers in the context of research and clinical practice.

  13. Highly overlapping winter diet in two sympatric lemming species revealed by DNA metabarcoding.

    Directory of Open Access Journals (Sweden)

    Eeva M Soininen

    Full Text Available Sympatric species are expected to minimize competition by partitioning resources, especially when these are limited. Herbivores inhabiting the High Arctic in winter are a prime example of a situation where food availability is anticipated to be low, and thus reduced diet overlap is expected. We present here the first assessment of diet overlap of high arctic lemmings during winter based on DNA metabarcoding of feces. In contrast to previous analyses based on microhistology, we found that the diets of both collared (Dicrostonyx groenlandicus and brown lemmings (Lemmus trimucronatus on Bylot Island were dominated by Salix while mosses, which were significantly consumed only by the brown lemming, were a relatively minor food item. The most abundant plant taxon, Cassiope tetragona, which alone composes more than 50% of the available plant biomass, was not detected in feces and can thus be considered to be non-food. Most plant taxa that were identified as food items were consumed in proportion to their availability and none were clearly selected for. The resulting high diet overlap, together with a lack of habitat segregation, indicates a high potential for resource competition between the two lemming species. However, Salix is abundant in the winter habitats of lemmings on Bylot Island and the non-Salix portion of the diets differed between the two species. Also, lemming grazing impact on vegetation during winter in the study area is negligible. Hence, it seems likely that the high potential for resource competition predicted between these two species did not translate into actual competition. This illustrates that even in environments with low primary productivity food resources do not necessarily generate strong competition among herbivores.

  14. DETECTION OF CANCER BIOMARKERS WITH NANOTECHNOLOGY

    Directory of Open Access Journals (Sweden)

    Lei Zhang

    2013-01-01

    Full Text Available Early detection of cancer biomarkers with high precision is critically important for cancer therapy. A variety of sensors based on different nanostructured materials have attracted intensive research interest due to their potential for highly sensitive and selective detection of cancer biomarkers. This review covers the use of a variety of nanostructured materials, including carbon nanotubes, silicon nanowires, gold nanoparticles and quantum dots, in the fabrication of sensors. Emphases are placed on how the detection systems work and what detection limits can be achieved. Some assays described in this review outperform established methods for cancer biomarker detection. It is highly promising that these sensors would soon move into commercial-scale production and find routine use in hospitals.

  15. Plasma Cystatin C and High-Density Lipoprotein Are Important Biomarkers of Alzheimer’s Disease and Vascular Dementia: A Cross-Sectional Study

    Science.gov (United States)

    Wang, Rui; Chen, Zhaoyu; Fu, Yongmei; Wei, Xiaobo; Liao, Jinchi; Liu, Xu; He, Bingjun; Xu, Yunqi; Zou, Jing; Yang, Xiaoyan; Weng, Ruihui; Tan, Sheng; McElroy, Christopher; Jin, Kunlin; Wang, Qing

    2017-01-01

    Objectives: Cystatin C (Cys C) and high-density lipoprotein (HDL) play critical roles in neurodegenerative diseases, such as dementia, Alzheimer’s disease (AD) and vascular dementia (VaD). However, whether they can be used as reliable biomarkers to distinguish patients with dementia from healthy subjects and to determine disease severity remain largely unknown. Methods: We conducted a cross-sectional study to determine plasma Cys C and HDL levels of 88 patients with dementia (43 AD patients, 45 VaD patients) and 45 healthy age-matched controls. The severity of dementia was determined based on the Schwab and England Activities of Daily Living (ADL) Scale, the Mini-mental State Examination (MMSE), the Global Deterioration Scale (GDS), the Lawton Instrumental ADL (IADL) Scale, and the Hachinski Ischemia Scale (Hachinski). Receiver operating characteristic (ROC) curves were calculated to determine the diagnostic accuracy of Cys C and HDL levels in distinguishing patients with dementia from healthy subjects. Results: We found that plasma Cys C levels were higher, but HDL levels were lower in AD and VaD patients respectively, compared to healthy control subjects. Yet, Cys C levels were highest among patients with VaD. Interestingly, plasma Cys C levels were significantly correlated with IADL Scale scores. In addition, the ROC curves for Cys C (area under the curve, AUC 0.816 for AD, AUC 0.841 for VaD) and HDL (AUC 0.800 for AD, AUC 0.731 for VaD) exhibited potential diagnostic value in distinguishing AD/VaD patients from healthy subjects. While the ROC curve for the combination of Cys C and HDL (AUC 0.873 for AD, AUC 0.897 for VaD) showed higher diagnostic accuracy in distinguishing AD/VaD patients from healthy subjects than the separate curves for each parameter. Conclusions: Our findings suggest that the inflammatory mediators Cys C and HDL may play important roles in the pathogenesis of dementia, and plasma Cys C and HDL levels may be useful screening tools for

  16. Proteomic biomarkers of preterm birth risk in women with polycystic ovary syndrome (PCOS: a systematic review and biomarker database integration.

    Directory of Open Access Journals (Sweden)

    Nicolas Galazis

    Full Text Available BACKGROUND: Preterm Birth (PTB is a major cause of neonatal mortality and morbidity. Women with Polycystic Ovary Syndrome (PCOS are at high risk of PTB. There is a need for research studies to investigate the mechanisms linking PCOS and PTB, to facilitate screening, and develop novel preventative strategies. OBJECTIVE: To list all the proteomic biomarkers of PTB and integrate this list with the PCOS biomarker database to identify commonly expressed biomarkers of the two conditions. SEARCH STRATEGY: A systematic review of PTB biomarkers and update of PCOS biomarker database. All eligible published studies on proteomic biomarkers for PTB and PCOS identified through various databases were evaluated. SELECTION CRITERIA: For the identification of the relevant studies, the following search terms were used: "proteomics", "proteomic", "preterm birth", "preterm labour", "proteomic biomarker" and "polycystic ovary syndrome". This search was restricted to humans only DATA COLLECTION AND ANALYSIS: A database on proteomic biomarkers for PTB was created while an already existing PCOS biomarker database was updated. The two databases were integrated and biomarkers that were co-expressed in both women with PCOS and PTB were identified and investigated. RESULTS: A panel of six proteomic biomarkers was similarly differentially expressed in women with PTB and women with PCOS compared to their respective controls (normal age-matched women in the case of PCOS studies and women with term pregnancy in the case of PTB studies. These biomarkers include Pyruvate kinase M1/M2, Vimentin, Fructose bisphosphonate aldolase A, Heat shock protein beta-1, Peroxiredoxin-1 and Transferrin. CONCLUSIONS: These proteomic biomarkers (Pyruvate kinase M1/M2, Vimentin, Fructose bisphosphonate aldolase A, Heat shock protein beta-1, Peroxiredoxin-1 and Transferrin can be potentially used to better understand the pathophysiological mechanisms linking PCOS and PTB. This would help to

  17. Biomarkers intersect with the exposome.

    Science.gov (United States)

    Rappaport, Stephen M

    2012-09-01

    The exposome concept promotes use of omic tools for discovering biomarkers of exposure and biomarkers of disease in studies of diseased and healthy populations. A two-stage scheme is presented for profiling omic features in serum to discover molecular biomarkers and then for applying these biomarkers in follow-up studies. The initial component, referred to as an exposome-wide-association study (EWAS), employs metabolomics and proteomics to interrogate the serum exposome and, ultimately, to identify, validate and differentiate biomarkers of exposure and biomarkers of disease. Follow-up studies employ knowledge-driven designs to explore disease causality, prevention, diagnosis, prognosis and treatment.

  18. YKL-40: a new biomarker in cardiovascular disease?

    DEFF Research Database (Denmark)

    Mathiasen, Anders Bruun; Henningsen, Kristoffer Mads Aaris; Harutyunyan, Marina Jurjevna;

    2010-01-01

    . But in spite of improved treatments, many patients are still plagued by a high frequency of angina symptoms, hospitalizations and a poor prognosis. There is a need for new independent or supplementary biomarkers that can help to predict cardiovascular disease and cardiovascular events earlier and more...... precisely, and thus accompany existing biomarkers in both primary and secondary cardiovascular prevention. One such potential new biomarker is the protein YKL-40. As an independent biomarker in both cardiovascular diseases and noncardiovascular diseases, current evidence suggests YKL-40 to be most useful...

  19. High quality maize centromere 10 sequence reveals evidence of frequent recombination events

    Directory of Open Access Journals (Sweden)

    Thomas Kai Wolfgruber

    2016-03-01

    Full Text Available The ancestral centromeres of maize contain long stretches of the tandemly arranged CentC repeat. The abundance of tandem DNA repeats and centromeric retrotransposons (CR have presented a significant challenge to completely assembling centromeres using traditional sequencing methods. Here we report a nearly complete assembly of the 1.85 Mb maize centromere 10 from inbred B73 using PacBio technology and BACs from the reference genome project. The error rates estimated from overlapping BAC sequences are 7 x 10-6 and 5 x 10-5 for mismatches and indels, respectively. The number of gaps in the region covered by the reassembly was reduced from 140 in the reference genome to three. Three expressed genes are located between 92 and 477 kb of the inferred ancestral CentC cluster, which lies within the region of highest centromeric repeat density. The improved assembly increased the count of full-length centromeric retrotransposons from 5 to 55 and revealed a 22.7 kb segmental duplication that occurred approximately 121,000 years ago. Our analysis provides evidence of frequent recombination events in the form of partial retrotransposons, deletions within retrotransposons, chimeric retrotransposons, segmental duplications including higher order CentC repeats, a deleted CentC monomer, centromere-proximal inversions, and insertion of mitochondrial sequences. Double-strand DNA break (DSB repair is the most plausible mechanism for these events and may be the major driver of centromere repeat evolution and diversity. This repair appears to be mediated by microhomology, suggesting that tandem repeats may have evolved to facilitate the repair of frequent DSBs in centromeres.

  20. Proteomic analysis of Ketogulonicigenium vulgare under glutathione reveals high demand for thiamin transport and antioxidant protection.

    Directory of Open Access Journals (Sweden)

    Qian Ma

    Full Text Available Ketogulonicigenium vulgare, though grows poorly when mono-cultured, has been widely used in the industrial production of the precursor of vitamin C with the coculture of Bacillus megaterium. Various efforts have been made to clarify the synergic pattern of this artificial microbial community and to improve the growth and production ability of K. vulgare, but there is still no sound explanation. In previous research, we found that the addition of reduced glutathione into K. vulgare monoculture could significantly improve its growth and productivity. By performing SEM and TEM, we observed that after adding GSH into K. vulgare monoculture, cells became about 4-6 folds elongated, and formed intracytoplasmic membranes (ICM. To explore the molecular mechanism and provide insights into the investigation of the synergic pattern of the co-culture system, we conducted a comparative iTRAQ-2-D-LC-MS/MS-based proteomic analysis of K. vulgare grown under reduced glutathione. Principal component analysis of proteomic data showed that after the addition of glutathione, proteins for thiamin/thiamin pyrophosphate (TPP transport, glutathione transport and the maintenance of membrane integrity, together with several membrane-bound dehydrogenases had significant up-regulation. Besides, several proteins participating in the pentose phosphate pathway and tricarboxylic acid cycle were also up-regulated. Additionally, proteins combating intracellular reactive oxygen species were also up-regulated, which similarly occurred in K. vulgare when the co-cultured B. megaterium cells lysed from our former research results. This study reveals the demand for transmembrane transport of substrates, especially thiamin, and the demand for antioxidant protection of K. vulgare.

  1. High-resolution genomic profiling of chronic lymphocytic leukemia reveals new recurrent genomic alterations.

    Science.gov (United States)

    Edelmann, Jennifer; Holzmann, Karlheinz; Miller, Florian; Winkler, Dirk; Bühler, Andreas; Zenz, Thorsten; Bullinger, Lars; Kühn, Michael W M; Gerhardinger, Andreas; Bloehdorn, Johannes; Radtke, Ina; Su, Xiaoping; Ma, Jing; Pounds, Stanley; Hallek, Michael; Lichter, Peter; Korbel, Jan; Busch, Raymonde; Mertens, Daniel; Downing, James R; Stilgenbauer, Stephan; Döhner, Hartmut

    2012-12-06

    To identify genomic alterations in chronic lymphocytic leukemia (CLL), we performed single-nucleotide polymorphism-array analysis using Affymetrix Version 6.0 on 353 samples from untreated patients entered in the CLL8 treatment trial. Based on paired-sample analysis (n = 144), a mean of 1.8 copy number alterations per patient were identified; approximately 60% of patients carried no copy number alterations other than those detected by fluorescence in situ hybridization analysis. Copy-neutral loss-of-heterozygosity was detected in 6% of CLL patients and was found most frequently on 13q, 17p, and 11q. Minimally deleted regions were refined on 13q14 (deleted in 61% of patients) to the DLEU1 and DLEU2 genes, on 11q22.3 (27% of patients) to ATM, on 2p16.1-2p15 (gained in 7% of patients) to a 1.9-Mb fragment containing 9 genes, and on 8q24.21 (5% of patients) to a segment 486 kb proximal to the MYC locus. 13q deletions exhibited proximal and distal breakpoint cluster regions. Among the most common novel lesions were deletions at 15q15.1 (4% of patients), with the smallest deletion (70.48 kb) found in the MGA locus. Sequence analysis of MGA in 59 samples revealed a truncating mutation in one CLL patient lacking a 15q deletion. MNT at 17p13.3, which in addition to MGA and MYC encodes for the network of MAX-interacting proteins, was also deleted recurrently.

  2. Salinity tolerance loci revealed in rice using high-throughput non-invasive phenotyping

    KAUST Repository

    Al-Tamimi, Nadia

    2016-11-17

    High-throughput phenotyping produces multiple measurements over time, which require new methods of analyses that are flexible in their quantification of plant growth and transpiration, yet are computationally economic. Here we develop such analyses and apply this to a rice population genotyped with a 700k SNP high-density array. Two rice diversity panels, indica and aus, containing a total of 553 genotypes, are phenotyped in waterlogged conditions. Using cubic smoothing splines to estimate plant growth and transpiration, we identify four time intervals that characterize the early responses of rice to salinity. Relative growth rate, transpiration rate and transpiration use efficiency (TUE) are analysed using a new association model that takes into account the interaction between treatment (control and salt) and genetic marker. This model allows the identification of previously undetected loci affecting TUE on chromosome 11, providing insights into the early responses of rice to salinity, in particular into the effects of salinity on plant growth and transpiration.

  3. Comparative transcriptome analysis within the Lolium/Festuca species complex reveals high sequence conservation

    DEFF Research Database (Denmark)

    Czaban, Adrian; Sharma, Sapna; Byrne, Stephen;

    2015-01-01

    -Festuca complex show very diverse phenotypes, including for many agronomically important traits. Analysis of sequenced transcriptomes of these non-model species may shed light on the molecular mechanisms underlying this phenotypic diversity. Results We have generated de novo transcriptome assemblies for four...... species from the Lolium-Festuca complex, ranging from 52,166 to 72,133 transcripts per assembly. We have also predicted a set of proteins and validated it with a high-confidence protein database from three closely related species (H. vulgare, B. distachyon and O. sativa). We have obtained gene family...... phenotypical differences within the complex (such as VRN2). The orthologous genes between the species have a very high %id (91,61%) and the majority of gene families were shared for all of them. It is likely that the knowledge of the genomes will be largely transferable between species within the complex....

  4. Elevated rates of gold mining in the Amazon revealed through high-resolution monitoring

    OpenAIRE

    Asner, Gregory P.; Llactayo, William; Tupayachi, Raul; Luna, Ernesto Ráez

    2013-01-01

    Commodity gold prices increased substantially following the 2008 global financial crisis. Gold demand has fueled a massive increase in mining activity, some of which is centered in the Amazon basin. Western Amazonian forests of Peru have become an epicenter for mostly illegal gold mining, but the clandestine nature of mining activities has made monitoring and reporting of forest losses extremely challenging. We combined high-resolution satellite and aircraft-based imaging with field surveys t...

  5. Effects of anesthetic agents on brain blood oxygenation level revealed with ultra-high field MRI.

    Directory of Open Access Journals (Sweden)

    Luisa Ciobanu

    Full Text Available During general anesthesia it is crucial to control systemic hemodynamics and oxygenation levels. However, anesthetic agents can affect cerebral hemodynamics and metabolism in a drug-dependent manner, while systemic hemodynamics is stable. Brain-wide monitoring of this effect remains highly challenging. Because T(2*-weighted imaging at ultra-high magnetic field strengths benefits from a dramatic increase in contrast to noise ratio, we hypothesized that it could monitor anesthesia effects on brain blood oxygenation. We scanned rat brains at 7T and 17.2T under general anesthesia using different anesthetics (isoflurane, ketamine-xylazine, medetomidine. We showed that the brain/vessels contrast in T(2*-weighted images at 17.2T varied directly according to the applied pharmacological anesthetic agent, a phenomenon that was visible, but to a much smaller extent at 7T. This variation is in agreement with the mechanism of action of these agents. These data demonstrate that preclinical ultra-high field MRI can monitor the effects of a given drug on brain blood oxygenation level in the absence of systemic blood oxygenation changes and of any neural stimulation.

  6. High extensibility of stress fibers revealed by in vitro micromanipulation with fluorescence imaging

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Tsubasa S. [Department of Biomolecular Sciences, Tohoku University (Japan); Sato, Masaaki [Department of Biomedical Engineering, Tohoku University (Japan); Department of Bioengineering and Robotics, Tohoku University (Japan); Deguchi, Shinji, E-mail: deguchi@nitech.ac.jp [Department of Bioengineering and Robotics, Tohoku University (Japan)

    2013-05-10

    Highlights: •We isolate contractile stress fibers from vascular smooth muscle cells. •We measure the extensibility of individual stress fibers. •We present the first direct evidence that individual stress fibers are highly extensible. •We quantitatively determine the local strain along the length of stress fibers. •The high extensibility we found is beyond that explained by a conventional model. -- Abstract: Stress fibers (SFs), subcellular bundles of actin and myosin filaments, are physically connected at their ends to cell adhesions. The intracellular force transmitted via SFs plays an essential role in cell adhesion regulation and downstream signaling. However, biophysical properties intrinsic to individual SFs remain poorly understood partly because SFs are surrounded by other cytoplasmic components that restrict the deformation of the embedded materials. To characterize their inherent properties independent of other structural components, we isolated SFs from vascular smooth muscle cells and mechanically stretched them by in vitro manipulation while visualizing strain with fluorescent quantum dots attached along their length. SFs were elongated along their entire length, with the length being approximately 4-fold of the stress-free length. This surprisingly high extensibility was beyond that explained by the tandem connection of actin filaments and myosin II bipolar filaments present in SFs, thus suggesting the involvement of other structural components in their passive biophysical properties.

  7. Potential Peripheral Biomarkers for the Diagnosis of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Seema Patel

    2011-01-01

    Full Text Available Advances in the discovery of a peripheral biomarker for the diagnosis of Alzheimer's would provide a way to better detect the onset of this debilitating disease in a manner that is both noninvasive and universally available. This paper examines the current approaches that are being used to discover potential biomarker candidates available in the periphery. The search for a peripheral biomarker that could be utilized diagnostically has resulted in an extensive amount of studies that employ several biological approaches, including the assessment of tissues, genomics, proteomics, epigenetics, and metabolomics. Although a definitive biomarker has yet to be confirmed, advances in the understanding of the mechanisms of the disease and major susceptibility factors have been uncovered and reveal promising possibilities for the future discovery of a useful biomarker.

  8. Aerosol Organic Matter-Trace Metal Relationships Revealed by Ultra-High Resolution Mass Spectrometry

    Science.gov (United States)

    Wozniak, A. S.; Sleighter, R. L.; Morton, P. L.; Landing, W. M.; Shelley, R. U.; Hatcher, P. G.

    2011-12-01

    Atmospheric delivery of aerosols is important for the biogeochemical cycling of organic matter (OM) and trace elements in marine environments. Aerosols over marine environments can be derived from marine sources or transported from continental regions of variable vegetative cover and anthropogenic influence. These different sources are key determinants of aerosol OM composition, as well as trace metal amounts and characteristics. Dust-influenced aerosols typically contain higher amounts of Fe than anthropogenic-influenced aerosols but have lesser % of soluble Fe (%FeS), believed to be the bioavailable form of Fe for marine phytoplankton. Four samples from the 2008 GEOTRACES intercalibration experiments (Miami, FL, USA) were analyzed by electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS) and related to both air mass back trajectories and %FeS. Three samples showed aerosol sources from the east consistent with Saharan dust inputs, while the fourth sample was derived in part from air masses to the north, influenced by the North American continent. This North American-influenced sample was collected following the 3 day period with the highest %FeS (1.3-1.7%) of the 11 day intercalibration experiment (mean = 0.4-1.1%). FT-ICR mass spectra showed 795 peaks common to the dust-influenced samples but absent from the North American-influenced sample. These peaks were assigned molecular formulas characterized by CHO and CHON compounds with lower H/C and O/C ratios than the 1257 formulas common to all 4 samples, suggesting that the dust-influenced aerosols carry OM that is less oxygenated and more condensed in structure along with Fe of lesser solubility. Air mass trajectory analyses revealed samples collected during a 2010 cruise in the North Atlantic Ocean to be characterized by European-influenced (anthropogenic), African-influenced (dust), and primarily marine air masses, making them ideal for further exploration of the

  9. Patterns of recombination activity on mouse chromosome 11 revealed by high resolution mapping.

    Directory of Open Access Journals (Sweden)

    Timothy Billings

    Full Text Available The success of high resolution genetic mapping of disease predisposition and quantitative trait loci in humans and experimental animals depends on the positions of key crossover events around the gene of interest. In mammals, the majority of recombination occurs at highly delimited 1-2 kb long sites known as recombination hotspots, whose locations and activities are distributed unevenly along the chromosomes and are tightly regulated in a sex specific manner. The factors determining the location of hotspots started to emerge with the finding of PRDM9 as a major hotspot regulator in mammals, however, additional factors modulating hotspot activity and sex specificity are yet to be defined. To address this limitation, we have collected and mapped the locations of 4829 crossover events occurring on mouse chromosome 11 in 5858 meioses of male and female reciprocal F1 hybrids of C57BL/6J and CAST/EiJ mice. This chromosome was chosen for its medium size and high gene density and provided a comparison with our previous analysis of recombination on the longest mouse chromosome 1. Crossovers were mapped to an average resolution of 127 kb, and thirteen hotspots were mapped to <8 kb. Most crossovers occurred in a small number of the most active hotspots. Females had higher recombination rate than males as a consequence of differences in crossover interference and regional variation of sex specific rates along the chromosome. Comparison with chromosome 1 showed that recombination events tend to be positioned in similar fashion along the centromere-telomere axis but independently of the local gene density. It appears that mammalian recombination is regulated on at least three levels, chromosome-wide, regional, and at individual hotspots, and these regulation levels are influenced by sex and genetic background but not by gene content.

  10. Force measurements on natural membrane nanovesicles reveal a composition-independent, high Young's modulus

    Science.gov (United States)

    Calò, Annalisa; Reguera, David; Oncins, Gerard; Persuy, Marie-Annick; Sanz, Guenhaël; Lobasso, Simona; Corcelli, Angela; Pajot-Augy, Edith; Gomila, Gabriel

    2014-01-01

    Mechanical properties of nano-sized vesicles made up of natural membranes are crucial to the development of stable, biocompatible nanocontainers with enhanced functional, recognition and sensing capabilities. Here we measure and compare the mechanical properties of plasma and inner membrane nanovesicles ~80 nm in diameter obtained from disrupted yeast Saccharomyces cerevisiae cells. We provide evidence of a highly deformable behaviour for these vesicles, able to support repeated wall-to-wall compressions without irreversible deformations, accompanied by a noticeably high Young's modulus (~300 MPa) compared to that obtained for reconstituted artificial liposomes of similar size and approaching that of some virus particles. Surprisingly enough, the results are approximately similar for plasma and inner membrane nanovesicles, in spite of their different lipid compositions, especially on what concerns the ergosterol content. These results point towards an important structural role of membrane proteins in the mechanical response of natural membrane vesicles and open the perspective to their potential use as robust nanocontainers for bioapplications.Mechanical properties of nano-sized vesicles made up of natural membranes are crucial to the development of stable, biocompatible nanocontainers with enhanced functional, recognition and sensing capabilities. Here we measure and compare the mechanical properties of plasma and inner membrane nanovesicles ~80 nm in diameter obtained from disrupted yeast Saccharomyces cerevisiae cells. We provide evidence of a highly deformable behaviour for these vesicles, able to support repeated wall-to-wall compressions without irreversible deformations, accompanied by a noticeably high Young's modulus (~300 MPa) compared to that obtained for reconstituted artificial liposomes of similar size and approaching that of some virus particles. Surprisingly enough, the results are approximately similar for plasma and inner membrane nanovesicles, in

  11. Biomarkers of necrotising soft tissue infections

    DEFF Research Database (Denmark)

    Hansen, Marco Bo; Simonsen, Ulf; Garred, Peter

    2015-01-01

    INTRODUCTION: The mortality and amputation rates are still high in patients with necrotising soft tissue infections (NSTIs). It would be ideal to have a set of biomarkers that enables the clinician to identify high-risk patients with NSTI on admission. The objectives of this study are to evaluate...

  12. Extracellular DNA amplicon sequencing reveals high levels of benthic eukaryotic diversity in the central Red Sea

    KAUST Repository

    Pearman, John K.

    2015-11-01

    The present study aims to characterize the benthic eukaryotic biodiversity patterns at a coarse taxonomic level in three areas of the central Red Sea (a lagoon, an offshore area in Thuwal and a shallow coastal area near Jeddah) based on extracellular DNA. High-throughput amplicon sequencing targeting the V9 region of the 18S rRNA gene was undertaken for 32 sediment samples. High levels of alpha-diversity were detected with 16,089 operational taxonomic units (OTUs) being identified. The majority of the OTUs were assigned to Metazoa (29.2%), Alveolata (22.4%) and Stramenopiles (17.8%). Stramenopiles (Diatomea) and Alveolata (Ciliophora) were frequent in a lagoon and in shallower coastal stations, whereas metazoans (Arthropoda: Maxillopoda) were dominant in deeper offshore stations. Only 24.6% of total OTUs were shared among all areas. Beta-diversity was generally lower between the lagoon and Jeddah (nearshore) than between either of those and the offshore area, suggesting a nearshore–offshore biodiversity gradient. The current approach allowed for a broad-range of benthic eukaryotic biodiversity to be analysed with significantly less labour than would be required by other traditional taxonomic approaches. Our findings suggest that next generation sequencing techniques have the potential to provide a fast and standardised screening of benthic biodiversity at large spatial and temporal scales.

  13. Extracellular DNA amplicon sequencing reveals high levels of benthic eukaryotic diversity in the central Red Sea.

    Science.gov (United States)

    Pearman, John K; Irigoien, Xabier; Carvalho, Susana

    2016-04-01

    The present study aims to characterize the benthic eukaryotic biodiversity patterns at a coarse taxonomic level in three areas of the central Red Sea (a lagoon, an offshore area in Thuwal and a shallow coastal area near Jeddah) based on extracellular DNA. High-throughput amplicon sequencing targeting the V9 region of the 18S rRNA gene was undertaken for 32 sediment samples. High levels of alpha-diversity were detected with 16,089 operational taxonomic units (OTUs) being identified. The majority of the OTUs were assigned to Metazoa (29.2%), Alveolata (22.4%) and Stramenopiles (17.8%). Stramenopiles (Diatomea) and Alveolata (Ciliophora) were frequent in a lagoon and in shallower coastal stations, whereas metazoans (Arthropoda: Maxillopoda) were dominant in deeper offshore stations. Only 24.6% of total OTUs were shared among all areas. Beta-diversity was generally lower between the lagoon and Jeddah (nearshore) than between either of those and the offshore area, suggesting a nearshore-offshore biodiversity gradient. The current approach allowed for a broad-range of benthic eukaryotic biodiversity to be analysed with significantly less labour than would be required by other traditional taxonomic approaches. Our findings suggest that next generation sequencing techniques have the potential to provide a fast and standardised screening of benthic biodiversity at large spatial and temporal scales.

  14. Chemical Diversity and Complexity of Scotch Whisky as Revealed by High-Resolution Mass Spectrometry

    Science.gov (United States)

    Kew, Will; Goodall, Ian; Clarke, David; Uhrín, Dušan

    2017-01-01

    Scotch Whisky is an important product, both culturally and economically. Chemically, Scotch Whisky is a complex mixture, which comprises thousands of compounds, the nature of which are largely unknown. Here, we present a thorough overview of the chemistry of Scotch Whisky as observed by Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Eighty-five whiskies, representing the majority of Scotch Whisky produced and sold, were analyzed by untargeted high-resolution mass spectrometry. Thousands of chemical formulae were assigned for each sample based on parts-per-billion mass accuracy of FT-ICR MS spectra. For the first time, isotopic fine structure analysis was used to confirm the assignment of high molecular weight CHOS species in Scotch Whisky. The assigned spectra were compared using a number of visualization techniques, including van Krevelen diagrams, double bond equivalence (DBE) plots, as well as heteroatomic compound class distributions. Additionally, multivariate analysis, including PCA and OPLS-DA, was used to interpret the data, with key compounds identified for discriminating between types of whisky (blend or malt) or maturation wood type. FT-ICR MS analysis of Scotch Whisky was shown to be of significant potential in further understanding of the complexity of mature spirit drinks and as a tool for investigating the chemistry of the maturation processes.

  15. Revealing complex function, process and pathway interactions with high-throughput expression and biological annotation data.

    Science.gov (United States)

    Singh, Nitesh Kumar; Ernst, Mathias; Liebscher, Volkmar; Fuellen, Georg; Taher, Leila

    2016-10-20

    The biological relationships both between and within the functions, processes and pathways that operate within complex biological systems are only poorly characterized, making the interpretation of large scale gene expression datasets extremely challenging. Here, we present an approach that integrates gene expression and biological annotation data to identify and describe the interactions between biological functions, processes and pathways that govern a phenotype of interest. The product is a global, interconnected network, not of genes but of functions, processes and pathways, that represents the biological relationships within the system. We validated our approach on two high-throughput expression datasets describing organismal and organ development. Our findings are well supported by the available literature, confirming that developmental processes and apoptosis play key roles in cell differentiation. Furthermore, our results suggest that processes related to pluripotency and lineage commitment, which are known to be critical for development, interact mainly indirectly, through genes implicated in more general biological processes. Moreover, we provide evidence that supports the relevance of cell spatial organization in the developing liver for proper liver function. Our strategy can be viewed as an abstraction that is useful to interpret high-throughput data and devise further experiments.

  16. Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements.

    Directory of Open Access Journals (Sweden)

    Erik Kristiansson

    Full Text Available The high and sometimes inappropriate use of antibiotics has accelerated the development of antibiotic resistance, creating a major challenge for the sustainable treatment of infections world-wide. Bacterial communities often respond to antibiotic selection pressure by acquiring resistance genes, i.e. mobile genetic elements that can be shared horizontally between species. Environmental microbial communities maintain diverse collections of resistance genes, which can be mobilized into pathogenic bacteria. Recently, exceptional environmental releases of antibiotics have been documented, but the effects on the promotion of resistance genes and the potential for horizontal gene transfer have yet received limited attention. In this study, we have used culture-independent shotgun metagenomics to investigate microbial communities in river sediments exposed to waste water from the production of antibiotics in India. Our analysis identified very high levels of several classes of resistance genes as well as elements for horizontal gene transfer, including integrons, transposons and plasmids. In addition, two abundant previously uncharacterized resistance plasmids were identified. The results suggest that antibiotic contamination plays a role in the promotion of resistance genes and their mobilization from environmental microbes to other species and eventually to human pathogens. The entire life-cycle of antibiotic substances, both before, under and after usage, should therefore be considered to fully evaluate their role in the promotion of resistance.

  17. Antarctic strict anaerobic microbiota from Deschampsia antarctica vascular plants rhizosphere reveals high ecology and biotechnology relevance.

    Science.gov (United States)

    Peixoto, Rafael José Marques; Miranda, Karla Rodrigues; Lobo, Leandro Araujo; Granato, Alessandra; de Carvalho Maalouf, Pedro; de Jesus, Hugo Emiliano; Rachid, Caio T C C; Moraes, Saulo Roni; Dos Santos, Henrique Fragoso; Peixoto, Raquel Silva; Rosado, Alexandre Soares; Domingues, Regina Maria Cavalcanti Pilotto

    2016-11-01

    The Antarctic soil microbial community has a crucial role in the growth and stabilization of higher organisms, such as vascular plants. Analysis of the soil microbiota composition in that extreme environmental condition is crucial to understand the ecological importance and biotechnological potential. We evaluated the efficiency of isolation and abundance of strict anaerobes in the vascular plant Deschampsia antarctica rhizosphere collected in the Antarctic's Admiralty Bay and associated biodiversity to metabolic perspective and enzymatic activity. Using anaerobic cultivation methods, we identified and isolated a range of microbial taxa whose abundance was associated with Plant Growth-Promoting Bacteria (PGPB) and presences were exclusively endemic to the Antarctic continent. Firmicutes was the most abundant phylum (73 %), with the genus Clostridium found as the most isolated taxa. Here, we describe two soil treatments (oxygen gradient and heat shock) and 27 physicochemical culture conditions were able to increase the diversity of anaerobic bacteria isolates. Heat shock treatment allowed to isolate a high percentage of new species (63.63 %), as well as isolation of species with high enzymatic activity (80.77 %), which would have potential industry application. Our findings contribute to the understanding of the role of anaerobic microbes regarding ecology, evolutionary, and biotechnological features essential to the Antarctic ecosystem.

  18. Massive quiescent cores in Orion. IV. Their supercritical state revealed by high resolution ammonia maps

    CERN Document Server

    Li, D; Zhang, Q; Chen, W

    2012-01-01

    We present combined VLA and GBT images of \\ammonia\\ inversion transitions (1,1) and (2,2) toward OMC2 and OMC3. We focus on the relatively quiescent Orion cores, which are away from the Trapezium cluster and have no sign of massive protostars nor evolved star formation, such as IRAS source, water maser, and methanol maser. The 5\\arcsec\\ angular resolution and $0.6 \\rm{}km s^{-1}$ velocity resolution of these data enable us to study the thermal and dynamic state of these cores at $\\sim{}0.02 \\rm{}pc$ scales, comparable to or smaller than those of the current dust continuum surveys. We measure temperatures for a total of 30 cores, with average masses and radii of $11 \\Ms$ and $0.039 \\rm{}pc$, respectively. Compared to other Gould Belt dense cores, the Orion cores have an unusually high gravitational-to-inetic energy ratio (virial mass ratio $R_{vir} > >1$), resembling results for other clouds forming high--mass stars. This results from Orion cores having velocity dispersions similar to those in, e.g., Perseus a...

  19. Recent and episodic volcanic and glacial activity on Mars revealed by the High Resolution Stereo Camera.

    Science.gov (United States)

    Neukum, G; Jaumann, R; Hoffmann, H; Hauber, E; Head, J W; Basilevsky, A T; Ivanov, B A; Werner, S C; van Gasselt, S; Murray, J B; McCord, T

    2004-12-23

    The large-area coverage at a resolution of 10-20 metres per pixel in colour and three dimensions with the High Resolution Stereo Camera Experiment on the European Space Agency Mars Express Mission has made it possible to study the time-stratigraphic relationships of volcanic and glacial structures in unprecedented detail and give insight into the geological evolution of Mars. Here we show that calderas on five major volcanoes on Mars have undergone repeated activation and resurfacing during the last 20 per cent of martian history, with phases of activity as young as two million years, suggesting that the volcanoes are potentially still active today. Glacial deposits at the base of the Olympus Mons escarpment show evidence for repeated phases of activity as recently as about four million years ago. Morphological evidence is found that snow and ice deposition on the Olympus construct at elevations of more than 7,000 metres led to episodes of glacial activity at this height. Even now, water ice protected by an insulating layer of dust may be present at high altitudes on Olympus Mons.

  20. High-speed atomic force microscopy reveals structural dynamics of amyloid β1-42 aggregates.

    Science.gov (United States)

    Watanabe-Nakayama, Takahiro; Ono, Kenjiro; Itami, Masahiro; Takahashi, Ryoichi; Teplow, David B; Yamada, Masahito

    2016-05-24

    Aggregation of amyloidogenic proteins into insoluble amyloid fibrils is implicated in various neurodegenerative diseases. This process involves protein assembly into oligomeric intermediates and fibrils with highly polymorphic molecular structures. These structural differences may be responsible for different disease presentations. For this reason, elucidation of the structural features and assembly kinetics of amyloidogenic proteins has been an area of intense study. We report here the results of high-speed atomic force microscopy (HS-AFM) studies of fibril formation and elongation by the 42-residue form of the amyloid β-protein (Aβ1-42), a key pathogenetic agent of Alzheimer's disease. Our data demonstrate two different growth modes of Aβ1-42, one producing straight fibrils and the other producing spiral fibrils. Each mode depends on initial fibril nucleus structure, but switching from one growth mode to another was occasionally observed, suggesting that fibril end structure fluctuated between the two growth modes. This switching phenomenon was affected by buffer salt composition. Our findings indicate that polymorphism in fibril structure can occur after fibril nucleation and is affected by relatively modest changes in environmental conditions.

  1. Sustained High Basal Motion of the Greenland Ice Sheet Revealed by Borehole Deformation

    Science.gov (United States)

    Ryser, Claudia; Luthi, Martin P.; Andrews, Lauren C.; Hoffman, Matthew, J.; Catania, Ginny A.; Hawley, Robert L.; Neumann, Thomas A.; Kristensen, Steen S.

    2014-01-01

    Ice deformation and basal motion characterize the dynamical behavior of the Greenland ice sheet (GrIS). We evaluate the contribution of basal motion from ice deformation measurements in boreholes drilled to the bed at two sites in the western marginal zone of the GrIS. We find a sustained high amount of basal motion contribution to surface velocity of 44-73 percent in winter, and up to 90 percent in summer. Measured ice deformation rates show an unexpected variation with depth that can be explained with the help of an ice-flow model as a consequence of stress transfer from slippery to sticky areas. This effect necessitates the use of high-order ice-flow models, not only in regions of fast-flowing ice streams but in all temperate-based areas of the GrIS. The agreement between modeled and measured deformation rates confirms that the recommended values of the temperature-dependent flow rate factor A are a good choice for ice-sheet models.

  2. High-frequency oscillations in distributed neural networks reveal the dynamics of human decision making

    Directory of Open Access Journals (Sweden)

    Adrian G Guggisberg

    2008-03-01

    Full Text Available We examine the relative timing of numerous brain regions involved in human decisions that are based on external criteria, learned information, personal preferences, or unconstrained internal considerations. Using magnetoencephalography (MEG and advanced signal analysis techniques, we were able to non-invasively reconstruct oscillations of distributed neural networks in the high-gamma frequency band (60–150 Hz. The time course of the observed neural activity suggested that two-alternative forced choice tasks are processed in four overlapping stages: processing of sensory input, option evaluation, intention formation, and action execution. Visual areas are activated fi rst, and show recurring activations throughout the entire decision process. The temporo-occipital junction and the intraparietal sulcus are active during evaluation of external values of the options, 250–500 ms after stimulus presentation. Simultaneously, personal preference is mediated by cortical midline structures. Subsequently, the posterior parietal and superior occipital cortices appear to encode intention, with different subregions being responsible for different types of choice. The cerebellum and inferior parietal cortex are recruited for internal generation of decisions and actions, when all options have the same value. Action execution was accompanied by activation peaks in the contralateral motor cortex. These results suggest that high-gamma oscillations as recorded by MEG allow a reliable reconstruction of decision processes with excellent spatiotemporal resolution.

  3. The architecture of the LkCa 15 transitional disk revealed by high-contrast imaging

    CERN Document Server

    Thalmann, C; Hodapp, K; Janson, M; Grady, C A; Min, M; Ovelar, M de Juan; Carson, J; Brandt, T; Bonnefoy, M; McElwain, M W; Leisenring, J; Dominik, C; Henning, T; Tamura, M

    2014-01-01

    We present four new epochs of Ks-band images of the young pre-transitional disk around LkCa 15, and perform extensive forward modeling to derive the physical parameters of the disk. We find indications of strongly anisotropic scattering (Henyey-Greenstein g = 0.67 [-0.11,+0.18]) and a significantly tapered gap edge ('round wall'), but see no evidence that the inner disk, whose existence is predicted by the spectral energy distribution, shadows the outer regions of the disk visible in our images. We marginally confirm the existence of an offset between the disk center and the star along the line of nodes; however, the magnitude of this offset (x = 27 [-20,+19] mas) is notably lower than that found in our earlier H-band images (Thalmann et al. 2010). Intriguingly, we also find, at high significance, an offset of y = 69 [-25, +49] mas perpendicular to the line of nodes. If confirmed by future observations, this would imply a highly elliptical -- or otherwise asymmetric -- disk gap with an effective eccentricity ...

  4. Serum biomarker tests are useful in delineating between patients with gastric atrophy and normal, healthy stomach

    Institute of Scientific and Technical Information of China (English)

    Katsunori Iijima; Yasuhiko Abe; Ryosuke Kikuchi; Tomoyuki Koike; Shuichi Ohara; Pentti Sipponen; Tooru Shimosegawa

    2009-01-01

    AIM: To study the value of serum biomarker tests to differentiate between patients with healthy or diseased stomach mucosa: i.e. those with Helicobacter pylori (H pylori) gastritis or atrophic gastritis, who have a high risk of gastric cancer or peptic ulcer diseases.METHODS: Among 162 Japanese outpatients, pepsinogenⅠ(PgⅠ) and Ⅱ(Pg Ⅱ) were measuredusing a conventional Japanese technique, and the European GastroPanel examination (PgⅠand Pg Ⅱ,gastrin-17 and H pylori antibodies). Gastroscopy with gastric biopsies was performed to classify the patients into those with healthy stomach mucosa, H pylori nonatrophic gastritis or atrophic gastritis. RESULTS: Pg Ⅰ and Pg Ⅱ assays with the GastroPanel and the Japanese method showed a highly significant correlation. For methodological reasons, however, serum Pg Ⅰ, but not Pg Ⅱ, was twice as high with the GastroPanel test as with the Japanese test.The biomarker assays revealed that 5% of subjects had advanced atrophic corpus gastritis which was also verified by endoscopic biopsies. GastroPanel examination revealed an additional seven patients who had either advanced atrophic gastritis limited to the antrum or antrum-predominant H pylori gastritis.When compared to the endoscopic biopsy findings,the GastroPanel examination classified the patients into groups with "healthy" or "diseased" stomach mucosa with 94% accuracy, 95% sensitivity and 93% specificity.CONCLUSION: Serum biomarker tests can be used to differentiate between subjects with healthy and diseased gastric mucosa with high accuracy.

  5. High-resolution spatiotemporal strain mapping reveals non-uniform deformation in micropatterned elastomers

    Science.gov (United States)

    Aksoy, B.; Rehman, A.; Bayraktar, H.; Alaca, B. E.

    2017-04-01

    Micropatterns are generated on a vast selection of polymeric substrates for various applications ranging from stretchable electronics to cellular mechanobiological systems. When these patterned substrates are exposed to external loading, strain field is primarily affected by the presence of microfabricated structures and similarly by fabrication-related defects. The capturing of such nonhomogeneous strain fields is of utmost importance in cases where study of the mechanical behavior with a high spatial resolution is necessary. Image-based non-contact strain measurement techniques are favorable and have recently been extended to scanning tunneling microscope and scanning electron microscope images for the characterization of mechanical properties of metallic materials, e.g. steel and aluminum, at the microscale. A similar real-time analysis of strain heterogeneity in elastomers is yet to be achieved during the entire loading sequence. The available measurement methods for polymeric materials mostly depend on cross-head displacement or precalibrated strain values. Thus, they suffer either from the lack of any real-time analysis, spatiotemporal distribution or high resolution in addition to a combination of these factors. In this work, these challenges are addressed by integrating a tensile stretcher with an inverted optical microscope and developing a subpixel particle tracking algorithm. As a proof of concept, the patterns with a critical dimension of 200 µm are generated on polydimethylsiloxane substrates and strain distribution in the vicinity of the patterns is captured with a high spatiotemporal resolution. In the field of strain measurement, there is always a tradeoff between minimum measurable strain value and spatial resolution. Current noncontact techniques on elastomers can deliver a strain resolution of 0.001% over a minimum length of 5 cm. More importantly, inhomogeneities within this quite large region cannot be captured. The proposed technique can

  6. Torque measurements reveal large process differences between materials during high solid enzymatic hydrolysis of pretreated lignocellulose

    Directory of Open Access Journals (Sweden)

    Palmqvist Benny

    2012-08-01

    Full Text Available Abstract Background A common trend in the research on 2nd generation bioethanol is the focus on intensifying the process and increasing the concentration of water insoluble solids (WIS throughout the process. However, increasing the WIS content is not without problems. For example, the viscosity of pretreated lignocellulosic materials is known to increase drastically with increasing WIS content. Further, at elevated viscosities, problems arise related to poor mixing of the material, such as poor distribution of the enzymes and/or difficulties with temperature and pH control, which results in possible yield reduction. Achieving good mixing is unfortunately not without cost, since the power requirements needed to operate the impeller at high viscosities can be substantial. This highly important scale-up problem can easily be overlooked. Results In this work, we monitor the impeller torque (and hence power input in a stirred tank reactor throughout high solid enzymatic hydrolysis (Arundo donax and spruce. Two different process modes were evaluated, where either the impeller speed or the impeller power input was kept constant. Results from hydrolysis experiments at a fixed impeller speed of 10 rpm show that a very rapid decrease in impeller torque is experienced during hydrolysis of pretreated arundo (i.e. it loses its fiber network strength, whereas the fiber strength is retained for a longer time within the spruce material. This translates into a relatively low, rather WIS independent, energy input for arundo whereas the stirring power demand for spruce is substantially larger and quite WIS dependent. By operating the impeller at a constant power input (instead of a constant impeller speed it is shown that power input greatly affects the glucose yield of pretreated spruce whereas the hydrolysis of arundo seems unaffected. Conclusions The results clearly highlight the large differences between the arundo and spruce materials, both in terms of

  7. High-resolution statistical mapping reveals gene territories in live yeast.

    Science.gov (United States)

    Berger, Axel B; Cabal, Ghislain G; Fabre, Emmanuelle; Duong, Tarn; Buc, Henri; Nehrbass, Ulf; Olivo-Marin, Jean-Christophe; Gadal, Olivier; Zimmer, Christophe

    2008-12-01

    The nonrandom positioning of genes inside eukaryotic cell nuclei is implicated in central nuclear functions. However, the spatial organization of the genome remains largely uncharted, owing to limited resolution of optical microscopy, paucity of nuclear landmarks and moderate cell sampling. We developed a computational imaging approach that creates high-resolution probabilistic maps of subnuclear domains occupied by individual loci in budding yeast through automated analysis of thousands of living cells. After validation, we applied the technique to genes involved in galactose metabolism and ribosome biogenesis. We found that genomic loci are confined to 'gene territories' much smaller than the nucleus, which can be remodeled during transcriptional activation, and that the nucleolus is an important landmark for gene positioning. The technique can be used to visualize and quantify territory positions relative to each other and to nuclear landmarks, and should advance studies of nuclear architecture and function.

  8. Adjustments with running speed reveal neuromuscular adaptations during landing associated with high mileage running training.

    Science.gov (United States)

    Verheul, Jasper; Clansey, Adam C; Lake, Mark J

    2016-12-08

    It remains to be determined whether running training influences the amplitude of lower limb muscle activations prior to and during the first half of stance, and whether such changes are associated with joint stiffness regulation and usage of stored energy from tendons. Therefore, the aim of this study was to investigate neuromuscular and movement adaptations before and during landing in response to running training across a range of speeds. Two groups of high mileage (HM; >45 km/wk, n=13) and low mileage (LM; muscular activations before landing. Estimated elastic work about the ankle was found to be higher in the HM runners which might play a role in reducing weight acceptance phase muscle activation levels and improve muscle activation efficiency with running training.

  9. Measuring Absolute RNA Copy Numbers at High Temporal Resolution Reveals Transcriptome Kinetics in Development

    Directory of Open Access Journals (Sweden)

    Nick D.L. Owens

    2016-01-01

    Full Text Available Transcript regulation is essential for cell function, and misregulation can lead to disease. Despite technologies to survey the transcriptome, we lack a comprehensive understanding of transcript kinetics, which limits quantitative biology. This is an acute challenge in embryonic development, where rapid changes in gene expression dictate cell fate decisions. By ultra-high-frequency sampling of Xenopus embryos and absolute normalization of sequence reads, we present smooth gene expression trajectories in absolute transcript numbers. During a developmental period approximating the first 8 weeks of human gestation, transcript kinetics vary by eight orders of magnitude. Ordering genes by expression dynamics, we find that “temporal synexpression” predicts common gene function. Remarkably, a single parameter, the characteristic timescale, can classify transcript kinetics globally and distinguish genes regulating development from those involved in cellular metabolism. Overall, our analysis provides unprecedented insight into the reorganization of maternal and embryonic transcripts and redefines our ability to perform quantitative biology.

  10. High molecular diversity of extraterrestrial organic matter in Murchison meteorite revealed 40 years after its fall.

    Science.gov (United States)

    Schmitt-Kopplin, Philippe; Gabelica, Zelimir; Gougeon, Régis D; Fekete, Agnes; Kanawati, Basem; Harir, Mourad; Gebefuegi, Istvan; Eckel, Gerhard; Hertkorn, Norbert

    2010-02-16

    Numerous descriptions of organic molecules present in the Murchison meteorite have improved our understanding of the early interstellar chemistry that operated at or just before the birth of our solar system. However, all molecular analyses were so far targeted toward selected classes of compounds with a particular emphasis on biologically active components in the context of prebiotic chemistry. Here we demonstrate that a nontargeted ultrahigh-resolution molecular analysis of the solvent-accessible organic fraction of Murchison extracted under mild conditions allows one to extend its indigenous chemical diversity to tens of thousands of different molecular compositions and likely millions of diverse structures. This molecular complexity, which provides hints on heteroatoms chronological assembly, suggests that the extraterrestrial chemodiversity is high compared to terrestrial relevant biological- and biogeochemical-driven chemical space.

  11. The High Mosaicity Illusion: Revealing the True Physical Characteristics of Macromolecular Crystals

    Science.gov (United States)

    Bellamy, Henry; Snell, Edward H.; Borgstahl, Gloria

    2000-01-01

    An experimental system and software have been developed for simultaneously measuring the diffraction resolution and mosaic spread of macromolecular crystals. Hundreds of reflection profiles over a wide resolution range were rapidly measured by using a charge coupled device (CCD) area detector in combination with superfine phi slicing data collection. The contributions of the X-ray beam to the reflection widths were minimized by using a highly-parallel, highly-monochromatic synchrotron source. These contributions and Lorentz effects were evaluated and deconvoluted from the recorded data. Data collection and processing is described. From one degree of superfine phi slice data collected on a crystal of manganese superoxide dismutase the mosaicity of 261 reflections were measured. The average mosaicity was 0.0101 degrees (0.0035) at the full-width-at-half-maximum (FWHM) and ranged from 0.0011 degrees to 0.0188 degrees. Each reflection profile was individually fit with two gaussian profiles with the first gaussian contributing 55% and the second contributing 35% of the reflection. On average, the mosaicity of the first gaussian was 0.0054 degrees (0.0015) and the second was 0.0061 degrees (0.0023). The mosaicity of the crystal was anisotropic with fh, f k, and fl values of 0.0068 degrees, 0.0140 degrees and 0.0046 degrees, respectively at the FWHM. The anisotropic mosaicity analysis indicates that the crystal is the most perfect in the I direction which corresponds to the favored growth direction of the crystal.

  12. Visual sensory processing deficits in patients with bipolar disorder revealed through high-density electrical mapping.

    LENUS (Irish Health Repository)

    Yeap, Sherlyn

    2009-11-01

    BACKGROUND: Etiological commonalities are apparent between bipolar disorder and schizophrenia. For example, it is becoming clear that both populations show similar electrophysiological deficits in the auditory domain. Recent studies have also shown robust visual sensory processing deficits in patients with schizophrenia using the event-related potential technique, but this has not been formally tested in those with bipolar disorder. Our goal here was to assess whether early visual sensory processing in patients with bipolar disorder, as indexed by decreased amplitude of the P1 component of the visual evoked potential (VEP), would show a similar deficit to that seen in those with schizophrenia. Since the P1 deficit has already been established as an endophenotype in schizophrenia, a finding of commonality between disorders would raise the possibility that it represents a measure of common genetic liability. METHODS: We visually presented isolated-check stimuli to euthymic patients with a diagnosis of bipolar disorder and age-matched healthy controls within a simple go\\/no-go task and recorded VEPs using high-density (72-channel) electroencephalography. RESULTS: The P1 VEP amplitude was substantially reduced in patients with bipolar disorder, with an effect size of f = 0.56 (large according to Cohen\\'s criteria). LIMITATIONS: Our sample size was relatively small and as such, did not allow for an examination of potential relations between the physiologic measures and clinical measures. CONCLUSION: This reduction in P1 amplitude among patients with bipolar disorder represents a dysfunction in early visual processing that is highly similar to that found repeatedly in patients with schizophrenia and their healthy first-degree relatives. Since the P1 deficit has been related to susceptibility genes for schizophrenia, our results raise the possibility that the deficit may in fact be more broadly related to the development of psychosis and that it merits further

  13. A novel high-throughput assay for islet respiration reveals uncoupling of rodent and human islets.

    Directory of Open Access Journals (Sweden)

    Jakob D Wikstrom

    Full Text Available BACKGROUND: The pancreatic beta cell is unique in its response to nutrient by increased fuel oxidation. Recent studies have demonstrated that oxygen consumption rate (OCR may be a valuable predictor of islet quality and long term nutrient responsiveness. To date, high-throughput and user-friendly assays for islet respiration are lacking. The aim of this study was to develop such an assay and to examine bioenergetic efficiency of rodent and human islets. METHODOLOGY/PRINCIPAL FINDINGS: The XF24 respirometer platform was adapted to islets by the development of a 24-well plate specifically designed to confine islets. The islet plate generated data with low inter-well variability and enabled stable measurement of oxygen consumption for hours. The F1F0 ATP synthase blocker oligomycin was used to assess uncoupling while rotenone together with myxothiazol/antimycin was used to measure the level of non-mitochondrial respiration. The use of oligomycin in islets was validated by reversing its effect in the presence of the uncoupler FCCP. Respiratory leak averaged to 59% and 49% of basal OCR in islets from C57Bl6/J and FVB/N mice, respectively. In comparison, respiratory leak of INS-1 cells and C2C12 myotubes was measured to 38% and 23% respectively. Islets from a cohort of human donors showed a respiratory leak of 38%, significantly lower than mouse islets. CONCLUSIONS/SIGNIFICANCE: The assay for islet respiration presented here provides a novel tool that can be used to study islet mitochondrial function in a relatively high-throughput manner. The data obtained in this study shows that rodent islets are less bioenergetically efficient than human islets as well as INS1 cells.

  14. Skinks (Reptilia: Scincidae) have highly conserved karyotypes as revealed by chromosome painting.

    Science.gov (United States)

    Giovannotti, M; Caputo, V; O'Brien, P C M; Lovell, F L; Trifonov, V; Cerioni, P Nisi; Olmo, E; Ferguson-Smith, M A; Rens, W

    2009-01-01

    Skinks represent the most diversified squamate reptiles with a great variation in body size and form, and are found worldwide in a variety of habitats. Their remarkable diversification has been accompanied by only a few chromosome rearrangements, resulting in highly-conservative chromosomal complements of these lizards. In this study cross-species chromosome painting using Scincus scincus (2n = 32) as the source genome, was used to detect the chromosomal rearrangements and homologies between the following skinks: Chalcides chalcides (2n = 28), C. ocellatus (2n = 28), Eumeces schneideri (2n = 32), Lepidothyris fernandi (2n = 30), Mabuya quinquetaeniata (2n = 32). The results of this study confirmed a high degree of chromosome conservation between these species. The main rearrangements in the studied skinks involve chromosomes 3, 5, 6 and 7 of S. scincus. These subtelocentric chromosomes are homologous to the p and q arms of metacentric pair 3 and 4 in C. chalcides, C. ocellatus, L. fernandi, and M. quinquetaeniata, while they are entirely conserved in E. schneideri. Other rearrangements involve S. scincus 11 in L. fernandi and M. quinquetaeniata, supporting the monophyly of Lygosominae, and one of the chromosomes S. scincus 12-16, in M. quinquetaeniata. In conclusion, our data support the monophyly of Scincidae and confirm that Scincus-Eumeces plus Chalcides do not form a monophyletic clade, suggesting that the Scincus-Eumeces clade is basal to other members of this family. This study represents the first time the whole genome of any reptile species has been used for cross-species chromosome painting to assess chromosomal evolution in this group of vertebrates.

  15. Comprehensive Red List assessment reveals exceptionally high extinction risk to Madagascar palms.

    Directory of Open Access Journals (Sweden)

    Mijoro Rakotoarinivo

    Full Text Available The establishment of baseline IUCN Red List assessments for plants is a crucial step in conservation planning. Nowhere is this more important than in biodiversity hotspots that are subject to significant anthropogenic pressures, such as Madagascar. Here, all Madagascar palm species are assessed using the IUCN Red List categories and criteria, version 3.1. Our results indicate that 83% of the 192 endemic species are threatened, nearly four times the proportion estimated for plants globally and exceeding estimates for all other comprehensively evaluated plant groups in Madagascar. Compared with a previous assessment in 1995, the number of Endangered and Critically Endangered species has substantially increased, due to the discovery of 28 new species since 1995, most of which are highly threatened. The conservation status of most species included in both the 1995 and the current assessments has not changed. Where change occurred, more species have moved to lower threat categories than to higher categories, because of improved knowledge of species and their distributions, rather than a decrease in extinction risk. However, some cases of genuine deterioration in conservation status were also identified. Palms in Madagascar are primarily threatened by habitat loss due to agriculture and biological resource use through direct exploitation or collateral damage. The recent extension of Madagascar's protected area network is highly beneficial for palms, substantially increasing the number of threatened species populations included within reserves. Notably, three of the eight most important protected areas for palms are newly designated. However, 28 threatened and data deficient species are not protected by the expanded network, including some Critically Endangered species. Moreover, many species occurring in protected areas are still threatened, indicating that threatening processes persist even in reserves. Definitive implementation of the new protected

  16. Proteome-based biomarkers in pancreatic cancer

    Institute of Scientific and Technical Information of China (English)

    Chen Sun; Ann H Rosendahl; Daniel Ansari; Roland Andersson

    2011-01-01

    Pancreatic cancer, as a highly malignant cancer and the fourth cause of cancer-related death in world, is characterized by dismal prognosis, due to rapid disease progression, highly invasive tumour phenotype, and resistance to chemotherapy. Despite significant advances in treatment of the disease during the past decade,the survival rate is little improved. A contributory factor to the poor outcome is the lack of appropriate sensitive and specific biomarkers for early diagnosis. Furthermore, biomarkers for targeting, directing and assessing therapeutic intervention, as well as for detection of residual or recurrent cancer are also needed. Thus, the identification of adequate biomarkers in pancreatic cancer is of extreme importance. Recently, accompanying the development of proteomic technology and devices, more and more potential biomarkers have appeared and are being reported. In this review, we provide an overview of the role of proteome-based biomarkers in pancreatic cancer, including tissue, serum, juice, urine and cell lines. We also discuss the possible mechanism and prospects in the future. That information hopefully might be helpful for further research in the field.

  17. Using Aptamers for Cancer Biomarker Discovery

    Directory of Open Access Journals (Sweden)

    Yun Min Chang

    2013-01-01

    Full Text Available Aptamers are single-stranded synthetic DNA- or RNA-based oligonucleotides that fold into various shapes to bind to a specific target, which includes proteins, metals, and molecules. Aptamers have high affinity and high specificity that are comparable to that of antibodies. They are obtained using iterative method, called (Systematic Evolution of Ligands by Exponential Enrichment SELEX and cell-based SELEX (cell-SELEX. Aptamers can be paired with recent advances in nanotechnology, microarray, microfluidics, and other technologies for applications in clinical medicine. One particular area that aptamers can shed a light on is biomarker discovery. Biomarkers are important in diagnosis and treatment of cancer. In this paper, we will describe ways in which aptamers can be used to discover biomarkers for cancer diagnosis and therapeutics.

  18. Active faults in the deformation zone off Noto Peninsula, Japan, revealed by high- resolution seismic profiles

    Science.gov (United States)

    Inoue, T.; Okamura, Y.; Murakami, F.; Kimura, H.; Ikehara, K.

    2008-12-01

    Recently, a lot of earthquakes occur in Japan. The deformation zone which many faults and folds have concentrated exists on the Japan Sea side of Japan. The 2007 Noto Hanto Earthquake (MJMA 6.9) and 2007 Chuetsu-oki Earthquake (MJMA 6.8) were caused by activity of parts of faults in this deformation zone. The Noto Hanto Earthquake occurred on 25 March, 2007 under the northwestern coast of Noto Peninsula, Ishikawa Prefecture, Japan. This earthquake is located in Quaternary deformation zone that is continued from northern margin of Noto Peninsula to southeast direction (Okamura, 2007a). National Institute of Advanced Industrial Science and Technology (AIST) carried out high-resolution seismic survey using Boomer and 12 channels short streamer cable in the northern part off Noto Peninsula, in order to clarify distribution and activities of active faults in the deformation zone. A twelve channels short streamer cable with 2.5 meter channel spacing developed by AIST and private corporation is designed to get high resolution seismic profiles in shallow sea area. The multi-channel system is possible to equip on a small fishing boat, because the data acquisition system is based on PC and the length of the cable is short and easy to handle. Moreover, because the channel spacing is short, this cable is very effective for a high- resolution seismic profiling survey in the shallow sea, and seismic data obtained by multi-channel cable can be improved by velocity analysis and CDP stack. In the northern part off Noto Peninsula, seismic profiles depicting geologic structure up to 100 meters deep under sea floor were obtained. The most remarkable reflection surface recognized in the seismic profiles is erosion surface at the Last Glacial Maximum (LGM). In the western part, sediments about 30 meters (40 msec) thick cover the erosional surface that is distributed under the shelf shallower than 100m in depth and the sediments thin toward offshore and east. Flexures like deformation in

  19. Protein biomarker enrichment by biomarker antibody complex elution for immunoassay biosensing.

    Science.gov (United States)

    Sabatte, Gwenola; Feitsma, Harma; Evers, Toon H; Prins, Menno W J

    2011-11-15

    It is very challenging to perform sample enrichment for protein biomarkers because proteins can easily change conformation and denature. In this paper we demonstrate protein enrichment suited for high-sensitivity integrated immuno-biosensing. The method enhances the concentration of the biomarkers and simultaneously removes matrix components that could interfere with the immunoassay. Biomarkers are captured using antibody coated magnetic particles and the biomarker antibody complexes are released by enzymatic elution. The eluted complexes are subsequently detected in a sandwich immunoassay biosensor. A scaling study of the enrichment process demonstrates an enrichment factor of 15 in buffer and plasma. We analyze the enrichment factor in terms of the three basic steps of the assay (capture, concentration, elution) and we quantify their respective efficiencies. The process is suited for integration into bio-analytical tools.

  20. Novel and highly diverse fungal endophytes in soybean revealed by the consortium of two different techniques.

    Science.gov (United States)

    de Souza Leite, Tiago; Cnossen-Fassoni, Andréia; Pereira, Olinto Liparini; Mizubuti, Eduardo Seiti Gomide; de Araújo, Elza Fernandes; de Queiroz, Marisa Vieira

    2013-02-01

    Fungal endophytes were isolated from the leaves of soybean cultivars in Brazil using two different isolation techniques - fragment plating and the innovative dilution-to-extinction culturing - to increase the species richness, frequency of isolates and diversity. A total of 241 morphospecies were obtained corresponding to 62 taxa that were identified by analysis of the internal transcribed spacer (ITS) of the ribosomal DNA (rDNA). The Phylum Ascomycota predominated, representing 99% and 95.2% of isolates in the Monsoy and Conquista cultivars, respectively, whereas the Phylum Basidiomycota represented 1% and 4.8% of isolates, respectively. The genera Ampelomyces, Annulohypoxylon, Guignardia, Leptospora, Magnaporthe, Ophiognomonia, Paraconiothyrium, Phaeosphaeriopsis, Rhodotorula, Sporobolomyces, and Xylaria for the first time were isolated from soybean; this suggests that soybean harbours novel and highly diverse fungi. The yeasts genera Rhodotorula and Sporobolomyces (subphylum Pucciniomycotina) represent the Phylum Basidiomycota. The species richness was greater when both isolation techniques were used. The diversity of fungal endophytes was similar in both cultivars when the same isolation technique was used except for Hill's index, N1. The use of ITS region sequences allowed the isolates to be grouped according to Order, Class and Phylum. Ampelomyces, Chaetomium, and Phoma glomerata are endophytic species that may play potential roles in the biological control of soybean pathogens. This study is one of the first to apply extinction-culturing to isolate fungal endophytes in plant leaves, thus contributing to the development and improvement of this technique for future studies.

  1. High Throughput Sequencing of T Cell Antigen Receptors Reveals a Conserved TCR Repertoire

    Science.gov (United States)

    Hou, Xianliang; Lu, Chong; Chen, Sisi; Xie, Qian; Cui, Guangying; Chen, Jianing; Chen, Zhi; Wu, Zhongwen; Ding, Yulong; Ye, Ping; Dai, Yong; Diao, Hongyan

    2016-01-01

    Abstract The T-cell receptor (TCR) repertoire is a mirror of the human immune system that reflects processes caused by infections, cancer, autoimmunity, and aging. Next-generation sequencing has become a powerful tool for deep TCR profiling. Herein, we used this technology to study the repertoire features of TCR beta chain in the blood of healthy individuals. Peripheral blood samples were collected from 10 healthy donors. T cells were isolated with anti-human CD3 magnetic beads according to the manufacturer's protocol. We then combined multiplex-PCR, Illumina sequencing, and IMGT/High V-QUEST to analyze the characteristics and polymorphisms of the TCR. Most of the individual T cell clones were present at very low frequencies, suggesting that they had not undergone clonal expansion. The usage frequencies of the TCR beta variable, beta joining, and beta diversity gene segments were similar among T cells from different individuals. Notably, the usage frequency of individual nucleotides and amino acids within complementarity-determining region (CDR3) intervals was remarkably consistent between individuals. Moreover, our data show that terminal deoxynucleotidyl transferase activity was biased toward the insertion of G (31.92%) and C (27.14%) over A (21.82%) and T (19.12%) nucleotides. Some conserved features could be observed in the composition of CDR3, which may inform future studies of human TCR gene recombination. PMID:26962778

  2. Temporal dynamics of motivation-cognitive control interactions revealed by high-resolution pupillometry

    Directory of Open Access Journals (Sweden)

    Kimberly Sarah Chiew

    2013-01-01

    Full Text Available Motivational manipulations, such as the presence of performance-contingent reward incentives, can have substantial influences on cognitive control. Previous evidence suggests that reward incentives may enhance cognitive performance specifically through increased preparatory, or proactive, control processes. The present study examined reward influences on cognitive control dynamics in the AX-Continuous Performance Task (AX-CPT, using high-resolution pupillometry. In the AX-CPT, contextual cues must be actively maintained over a delay in order to appropriately respond to ambiguous target probes. A key feature of the task is that it permits dissociable characterization of preparatory, proactive control processes (i.e., utilization of context and reactive control processes (i.e., target-evoked interference resolution. Task performance profiles suggested that reward incentives enhanced proactive control (context utilization. Critically, pupil dilation was also increased on reward incentive trials during context maintenance periods, suggesting trial-specific shifts in proactive control, particularly when context cues indicated the need to overcome the dominant target response bias. Reward incentives had both transient (i.e., trial-by-trial and sustained (i.e., block-based effects on pupil dilation, which may reflect distinct underlying processes. The transient pupillary effects were present even when comparing against trials matched in task performance, suggesting a unique motivational influence of reward incentives. These results suggest that pupillometry may be a useful technique for investigating reward motivational signals and their dynamic influence on cognitive control.

  3. Temporal dynamics of motivation-cognitive control interactions revealed by high-resolution pupillometry.

    Science.gov (United States)

    Chiew, Kimberly S; Braver, Todd S

    2013-01-01

    Motivational manipulations, such as the presence of performance-contingent reward incentives, can have substantial influences on cognitive control. Previous evidence suggests that reward incentives may enhance cognitive performance specifically through increased preparatory, or proactive, control processes. The present study examined reward influences on cognitive control dynamics in the AX-Continuous Performance Task (AX-CPT), using high-resolution pupillometry. In the AX-CPT, contextual cues must be actively maintained over a delay in order to appropriately respond to ambiguous target probes. A key feature of the task is that it permits dissociable characterization of preparatory, proactive control processes (i.e., utilization of context) and reactive control processes (i.e., target-evoked interference resolution). Task performance profiles suggested that reward incentives enhanced proactive control (context utilization). Critically, pupil dilation was also increased on reward incentive trials during context maintenance periods, suggesting trial-specific shifts in proactive control, particularly when context cues indicated the need to overcome the dominant target response bias. Reward incentives had both transient (i.e., trial-by-trial) and sustained (i.e., block-based) effects on pupil dilation, which may reflect distinct underlying processes. The transient pupillary effects were present even when comparing against trials matched in task performance, suggesting a unique motivational influence of reward incentives. These results suggest that pupillometry may be a useful technique for investigating reward motivational signals and their dynamic influence on cognitive control.

  4. Genomic analysis of six new Geobacillus strains reveals highly conserved carbohydrate degradation architectures and strategies

    Directory of Open Access Journals (Sweden)

    Phillip eBrumm

    2015-05-01

    Full Text Available In this work we report the whole genome sequences of six new Geobacillus xylanolytic strains along with the genomic analysis of their capability to degrade carbohydrates.. The six sequenced Geobacillus strains described here have a range of GC contents from 43.9% to 52.5% and clade with named Geobacillus species throughout the entire genus. We have identified a ~200 kb unique super-cluster in all six strains, containing five to eight distinct carbohydrate degradation clusters in a single genomic region, a feature not seen in other genera. The Geobacillus strains rely on a small number of secreted enzymes located within distinct clusters for carbohydrate utilization, in contrast to most biomass-degrading organisms which contain numerous secreted enzymes located randomly throughout the genomes. All six strains are able to utilize fructose, arabinose, xylose, mannitol, gluconate, xylan, and α-1,6-glucosides. The gene clusters for utilization of these seven substrates have identical organization and the individual proteins have a high percent identity to their homologs. The strains show significant differences in their ability to utilize inositol, sucrose, lactose, α-mannosides, α-1,4-glucosides and arabinan.

  5. High-throughput sequencing reveals an altered T cell repertoire in X-linked agammaglobulinemia.

    Science.gov (United States)

    Ramesh, Manish; Simchoni, Noa; Hamm, David; Cunningham-Rundles, Charlotte

    2015-12-01

    To examine the T cell receptor structure in the absence of B cells, the TCR β CDR3 was sequenced from DNA of 15 X-linked agammaglobulinemia (XLA) subjects and 18 male controls, using the Illumina HiSeq platform and the ImmunoSEQ analyzer. V gene usage and the V-J combinations, derived from both productive and non-productive sequences, were significantly different between XLA samples and controls. Although the CDR3 length was similar for XLA and control samples, the CDR3 region of the XLA T cell receptor contained significantly fewer deletions and insertions in V, D, and J gene segments, differences intrinsic to the V(D)J recombination process and not due to peripheral T cell selection. XLA CDR3s demonstrated fewer charged amino acid residues, more sharing of CDR3 sequences, and almost completely lacked a population of highly modified Vβ gene segments found in control DNA, suggesting both a skewed and contracted T cell repertoire in XLA.

  6. Carrier behavior of HgTe under high pressure revealed by Hall effect measurement

    Institute of Scientific and Technical Information of China (English)

    胡廷静; 崔晓岩; 李雪飞; 王婧姝; 吕秀梅; 王棱升; 杨景海; 高春晓

    2015-01-01

    We investigate the carrier behavior of HgTe under high pressures up to 23 GPa using in situ Hall effect measurements. As the phase transitions from zinc blende to cinnabar, then to rock salt, and finally to Cmcm occur, all the parameters change discontinuously. The conductivity variation under compression is described by the carrier parameters. For the zinc blende phase, both the decrease of carrier concentration and the increase of mobility indicate the overlapped valence band and conduction band separates with pressure. Pressure causes an increase in the hole concentration of HgTe in the cinnabar phase, which leads to the carrier-type inversion and the lowest mobility at 5.6 GPa. In the phase transition process from zinc blende to rock salt, Te atoms are the major ones in atomic movements in the pressure regions of 1.0–1.5 GPa and 1.8–3.1 GPa, whereas Hg atoms are the major ones in the pressure regions of 1.5–1.8 GPa and 3.1–7.7 GPa. The polar optical scattering of the rock salt phase decreases with pressure.

  7. THE NEAREST HIGH-VELOCITY STARS REVEALED BY LAMOST DATA RELEASE 1

    Energy Technology Data Exchange (ETDEWEB)

    Zhong, Jing; Chen, Li; Hou, Jinliang; Shen, Shiyin; Shao, Zhengyi; Li, Jing [Key Laboratory for Research in Galaxies and Cosmology, Shanghai Astronomical Observatory, Chinese Academy of Sciences, 80 Nandan Road, Shanghai 200030 (China); Liu, Chao; Luo, Ali; Shi, Jianrong; Zhang, Haotong; Yang, Ming; Deng, Licai [Key Laboratory of Optical Astronomy, National Astronomical Observatories, Chinese Academy of Sciences, Datun Road 20A, Beijing 100012 (China); De Grijs, Richard [Kavli Institute for Astronomy and Astrophysics and Department of Astronomy, Peking University, Yi He Yuan Lu 5, Hai Dian District, Beijing 100871 (China); Jin, Ge [University of Science and Technology of China, Hefei 230026 (China); Zhang, Yong; Hou, Yonghui; Zhang, Zhenchao, E-mail: jzhong@shao.ac.cn [Nanjing Institute of Astronomical Optics and Technology, National Astronomical Observatories, Chinese Academy of Sciences, Nanjing 210042 (China)

    2014-07-01

    We report the discovery of 28 candidate high-velocity stars (HVSs) at heliocentric distances of less than 3 kpc, based on the Large Sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) Data Release 1. Our sample of HVS candidates covers a much broader color range than the equivalent ranges discussed in previous studies and comprises the first and largest sample of HVSs in the immediate solar neighborhood, at heliocentric distances less than 1-3 kpc. The observed as well as the derived parameters for all candidates are sufficiently accurate to allow us to ascertain their nature as genuine HVSs, of which a subset of 12 objects represents the most promising candidates. Our results also highlight the great potential of discovering statistically large numbers of HVSs of different spectral types in LAMOST survey data. This will ultimately enable us to achieve a better understanding of the nature of Galactic HVSs and their ejection mechanisms, and to constrain the structure of the Galaxy.

  8. Coseismic landslides reveal near-surface rock strength in a high-relief tectonically active setting

    Science.gov (United States)

    Gallen, Sean F; Clark, Marin K; Godt, Jonathan W.

    2014-01-01

    We present quantitative estimates of near-surface rock strength relevant to landscape evolution and landslide hazard assessment for 15 geologic map units of the Longmen Shan, China. Strength estimates are derived from a novel method that inverts earthquake peak ground acceleration models and coseismic landslide inventories to obtain material proper- ties and landslide thickness. Aggregate rock strength is determined by prescribing a friction angle of 30° and solving for effective cohesion. Effective cohesion ranges are from 70 kPa to 107 kPa for 15 geologic map units, and are approximately an order of magnitude less than typical laboratory measurements, probably because laboratory tests on hand-sized specimens do not incorporate the effects of heterogeneity and fracturing that likely control near-surface strength at the hillslope scale. We find that strength among the geologic map units studied varies by less than a factor of two. However, increased weakening of units with proximity to the range front, where precipitation and active fault density are the greatest, suggests that cli- matic and tectonic factors overwhelm lithologic differences in rock strength in this high-relief tectonically active setting.

  9. Chemoecological Screening Reveals High Bioactivity in Diverse Culturable Portuguese Marine Cyanobacteria

    Directory of Open Access Journals (Sweden)

    Vitor M. Vasconcelos

    2013-04-01

    Full Text Available Marine cyanobacteria, notably those from tropical regions, are a rich source of bioactive secondary metabolites. Tropical marine cyanobacteria often grow to high densities in the environment, allowing direct isolation of many secondary metabolites from field-collected material. However, in temperate environments culturing is usually required to produce enough biomass for investigations of their chemical constituents. In this work, we cultured a selection of novel and diverse cyanobacteria isolated from the Portuguese coast, and tested their organic extracts in a series of ecologically-relevant bioassays. The majority of the extracts showed activity in at least one of the bioassays, all of which were run in very small scale. Phylogenetically related isolates exhibited different activity profiles, highlighting the value of microdiversity for bioprospection studies. Furthermore, LC-MS analyses of selected active extracts suggested the presence of previously unidentified secondary metabolites. Overall, the screening strategy employed here, in which previously untapped cyanobacterial diversity was combined with multiple bioassays, proved to be a successful strategy and allowed the selection of several strains for further investigations based on their bioactivity profiles.

  10. Chemoecological screening reveals high bioactivity in diverse culturable Portuguese marine cyanobacteria.

    Science.gov (United States)

    Leão, Pedro N; Ramos, Vitor; Gonçalves, Patrício B; Viana, Flávia; Lage, Olga M; Gerwick, William H; Vasconcelos, Vitor M

    2013-04-22

    Marine cyanobacteria, notably those from tropical regions, are a rich source of bioactive secondary metabolites. Tropical marine cyanobacteria often grow to high densities in the environment, allowing direct isolation of many secondary metabolites from field-collected material. However, in temperate environments culturing is usually required to produce enough biomass for investigations of their chemical constituents. In this work, we cultured a selection of novel and diverse cyanobacteria isolated from the Portuguese coast, and tested their organic extracts in a series of ecologically-relevant bioassays. The majority of the extracts showed activity in at least one of the bioassays, all of which were run in very small scale. Phylogenetically related isolates exhibited different activity profiles, highlighting the value of microdiversity for bioprospection studies. Furthermore, LC-MS analyses of selected active extracts suggested the presence of previously unidentified secondary metabolites. Overall, the screening strategy employed here, in which previously untapped cyanobacterial diversity was combined with multiple bioassays, proved to be a successful strategy and allowed the selection of several strains for further investigations based on their bioactivity profiles.

  11. Using DNA metabarcoding to investigate honey bee foraging reveals limited flower use despite high floral availability

    Science.gov (United States)

    de Vere, Natasha; Jones, Laura E.; Gilmore, Tegan; Moscrop, Jake; Lowe, Abigail; Smith, Dan; Hegarty, Matthew J.; Creer, Simon; Ford, Col R.

    2017-01-01

    Understanding which flowers honey bees (Apis mellifera) use for forage can help us to provide suitable plants for healthy honey bee colonies. Accordingly, honey DNA metabarcoding provides a valuable tool for investigating pollen and nectar collection. We investigated early season (April and May) floral choice by honey bees provided with a very high diversity of flowering plants within the National Botanic Garden of Wales. There was a close correspondence between the phenology of flowering and the detection of plants within the honey. Within the study area there were 437 genera of plants in flower during April and May, but only 11% of these were used. Thirty-nine plant taxa were recorded from three hives but only ten at greater than 1%. All three colonies used the same core set of native or near-native plants, typically found in hedgerows and woodlands. The major plants were supplemented with a range of horticultural species, with more variation in plant choice between the honey bee colonies. We conclude that during the spring, honey bees need access to native hedgerows and woodlands to provide major plants for foraging. Gardens provide supplementary flowers that may increase the nutritional diversity of the honey bee diet. PMID:28205632

  12. Multilocus spacer analysis revealed highly homogeneous genetic background of Asian type of Borrelia miyamotoi.

    Science.gov (United States)

    Mukhacheva, Tatyana A; Salikhova, Irina I; Kovalev, Sergey Y

    2015-04-01

    Borrelia miyamotoi, a member of the relapsing fever group borreliae, was first isolated in Japan and subsequently found in Ixodes ticks in North America, Europe and Russia. Currently, there are three types of B. miyamotoi: Asian or Siberian (transmitted mainly by Ixodes persulcatus), European (Ixodesricinus) and American (Ixodesscapularis and Ixodespacificus). Despite the great genetic distances between B. miyamotoi types, isolates within a type are characterised by an extremely low genetic variability. In particular, strains of B. miyamotoi of Asian type, isolated in Russia from the Baltic sea to the Far East, have been shown to be identical based on the analysis of several conventional genetic markers, such as 16S rRNA, flagellin, outer membrane protein p66 and glpQ genes. Thus, protein or rRNA - coding genes were shown not to be informative enough in studying genetic diversity of B. miyamotoi within a type. In the present paper, we have attempted to design a new multilocus technique based on eight non-coding intergenic spacers (3686bp in total) and have applied it to the analysis of intra-type genetic variability of В. miyamotoi detected in different regions of Russia and from two tick species, I. persulcatus and Ixodespavlovskyi. However, even though potentially the most variable loci were selected, no genetic variability between studied DNA samples was found, except for one nucleotide substitution in two of them. The sequences obtained were identical to those of the reference strain FR64b. Analysis of the data obtained with the GenBank sequences indicates a highly homogeneous genetic background of B. miyamotoi from the Baltic Sea to the Japanese Islands. In this paper, a hypothesis of clonal expansion of B. miyamotoi is discussed, as well as possible mechanisms for the rapid dissemination of one B. miyamotoi clone over large distances.

  13. Canine tarsal architecture as revealed by high-resolution computed tomography.

    Science.gov (United States)

    Galateanu, G; Apelt, D; Aizenberg, I; Saragusty, J; Hildebrandt, T B

    2013-06-01

    Central tarsal bone (CTB) fractures are well documented and are a subject of increasing importance in human, equine and canine athletes although the mechanism of these fractures in dogs is not fully understood and an extrapolation from human medicine may not be accurate. This study reports the use of high-resolution computed tomography (CT) of 91 tarsal joints from 47 dogs to generate a more detailed in situ anatomical description of the CTB architecture in order to obtain a better understanding of the pathogenesis of CTB fractures in this species. The dogs studied represented a wide range of ages, breeds and levels of habitual physical activity and the angles of the tarsal joints studied ranged between maximal flexion (16.4°) and maximal extension (159.1°). Regardless of tarsal angle, the CTB articulated with the calcaneus exclusively at the level of its plantar process (PPCTB) in all dogs. The PPCTB presented two distinct parts in all dogs, a head and a neck. The calcaneus tended to rely on the PPCTB neck during flexion and on the PPCTB head during extension. This study describes new tarsal elements for the first time, including the calcaneal articular process, the fourth tarsal bone plantar articular process and the talar plantar prominence of the CTB. Based on calcaneo-PPCTB architecture, it is postulated that the PPCTB is a keystone structure and that at least some of CTB fractures in dogs could either commence at or are induced at this level due to the impingement forces exercised by the calcaneus.

  14. Contrast discrimination at high contrasts reveals the influence of local light adaptation on contrast processing.

    Science.gov (United States)

    Kingdom, F A; Whittle, P

    1996-03-01

    Previous measurements of contrast discrimination threshold, delta C, as a function of pedestal contrast, C, for sine-wave gratings have shown a power law relationship between delta C and C at suprathreshold levels of C. However, these studies have rarely used contrasts greater than 50%. Whittle (1986), using incremental and decremental patches, found that delta C increased with C only up to about 50%. At higher contrasts it decreased. Since a periodic stimulus can be considered to be composed of increments and decrements, we thought we might find such an inverse U-shaped function for gratings if we used contrasts up to 100%. We tested this for both sine-wave and square-wave stimuli at spatial frequencies from 0.0625 to 8.0 c/deg. We found that for frequencies up to 0.5 c/deg, delta C in nearly all cases 'dipped down' after about C = 50% contrast. At 4.0 and 8.0 c/deg, however, no dip-down occurred. Additional experiments showed that the dip-down was unlikely to be due to cortical long-term adaptation and most likely an effect of localized light adaptation to the dark bars. We argue that the absence of dip-down at high spatial frequencies was mainly due to the attenuation of contrast by the optics of the eye. As for the results of Whittle (1986), a Weber's Law in W = (Lmax-Lmin)/Lmin describes the inverse U-shaped contrast discrimination function well. Two other contrast expressions also linearize the data on log-log plots. We show how some familiar notions about the physiological operation of localized light adaptation can easily account for the form of the contrast discrimination function. Finally we estimate the number of discriminable steps in contrast from detection threshold to maximum contrast for the various spatial frequencies tested.

  15. Phylogenetic analysis reveals a high prevalence of Sporothrix brasiliensis in feline sporotrichosis outbreaks.

    Science.gov (United States)

    Rodrigues, Anderson Messias; de Melo Teixeira, Marcus; de Hoog, G Sybren; Schubach, Tânia Maria Pacheco; Pereira, Sandro Antonio; Fernandes, Geisa Ferreira; Bezerra, Leila Maria Lopes; Felipe, Maria Sueli; de Camargo, Zoilo Pires

    2013-01-01

    Sporothrix schenckii, previously assumed to be the sole agent of human and animal sporotrichosis, is in fact a species complex. Recently recognized taxa include S. brasiliensis, S. globosa, S. mexicana, and S. luriei, in addition to S. schenckii sensu stricto. Over the last decades, large epidemics of sporotrichosis occurred in Brazil due to zoonotic transmission, and cats were pointed out as key susceptible hosts. In order to understand the eco-epidemiology of feline sporotrichosis and its role in human sporotrichosis a survey was conducted among symptomatic cats. Prevalence and phylogenetic relationships among feline Sporothrix species were investigated by reconstructing their phylogenetic origin using the calmodulin (CAL) and the translation elongation factor-1 alpha (EF1α) loci in strains originated from Rio de Janeiro (RJ, n = 15), Rio Grande do Sul (RS, n = 10), Paraná (PR, n = 4), São Paulo (SP, n =3) and Minas Gerais (MG, n = 1). Our results showed that S. brasiliensis is highly prevalent among cats (96.9%) with sporotrichosis, while S. schenckii was identified only once. The genotype of Sporothrix from cats was found identical to S. brasiliensis from human sources confirming that the disease is transmitted by cats. Sporothrix brasiliensis presented low genetic diversity compared to its sister taxon S. schenckii. No evidence of recombination in S. brasiliensis was found by split decomposition or PHI-test analysis, suggesting that S. brasiliensis is a clonal species. Strains recovered in states SP, MG and PR share the genotype of the RJ outbreak, different from the RS clone. The occurrence of separate genotypes among strains indicated that the Brazilian S. brasiliensis epidemic has at least two distinct sources. We suggest that cats represent a major host and the main source of cat and human S. brasiliensis infections in Brazil.

  16. Phylogenetic analysis reveals a high prevalence of Sporothrix brasiliensis in feline sporotrichosis outbreaks.

    Directory of Open Access Journals (Sweden)

    Anderson Messias Rodrigues

    Full Text Available Sporothrix schenckii, previously assumed to be the sole agent of human and animal sporotrichosis, is in fact a species complex. Recently recognized taxa include S. brasiliensis, S. globosa, S. mexicana, and S. luriei, in addition to S. schenckii sensu stricto. Over the last decades, large epidemics of sporotrichosis occurred in Brazil due to zoonotic transmission, and cats were pointed out as key susceptible hosts. In order to understand the eco-epidemiology of feline sporotrichosis and its role in human sporotrichosis a survey was conducted among symptomatic cats. Prevalence and phylogenetic relationships among feline Sporothrix species were investigated by reconstructing their phylogenetic origin using the calmodulin (CAL and the translation elongation factor-1 alpha (EF1α loci in strains originated from Rio de Janeiro (RJ, n = 15, Rio Grande do Sul (RS, n = 10, Paraná (PR, n = 4, São Paulo (SP, n =3 and Minas Gerais (MG, n = 1. Our results showed that S. brasiliensis is highly prevalent among cats (96.9% with sporotrichosis, while S. schenckii was identified only once. The genotype of Sporothrix from cats was found identical to S. brasiliensis from human sources confirming that the disease is transmitted by cats. Sporothrix brasiliensis presented low genetic diversity compared to its sister taxon S. schenckii. No evidence of recombination in S. brasiliensis was found by split decomposition or PHI-test analysis, suggesting that S. brasiliensis is a clonal species. Strains recovered in states SP, MG and PR share the genotype of the RJ outbreak, different from the RS clone. The occurrence of separate genotypes among strains indicated that the Brazilian S. brasiliensis epidemic has at least two distinct sources. We suggest that cats represent a major host and the main source of cat and human S. brasiliensis infections in Brazil.

  17. Large-scale mitochondrial DNA analysis of the domestic goat reveals six haplogroups with high diversity.

    Directory of Open Access Journals (Sweden)

    Saeid Naderi

    Full Text Available BACKGROUND: From the beginning of domestication, the transportation of domestic animals resulted in genetic and demographic processes that explain their present distribution and genetic structure. Thus studying the present genetic diversity helps to better understand the history of domestic species. METHODOLOGY/PRINCIPAL FINDINGS: The genetic diversity of domestic goats has been characterized with 2430 individuals from all over the old world, including 946 new individuals from regions poorly studied until now (mainly the Fertile Crescent. These individuals represented 1540 haplotypes for the HVI segment of the mitochondrial DNA (mtDNA control region. This large-scale study allowed the establishment of a clear nomenclature of the goat maternal haplogroups. Only five of the six previously defined groups of haplotypes were divergent enough to be considered as different haplogroups. Moreover a new mitochondrial group has been localized around the Fertile Crescent. All groups showed very high haplotype diversity. Most of this diversity was distributed among groups and within geographic regions. The weak geographic structure may result from the worldwide distribution of the dominant A haplogroup (more than 90% of the individuals. The large-scale distribution of other haplogroups (except one, may be related to human migration. The recent fragmentation of local goat populations into discrete breeds is not detectable with mitochondrial markers. The estimation of demographic parameters from mismatch analyses showed that all groups had a recent demographic expansion corresponding roughly to the period when domestication took place. But even with a large data set it remains difficult to give relative dates of expansion for different haplogroups because of large confidence intervals. CONCLUSIONS/SIGNIFICANCE: We propose standard criteria for the definition of the different haplogroups based on the result of mismatch analysis and on the use of sequences of

  18. Coherent pipeline for biomarker discovery using mass spectrometry and bioinformatics

    Directory of Open Access Journals (Sweden)

    Al-Shahib Ali

    2010-08-01

    Full Text Available Abstract Background Robust biomarkers are needed to improve microbial identification and diagnostics. Proteomics methods based on mass spectrometry can be used for the discovery of novel biomarkers through their high sensitivity and specificity. However, there has been a lack of a coherent pipeline connecting biomarker discovery with established approaches for evaluation and validation. We propose such a pipeline that uses in silico methods for refined biomarker discovery and confirmation. Results The pipeline has four main stages: Sample preparation, mass spectrometry analysis, database searching and biomarker validation. Using the pathogen Clostridium botulinum as a model, we show that the robustness of candidate biomarkers increases with each stage of the pipeline. This is enhanced by the concordance shown between various database search algorithms for peptide identification. Further validation was done by focusing on the peptides that are unique to C. botulinum strains and absent in phylogenetically related Clostridium species. From a list of 143 peptides, 8 candidate biomarkers were reliably identified as conserved across C. botulinum strains. To avoid discarding other unique peptides, a confidence scale has been implemented in the pipeline giving priority to unique peptides that are identified by a union of algorithms. Conclusions This study demonstrates that implementing a coherent pipeline which includes intensive bioinformatics validation steps is vital for discovery of robust biomarkers. It also emphasises the importance of proteomics based methods in biomarker discovery.

  19. Acute kidney injury in children: Enhancing diagnosis with novel biomarkers

    Directory of Open Access Journals (Sweden)

    Samuel Nkachukwu Uwaezuoke

    2016-07-01

    Full Text Available This narrative review aims to appraise the sensitivity and specificity of novel biomarkers in identifying acute kidney injury (AKI in children. Serum creatinine represents a poor traditional biomarker for AKI due to some limitations. Although alternative reliable biomarkers that would better identify individuals at high risk for developing AKI, identify AKI early enough, monitor its progression and patients' recovery, as well as identify those patients at higher risk for poor outcomes are not yet available in renal care, the search-light has recently been focused on various novel biomarkers, some of which could provide this information in time ahead. Several studies have established their predictive value. However, none of them could solely fulfill all the criteria of the ideal biomarker. Therefore, to increase their sensitivity and specificity and enhance the diagnosis of AKI, constellations of different biomarkers with specific features are probably required. In future, the diagnostic evaluation of AKI in intensive care units will have to undergo a paradigm shift from serum creatinine as the traditional biomarker to tissue-specific injury biomarkers. A panel of these novel biomarkers employed at the bedside setting will ultimately revolutionize the diagnosis and prognostication of AKI in children.

  20. Genetic Analysis of long-lived families reveals novel variants influencing high density-lipoprotein cholesterol

    Directory of Open Access Journals (Sweden)

    Mary F Feitosa

    2014-06-01

    Full Text Available The plasma levels of high-density lipoprotein cholesterol (HDL have an inverse relationship to the risks of atherosclerosis and cardiovascular disease, and have also been associated with longevity. We sought to identify novel loci for HDL that could potentially provide new insights into biological regulation of HDL metabolism in healthy-longevous subjects. We performed a genome-wide association scan on HDL using a mixed model approach to account for family structure using kinship coefficients. A total of 4,114 subjects of European descent (480 families were genotyped at ~2.3 million SNPs and ~38 million SNPs were imputed using the 1000 Genome Cosmopolitan reference panel in MACH. We identified novel variants near-NLRP1 (17p13 associated with an increase of HDL levels at genome-wide significant level (p< 5.0E-08. Additionally, several CETP (16q21 and ZNF259-APOA5-A4-C3-A1 (11q23.3 variants associated with HDL were found, replicating those previously reported in the literature. A possible regulatory variant upstream of NLRP1 that is associated with HDL in these elderly LLFS subjects may also contribute to their longevity and health. Our NLRP1 intergenic SNPs show a potential regulatory function in ENCODE; however, it is not clear whether they regulate NLRP1 or other more remote gene. NLRP1 plays an important role in the induction of apoptosis, and its inflammasome is critical for mediating innate immune responses. Nlrp1a (a mouse ortholog of human NLRP1 interacts with SREBP-1a (17p11 which has a fundamental role in lipid concentration and composition, and is involved in innate immune response in macrophages. The NLRP1 region is conserved in mammals, but also has evolved adaptively showing signals of positive selection in European populations that might confer an advantage. NLRP1 intergenic SNPs have also been associated with immunity/inflammasome disorders which highlights the biological importance of this chromosomal region.

  1. Physiological and proteomic analyses of leaves from the halophyte Tangut Nitraria reveals diverse response pathways critical for high salinity tolerance

    Directory of Open Access Journals (Sweden)

    Tielong eCheng

    2015-02-01

    Full Text Available Soil salinization poses a serious threat to the environment and agricultural productivity worldwide. Studies on the physiological and molecular mechanisms of salinity tolerance in halophytic plants provide valuable information to enhance their salt tolerance. Tangut Nitraria is a widely distributed halophyte in saline–alkali soil in the northern areas of China. In this study, we used a proteomic approach to investigate the molecular pathways of the high salt tolerance of T. Nitraria. We analyzed the changes in biomass, photosynthesis, and redox-related enzyme activities in T. Nitraria leaves from plant seedlings treated with high salt concentration. Comparative proteomic analysis of the leaves revealed that the expression of 71 proteins was significantly altered after salinity treatments of T. Nitraria. These salinity-responsive proteins were mainly involved in photosynthesis, redox homeostasis, stress/defense, carbohydrate and energy metabolism, protein metabolism, signal transduction, and membrane transport. Results showed that the reduction of photosynthesis under salt stress was attributed to the down-regulation of the enzymes and proteins involved in the light reaction and Calvin cycle. Protein–protein interaction analysis revealed that the proteins involved in redox homeostasis, photosynthesis, and energy metabolism constructed two types of response networks to high salt stress. T. Nitraria plants developed diverse mechanisms for scavenging reactive oxygen species in their leaves to cope with stress induced by high salinity. This study provides important information regarding the salt tolerance of the halophyte T. Nitraria.

  2. Emerging Biomarkers in Glioblastoma

    Energy Technology Data Exchange (ETDEWEB)

    McNamara, Mairéad G.; Sahebjam, Solmaz; Mason, Warren P., E-mail: warren.mason@uhn.ca [Pencer Brain Tumor Centre, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, Ontario M5G 2M9 (Canada)

    2013-08-22

    Glioblastoma, the most common primary brain tumor, has few available therapies providing significant improvement in survival. Molecular signatures associated with tumor aggressiveness as well as with disease progression and their relation to differences in signaling pathways implicated in gliomagenesis have recently been described. A number of biomarkers which have potential in diagnosis, prognosis and prediction of response to therapy have been identified and along with imaging modalities could contribute to the clinical management of GBM. Molecular biomarkers including O(6)-methlyguanine-DNA-methyltransferase (MGMT) promoter and deoxyribonucleic acid (DNA) methylation, loss of heterozygosity (LOH) of chromosomes 1p and 19q, loss of heterozygosity 10q, isocitrate dehydrogenase (IDH) mutations, epidermal growth factor receptor (EGFR), epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1 (ELTD1), vascular endothelial growth factor (VEGF), tumor suppressor protein p53, phosphatase and tensin homolog (PTEN), p16INK4a gene, cytochrome c oxidase (CcO), phospholipid metabolites, telomerase messenger expression (hTERT messenger ribonucleic acid [mRNA]), microRNAs (miRNAs), cancer stem cell markers and imaging modalities as potential biomarkers are discussed. Inclusion of emerging biomarkers in prospective clinical trials is warranted in an effort for more effective personalized therapy in the future.

  3. A SNP based high-density linkage map of Apis cerana reveals a high recombination rate similar to Apis mellifera.

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    Yuan Yuan Shi

    Full Text Available BACKGROUND: The Eastern honey bee, Apis cerana Fabricius, is distributed in southern and eastern Asia, from India and China to Korea and Japan and southeast to the Moluccas. This species is also widely kept for honey production besides Apis mellifera. Apis cerana is also a model organism for studying social behavior, caste determination, mating biology, sexual selection, and host-parasite interactions. Few resources are available for molecular research in this species, and a linkage map was never constructed. A linkage map is a prerequisite for quantitative trait loci mapping and for analyzing genome structure. We used the Chinese honey bee, Apis cerana cerana to construct the first linkage map in the Eastern honey bee. RESULTS: F2 workers (N = 103 were genotyped for 126,990 single nucleotide polymorphisms (SNPs. After filtering low quality and those not passing the Mendel test, we obtained 3,000 SNPs, 1,535 of these were informative and used to construct a linkage map. The preliminary map contains 19 linkage groups, we then mapped the 19 linkage groups to 16 chromosomes by comparing the markers to the genome of A. mellfiera. The final map contains 16 linkage groups with a total of 1,535 markers. The total genetic distance is 3,942.7 centimorgans (cM with the largest linkage group (180 loci measuring 574.5 cM. Average marker interval for all markers across the 16 linkage groups is 2.6 cM. CONCLUSION: We constructed a high density linkage map for A. c. cerana with 1,535 markers. Because the map is based on SNP markers, it will enable easier and faster genotyping assays than randomly amplified polymorphic DNA or microsatellite based maps used in A. mellifera.

  4. Biomarkers for wound healing and their evaluation.

    Science.gov (United States)

    Patel, S; Maheshwari, A; Chandra, A

    2016-01-01

    A biological marker (biomarker) is a substance used as an indicator of biological state. Advances in genomics, proteomics and molecular pathology have generated many candidate biomarkers with potential clinical value. Research has identified several cellular events and mediators associated with wound healing that can serve as biomarkers. Macrophages, neutrophils, fibroblasts and platelets release cytokines molecules including TNF-α, interleukins (ILs) and growth factors, of which platelet-derived growth factor (PDGF) holds the greatest importance. As a result, various white cells and connective tissue cells release both matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs). Studies have demonstrated that IL-1, IL-6, and MMPs, levels above normal, and an abnormally high MMP/TIMP ratio are often present in non-healing wounds. Clinical examination of wounds for these mediators could predict which wounds will heal and which will not, suggesting use of these chemicals as biomarkers of wound healing. There is also evidence that the application of growth factors like PDGF will alleviate the recuperating process of chronic, non-healing wounds. Finding a specific biomarker for wound healing status would be a breakthrough in this field and helping treat impaired wound healing.

  5. Biomarkers in the Management of Difficult Asthma.

    Science.gov (United States)

    Schleich, Florence; Demarche, Sophie; Louis, Renaud

    2016-01-01

    Difficult asthma is a heterogeneous disease of the airways including various types of bronchial inflammation and various degrees of airway remodeling. Therapeutic response of severe asthmatics can be predicted by the use of biomarkers of Type2-high or Type2-low inflammation. Based on sputum cell analysis, four inflammatory phenotypes have been described. As induced sputum is timeconsuming and expensive technique, surrogate biomarkers are useful in clinical practice. Eosinophilic phenotype is likely to reflect ongoing adaptive immunity in response to allergen. Several biomarkers of eosinophilic asthma are easily available in clinical practice (blood eosinophils, serum IgE, exhaled nitric oxyde, serum periostin). Neutrophilic asthma is thought to reflect innate immune system activation in response to pollutants or infectious agents while paucigranulocytic asthma is thought to be not inflammatory and characterized by smooth muscle dysfunction. We currently lack of user-friendly biomarkers of neutrophilic asthma and airway remodeling. In this review, we summarize the biomarkers available for the management of difficult asthma.

  6. Network analysis identifies SOD2 mRNA as a potential biomarker for Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Jose A Santiago

    Full Text Available Increasing evidence indicates that Parkinson's disease (PD and type 2 diabetes (T2DM share dysregulated molecular networks. We identified 84 genes shared between PD and T2DM from curated disease-gene databases. Nitric oxide biosynthesis, lipid and carbohydrate metabolism, insulin secretion and inflammation were identified as common dysregulated pathways. A network prioritization approach was implemented to rank genes according to their distance to seed genes and their involvement in common biological pathways. Quantitative polymerase chain reaction assays revealed that a highly ranked gene, superoxide dismutase 2 (SOD2, is upregulated in PD patients compared to healthy controls in 192 whole blood samples from two independent clinical trials, the Harvard Biomarker Study (HBS and the Diagnostic and Prognostic Biomarkers in Parkinson's disease (PROBE. The results from this study reinforce the idea that shared molecular networks between PD and T2DM provides an additional source of biologically meaningful biomarkers. Evaluation of this biomarker in de novo PD patients and in a larger prospective longitudinal study is warranted.

  7. High-throughput sequence analysis reveals structural diversity and improved potency among RNA inhibitors of HIV reverse transcriptase.

    Science.gov (United States)

    Ditzler, Mark A; Lange, Margaret J; Bose, Debojit; Bottoms, Christopher A; Virkler, Katherine F; Sawyer, Andrew W; Whatley, Angela S; Spollen, William; Givan, Scott A; Burke, Donald H

    2013-02-01

    Systematic evolution of ligands through exponential enrichment (SELEX) is a well-established method for generating nucleic acid populations that are enriched for specified functions. High-throughput sequencing (HTS) enhances the power of comparative sequence analysis to reveal details of how RNAs within these populations recognize their targets. We used HTS analysis to evaluate RNA populations selected to bind type I human immunodeficiency virus reverse transcriptase (RT). The populations are enriched in RNAs of independent lineages that converge on shared motifs and in clusters of RNAs with nearly identical sequences that share common ancestry. Both of these features informed inferences of the secondary structures of enriched RNAs, their minimal structural requirements and their stabilities in RT-aptamer complexes. Monitoring population dynamics in response to increasing selection pressure revealed RNA inhibitors of RT that are more potent than the previously identified pseudoknots. Improved potency was observed for inhibition of both purified RT in enzymatic assays and viral replication in cell-based assays. Structural and functional details of converged motifs that are obscured by simple consensus descriptions are also revealed by the HTS analysis. The approach presented here can readily be generalized for the efficient and systematic post-SELEX development of aptamers for down-stream applications.

  8. Population genetic studies revealed local adaptation in a high gene-flow marine fish, the small yellow croaker (Larimichthys polyactis.

    Directory of Open Access Journals (Sweden)

    Le Wang

    Full Text Available The genetic differentiation of many marine fish species is low. Yet local adaptation may be common in marine fish species as the vast and changing marine environment provides more chances for natural selection. Here, we used anonymous as well as known protein gene linked microsatellites and mitochondrial DNA to detect the population structure of the small yellow croaker (Larimichthys polyactis in the Northwest Pacific marginal seas. Among these loci, we detected at least two microsatellites, anonymous H16 and HSP27 to be clearly under diversifying selection in outlier tests. Sequence cloning and analysis revealed that H16 was located in the intron of BAHCC1 gene. Landscape genetic analysis showed that H16 mutations were significantly associated with temperature, which further supported the diversifying selection at this locus. These marker types presented different patterns of population structure: (i mitochondrial DNA phylogeny showed no evidence of genetic divergence and demonstrated only one glacial linage; (ii population differentiation using putatively neutral microsatellites presented a pattern of high gene flow in the L. polyactis. In addition, several genetic barriers were identified; (iii the population differentiation pattern revealed by loci under diversifying selection was rather different from that revealed by putatively neutral loci. The results above suggest local adaptation in the small yellow croaker. In summary, population genetic studies based on different marker types disentangle the effects of demographic history, migration, genetic drift and local adaptation on population structure and also provide valuable new insights for the design of management strategies in L. polyactis.

  9. As if Biomarker Discovery Isn't Hard Enough: the Consequences of Poorly Characterized Reagents

    Energy Technology Data Exchange (ETDEWEB)

    Rodland, Karin D.

    2014-02-04

    The advent of high throughput omic technologies over the past two decades has driven a vast expansion in the search for clinical biomarkers, as manifested by the plethora of publications on biomarker discovery (over 8,600) listed on PubMed since 2000. Unfortunately, the same time period has seen a relative dearth of clinically validated biomarkers that have received FDA approval; only 10 new cancer biomarkers have been approved by the FDA in the same time period [1].

  10. Circulating (CD3−CD19+CD20−IgD−CD27highCD38high) Plasmablasts: A Promising Cellular Biomarker for Immune Activity for Anti-PLA2R1 Related Membranous Nephropathy?

    Science.gov (United States)

    Beukinga, Ingrid; Willard-Gallo, Karen; Nortier, Joëlle; Pradier, Olivier

    2016-01-01

    Membranous nephropathy (MN) is a kidney specific autoimmune disease mainly mediated by anti-phospholipase A2 receptor 1 autoantibody (PLA2R1 Ab). The adequate assessment of chimeric anti-CD20 monoclonal antibody, rituximab (RTX), efficacy is still needed to improve clinical outcome of patient with MN. We evaluated the modification of plasmablasts (CD3−CD19+CD20−IgD−CD27highCD38high), a useful biomarker of RTX response in other autoimmune diseases, and memory (CD3−CD19+CD20+IgD−CD27+CD38−) and naive (CD3−CD19+CD20+IgD+CD27−CD38low) B cells by fluorescence-activated cell sorter analysis in PLA2R1 related MN in one patient during the 4 years of follow-up after RTX. RTX induced complete disappearance of CD19+ B cells, plasmablasts, and memory B cells as soon as day 15. Despite severe CD19+ lymphopenia, plasmablasts and memory B cells reemerged early before naive B cells (days 45, 90, and 120, resp.). During the follow-up, plasmablasts decreased more rapidly than memory B cells but still remained elevated as compared to day 0 of RTX. Concomitantly, anti-PLA2R1 Ab increased progressively. Our single case report suggests that, besides monitoring of serum anti-PLA2R1 Ab level, enumeration of circulating plasmablasts and memory B cells represents an attractive and complementary tool to assess immunological activity and efficacy of RTX induced B cells depletion in anti-PLA2R1 Ab related MN. PMID:27493452

  11. Gene expression in the scleractinian Acropora microphthalma exposed to high solar irradiance reveals elements of photoprotection and coral bleaching.

    Directory of Open Access Journals (Sweden)

    Antonio Starcevic

    Full Text Available BACKGROUND: The success of tropical reef-building corals depends on the metabolic co-operation between the animal host and the photosynthetic performance of endosymbiotic algae residing within its cells. To examine the molecular response of the coral Acropora microphthalma to high levels of solar irradiance, a cDNA library was constructed by PCR-based suppression subtractive hybridisation (PCR-SSH from mRNA obtained by transplantation of a colony from a depth of 12.7 m to near-surface solar irradiance, during which the coral became noticeably paler from loss of endosymbionts in sun-exposed tissues. METHODOLOGY/PRINCIPAL FINDINGS: A novel approach to sequence annotation of the cDNA library gave genetic evidence for a hypothetical biosynthetic pathway branching from the shikimic acid pathway that leads to the formation of 4-deoxygadusol. This metabolite is a potent antioxidant and expected precursor of the UV-protective mycosporine-like amino acids (MAAs, which serve as sunscreens in coral phototrophic symbiosis. Empirical PCR based evidence further upholds the contention that the biosynthesis of these MAA sunscreens is a 'shared metabolic adaptation' between the symbiotic partners. Additionally, gene expression induced by enhanced solar irradiance reveals a cellular mechanism of light-induced coral bleaching that invokes a Ca(2+-binding synaptotagmin-like regulator of SNARE protein assembly of phagosomal exocytosis, whereby algal partners are lost from the symbiosis. CONCLUSIONS/SIGNIFICANCE: Bioinformatics analyses of DNA sequences obtained by differential gene expression of a coral exposed to high solar irradiance has revealed the identification of putative genes encoding key steps of the MAA biosynthetic pathway. Revealed also by this treatment are genes that implicate exocytosis as a cellular process contributing to a breakdown in the metabolically essential partnership between the coral host and endosymbiotic algae, which manifests as coral

  12. Accurate and High-Coverage Immune Repertoire Sequencing Reveals Characteristics of Antibody Repertoire Diversification in Young Children with Malaria

    Science.gov (United States)

    Jiang, Ning

    Accurately measuring the immune repertoire sequence composition, diversity, and abundance is important in studying repertoire response in infections, vaccinations, and cancer immunology. Using molecular identifiers (MIDs) to tag mRNA molecules is an effective method in improving the accuracy of immune repertoire sequencing (IR-seq). However, it is still difficult to use IR-seq on small amount of clinical samples to achieve a high coverage of the repertoire diversities. This is especially challenging in studying infections and vaccinations where B cell subpopulations with fewer cells, such as memory B cells or plasmablasts, are often of great interest to study somatic mutation patterns and diversity changes. Here, we describe an approach of IR-seq based on the use of MIDs in combination with a clustering method that can reveal more than 80% of the antibody diversity in a sample and can be applied to as few as 1,000 B cells. We applied this to study the antibody repertoires of young children before and during an acute malaria infection. We discovered unexpectedly high levels of somatic hypermutation (SHM) in infants and revealed characteristics of antibody repertoire development in young children that would have a profound impact on immunization in children.

  13. Genome-wide analysis of the world's sheep breeds reveals high levels of historic mixture and strong recent selection.

    Science.gov (United States)

    Kijas, James W; Lenstra, Johannes A; Hayes, Ben; Boitard, Simon; Porto Neto, Laercio R; San Cristobal, Magali; Servin, Bertrand; McCulloch, Russell; Whan, Vicki; Gietzen, Kimberly; Paiva, Samuel; Barendse, William; Ciani, Elena; Raadsma, Herman; McEwan, John; Dalrymple, Brian

    2012-02-01

    Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep populations contain high SNP diversity and have retained an effective population size much higher than most cattle or dog breeds, suggesting domestication occurred from a broad genetic base. Extensive haplotype sharing and generally low divergence time between breeds reveal frequent genetic exchange has occurred during the development of modern breeds. A scan of the genome for selection signals revealed 31 regions containing genes for coat pigmentation, skeletal morphology, body size, growth, and reproduction. We demonstrate the strongest selection signal has occurred in response to breeding for the absence of horns. The high density map of genetic variability provides an in-depth view of the genetic history for this important livestock species.

  14. Genome-wide analysis of the world's sheep breeds reveals high levels of historic mixture and strong recent selection.

    Directory of Open Access Journals (Sweden)

    James W Kijas

    2012-02-01

    Full Text Available Through their domestication and subsequent selection, sheep have been adapted to thrive in a diverse range of environments. To characterise the genetic consequence of both domestication and selection, we genotyped 49,034 SNP in 2,819 animals from a diverse collection of 74 sheep breeds. We find the majority of sheep populations contain high SNP diversity and have retained an effective population size much higher than most cattle or dog breeds, suggesting domestication occurred from a broad genetic base. Extensive haplotype sharing and generally low divergence time between breeds reveal frequent genetic exchange has occurred during the development of modern breeds. A scan of the genome for selection signals revealed 31 regions containing genes for coat pigmentation, skeletal morphology, body size, growth, and reproduction. We demonstrate the strongest selection signal has occurred in response to breeding for the absence of horns. The high density map of genetic variability provides an in-depth view of the genetic history for this important livestock species.

  15. High-Throughput siRNA Screening to Reveal GATA-2 Upstream Transcriptional Mechanisms in Hematopoietic Cells.

    Directory of Open Access Journals (Sweden)

    Yo Saito

    Full Text Available Hematopoietic stem cells can self-renew and differentiate into all blood cell types. The transcription factor GATA-2 is expressed in both hematopoietic stem and progenitor cells and is essential for cell proliferation, survival, and differentiation. Recently, evidence from studies of aplastic anemia, MonoMAC syndrome, and lung cancer has demonstrated a mechanistic link between GATA-2 and human pathophysiology. GATA-2-dependent disease processes have been extensively analyzed; however, the transcriptional mechanisms upstream of GATA-2 remain less understood. Here, we conducted high-throughput small-interfering-RNA (siRNA library screening and showed that YN-1, a human erythroleukemia cell line, expressed high levels of GATA-2 following the activation of the hematopoietic-specific 1S promoter. As transient luciferase reporter assay in YN-1 cells revealed the highest promoter activity in the 1S promoter fused with GATA-2 intronic enhancer (+9.9 kb/1S; therefore, we established a cell line capable of stably expressing +9.9 kb/1S-Luciferase. Subsequently, we screened 995 transcription factor genes and revealed that CITED2 acts as a GATA-2 activator in human hematopoietic cells. These results provide novel insights into and further identify the regulatory mechanism of GATA-2.

  16. High resolution genetic mapping by genome sequencing reveals genome duplication and tetraploid genetic structure of the diploid Miscanthus sinensis.

    Directory of Open Access Journals (Sweden)

    Xue-Feng Ma

    Full Text Available We have created a high-resolution linkage map of Miscanthus sinensis, using genotyping-by-sequencing (GBS, identifying all 19 linkage groups for the first time. The result is technically significant since Miscanthus has a very large and highly heterozygous genome, but has no or limited genomics information to date. The composite linkage map containing markers from both parental linkage maps is composed of 3,745 SNP markers spanning 2,396 cM on 19 linkage groups with a 0.64 cM average resolution. Comparative genomics analyses of the M. sinensis composite linkage map to the genomes of sorghum, maize, rice, and Brachypodium distachyon indicate that sorghum has the closest syntenic relationship to Miscanthus compared to other species. The comparative results revealed that each pair of the 19 M. sinensis linkages aligned to one sorghum chromosome, except for LG8, which mapped to two sorghum chromosomes (4 and 7, presumably due to a chromosome fusion event after genome duplication. The data also revealed several other chromosome rearrangements relative to sorghum, including two telomere-centromere inversions of the sorghum syntenic chromosome 7 in LG8 of M. sinensis and two paracentric inversions of sorghum syntenic chromosome 4 in LG7 and LG8 of M. sinensis. The results clearly demonstrate, for the first time, that the diploid M. sinensis is tetraploid origin consisting of two sub-genomes. This complete and high resolution composite linkage map will not only serve as a useful resource for novel QTL discoveries, but also enable informed deployment of the wealth of existing genomics resources of other species to the improvement of Miscanthus as a high biomass energy crop. In addition, it has utility as a reference for genome sequence assembly for the forthcoming whole genome sequencing of the Miscanthus genus.

  17. MicroRNAs as potential biomarkers in malignant pleural mesothelioma

    Directory of Open Access Journals (Sweden)

    Santoni-Rugiu E

    2015-12-01

    Full Text Available Eric Santoni-Rugiu, Morten Andersen, Morten Grauslund Laboratory of Molecular Pathology, Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Abstract: Malignant pleural mesothelioma (MPM, a highly lethal cancer strictly related to asbestos exposure, is usually characterized by delayed diagnosis, resistance to current therapies, and dismal prognosis. MPM is difficult to distinguish histologically from nonmalignant reactive mesothelial proliferations (RMPs as there are no clinically validated immunohistochemical markers yet and the main diagnostic criterion remains deep invasion into the pleura and underlying fat tissue, which is often not appreciable in small pleural biopsies. In this regard, microRNAs (miRNAs, given their size and stability, are particularly attractive biomarkers in formalin-fixed paraffin-embedded tissue specimens for routine pathology. Moreover, circulating miRNAs appear to be promising biomarkers for early detection and monitoring of patients with MPM. Here, we review the studies mostly performed by miRNA arrays and reverse transcription-quantitative polymerase chain reaction in formalin-fixed paraffin-embedded or frozen tissue samples, MPM cell lines, and blood/plasma/serum samples that have highlighted the potential of miRNAs as biomarkers in MPM. Certain studies have pointed to the ability of miRNAs to distinguish the different histological MPM subtypes or separate MPM from lung adenocarcinoma, and other investigations have revealed that miRNAs can aid in differentiating MPM from RMP or have prognostic value in predicting the patient outcome. Mechanistic aspects of the involvement of miRNAs in mesothelioma genesis and possible use of miRNAs as future therapeutic targets in MPM are also emphasized. Finally, limitations of the data currently obtained due to the drawbacks of reverse transcription-quantitative polymerase chain reaction, heterogeneity of MPM tissue samples, and

  18. Post-glacial variability of sea ice cover, river run-off and biological production in the western Laptev Sea (Arctic Ocean) - A high-resolution biomarker study

    Science.gov (United States)

    Hörner, T.; Stein, R.; Fahl, K.; Birgel, D.

    2016-07-01

    Multi-proxy biomarker measurements were applied on two sediment cores (PS51/154, PS51/159) to reconstruct sea ice cover (IP25), biological production (brassicasterol, dinosterol) and river run-off (campesterol, β-sitosterol) in the western Laptev Sea over the last ∼17 ka with unprecedented temporal resolution. The absence of IP25 from 17.2 to 15.5 ka, in combination with minimum concentration of phytoplankton biomarkers, suggests that the western Laptev Sea shelf was mostly covered with permanent sea ice. Very minor river run-off and restricted biological production occurred during this cold interval. From ∼16 ka until 7.5 ka, a long-term decrease of terrigenous (riverine) organic matter and a coeval increase of marine organic matter reflect the gradual establishment of fully marine conditions in the western Laptev Sea, caused by the onset of the post-glacial transgression. Intensified river run-off and reduced sea ice cover characterized the time interval between 15.2 and 12.9 ka, including the Bølling/Allerød warm period (14.7-12.9 ka). Prominent peaks of the DIP25 Index coinciding with maximum abundances of subpolar foraminifers, are interpreted as pulses of Atlantic water inflow on the western Laptev Sea shelf. After the warm period, a sudden return to severe sea ice conditions with strongest ice-coverage between 11.9 and 11 ka coincided with the Younger Dryas (12.9-11.6 ka). At the onset of the Younger Dryas, a distinct alteration of the ecosystem (reflected in a distinct drop in terrigenous and phytoplankton biomarkers) was detected. During the last 7 ka, the sea ice proxies reflect a cooling of the Laptev Sea spring/summer season. This cooling trend was superimposed by a short-term variability in sea ice coverage, probably representing Bond cycles (1500 ± 500 ka) that are related to solar activity changes. Hence, atmospheric circulation changes were apparently able to affect the sea ice conditions on the Laptev Sea shelf under modern sea level

  19. High Throughput ELISAs to Measure a Unique Glycan on Transferrin in Cerebrospinal Fluid: A Possible Extension toward Alzheimer's Disease Biomarker Development

    Directory of Open Access Journals (Sweden)

    Keiro Shirotani

    2011-01-01

    Full Text Available We have established high-throughput lectin-antibody ELISAs to measure different glycans on transferrin (Tf in cerebrospinal fluid (CSF using lectins and an anti-transferrin antibody (TfAb. Lectin blot and precipitation analysis of CSF revealed that PVL (Psathyrella velutina lectin bound an unique N-acetylglucosamine-terminated N-glycans on “CSF-type” Tf whereas SSA (Sambucus sieboldiana agglutinin bound α2,6-N-acetylneuraminic acid-terminated N-glycans on “serum-type” Tf. PVL-TfAb ELISA of 0.5 μL CSF samples detected “CSF-type” Tf but not “serum-type” Tf whereas SSA-TfAb ELISA detected “serum-type” Tf but not “CSF-type” Tf, demonstrating the specificity of the lectin-TfAb ELISAs. In idiopathic normal pressure hydrocephalus (iNPH, a senile dementia associated with ventriculomegaly, amounts of the SSA-reactive Tf were significantly higher than in non-iNPH patients, indicating that Tf glycan analysis by the high-throughput lectin-TfAb ELISAs could become practical diagnostic tools for iNPH. The lectin-antibody ELISAs of CSF proteins might be useful for diagnosis of the other neurological diseases.

  20. IDBD: infectious disease biomarker database.

    Science.gov (United States)

    Yang, In Seok; Ryu, Chunsun; Cho, Ki Joon; Kim, Jin Kwang; Ong, Swee Hoe; Mitchell, Wayne P; Kim, Bong Su; Oh, Hee-Bok; Kim, Kyung Hyun

    2008-01-01

    Biomarkers enable early diagnosis, guide molecularly targeted therapy and monitor the activity and therapeutic responses across a variety of diseases. Despite intensified interest and research, however, the overall rate of development of novel biomarkers has been falling. Moreover, no solution is yet available that efficiently retrieves and processes biomarker information pertaining to infectious diseases. Infectious Disease Biomarker Database (IDBD) is one of the first efforts to build an easily accessible and comprehensive literature-derived database covering known infectious disease biomarkers. IDBD is a community annotation database, utilizing collaborative Web 2.0 features, providing a convenient user interface to input and revise data online. It allows users to link infectious diseases or pathogens to protein, gene or carbohydrate biomarkers through the use of search tools. It supports various types of data searches and application tools to analyze sequence and structure features of potential and validated biomarkers. Currently, IDBD integrates 611 biomarkers for 66 infectious diseases and 70 pathogens. It is publicly accessible at http://biomarker.cdc.go.kr and http://biomarker.korea.ac.kr.

  1. Scrutinizing the Biomarkers for the Neglected Chagas Disease: How Remarkable!

    Science.gov (United States)

    Pinho, Rosa T.; Waghabi, Mariana C.; Cardillo, Fabíola; Mengel, José; Antas, Paulo R. Z.

    2016-01-01

    Biomarkers or biosignature profiles have become accessible over time in population-based studies for Chagas disease. Thus, the identification of consistent and reliable indicators of the diagnosis and prognosis of patients with heart failure might facilitate the prioritization of therapeutic management to those with the highest chance of contracting this disease. The purpose of this paper is to review the recent state and the upcoming trends in biomarkers for human Chagas disease. As an emerging concept, we propose a classification of biomarkers based on plasmatic-, phenotype-, antigenic-, genetic-, and management-related candidates. The available data revisited here reveal the lessons learned thus far and the existing challenges that still lie ahead to enable biomarkers to be employed consistently in risk evaluation for this disease. There is a strong need for biomarker validation, particularly for biomarkers that are specific to the clinical forms of Chagas disease. The current failure to achieve the eradication of the transmission of this disease has produced determination to solve this validation issue. Finally, it would be strategic to develop a wide variety of biomarkers and to test them in both preclinical and clinical trials. PMID:27563302

  2. High dose trans-10,cis-12 CLA increases lean body mass in hamsters, but elevates levels of plasma lipids and liver enzyme biomarkers.

    Science.gov (United States)

    Liu, Xiaoran; Joseph, Shama V; Wakefield, Andrew P; Aukema, Harold M; Jones, Peter J H

    2012-01-01

    The current study examined the efficacy of graded doses of c9,t11 and t10,c12 CLA isomers on body composition, energy expenditure, hepatic and serum lipid liver biomarkers in hamsters. Animals (n = 105) were randomized to seven treatments (control, 1, 2, 3% of c9,t11; 1, 2, 3% of t10,c12) for 28 days. After 28 days treatment, 1-3% of t10,c12 lowered (p CLA isomers. The 2%, 3% t10,c12 groups presented elevated (p CLA lowered (p CLA has less potent actions than t10,c12 CLA. We conclude that the actions of CLA on energy and lipid metabolism are form and dose dependent in the hamster model.

  3. Differential Proteomic Analysis by iTRAQ Reveals the Mechanism of Pyropia haitanensis Responding to High Temperature Stress

    Science.gov (United States)

    Shi, Jianzhi; Chen, Yuting; Xu, Yan; Ji, Dehua; Chen, Changsheng; Xie, Chaotian

    2017-01-01

    Global warming increases sea temperature and leads to high temperature stress, which affects the yield and quality of Pyropia haitanensis. To understand the molecular mechanisms underlying high temperature stress in a high temperature tolerance strain Z-61, the iTRAQ technique was employed to reveal the global proteomic response of Z-61 under different durations of high temperature stress. We identified 151 differentially expressed proteins and classified them into 11 functional categories. The 4 major categories of these are protein synthesis and degradation, photosynthesis, defense response, and energy and carbohydrate metabolism. These findings indicated that photosynthesis, protein synthesis, and secondary metabolism are inhibited by heat to limit damage to a repairable level. As time progresses, misfolded proteins and ROS accumulate and lead to the up-regulation of molecular chaperones, proteases, and antioxidant systems. Furthermore, to cope with cells injured by heat, PCD works to remove them. Additionally, sulfur assimilation and cytoskeletons play essential roles in maintaining cellular and redox homeostasis. These processes are based on signal transduction in the phosphoinositide pathway and multiple ways to supply energy. Conclusively, Z-61 establishes a new steady-state balance of metabolic processes and survives under higher temperature stress. PMID:28303955

  4. Urinary Sugars--A Biomarker of Total Sugars Intake.

    Science.gov (United States)

    Tasevska, Natasha

    2015-07-01

    Measurement error in self-reported sugars intake may explain the lack of consistency in the epidemiologic evidence on the association between sugars and disease risk. This review describes the development and applications of a biomarker of sugars intake, informs its future use and recommends directions for future research. Recently, 24 h urinary sucrose and fructose were suggested as a predictive biomarker for total sugars intake, based on findings from three highly controlled feeding studies conducted in the United Kingdom. From this work, a calibration equation for the biomarker that provides an unbiased measure of sugars intake was generated that has since been used in two US-based studies with free-living individuals to assess measurement error in dietary self-reports and to develop regression calibration equations that could be used in future diet-disease analyses. Further applications of the biomarker include its use as a surrogate measure of intake in diet-disease association studies. Although this biomarker has great potential and exhibits favorable characteristics, available data come from a few controlled studies with limited sample sizes conducted in the UK. Larger feeding studies conducted in different populations are needed to further explore biomarker characteristics and stability of its biases, compare its performance, and generate a unique, or population-specific biomarker calibration equations to be applied in future studies. A validated sugars biomarker is critical for informed interpretation of sugars-disease association studies.

  5. Chiral Biomarkers and Microfossils in Carbonaceous Meteorites

    Science.gov (United States)

    Hoover, Richard B.

    2010-01-01

    Homochirality of the biomolecules (D-sugars of DNA and RNA and L-amino acids of proteins) is a fundamental property of all life on Earth. Abiotic mechanisms yield racemic mixtures (D/L=1) of chiral molecules and after the death of an organism, the enantiopure chiral biomolecules slowly racemize. Several independent investigators have now established that the amino acids present in CI1 and CM2 carbonaceous meteorites have a moderate to strong excess of the L-enantiomer. Stable isotope data have established that these amino acids are both indigenous and extraterrestrial. Carbonaceous meteorites also contain many other strong chemical biomarkers including purines and pyrimidines (nitrogen heterocycles of nucleic acids); pristine and phytane (components of the chlorophyll pigment) and morphological biomarkers (microfossils of filamentous cyanobacteria). Energy dispersive X-ray Spectroscopy (EDS) analysis reveals that nitrogen is below the detectability level in most of the meteorite filaments as well as in Cambrian Trilobites and filaments of 2.7 Gya Archaean cyanobacteria from Karelia. The deficiency of nitrogen in the filaments and the total absence of sugars, of twelve of the life-critical protein amino acids, and two of the nucleobases of DNA and RNA provide clear and convincing evidence that these filaments are not modern biological contaminants. This paper reviews the chiral, chemical biomarkers morphological biomarkers and microfossils in carbonaceous meteorites. This paper reviews chiral and morphological biomarkers and discusses the missing nitrogen, sugars, protein amino acids, and nucleobases as ?bio-discriminators? that exclude modern biological contaminants as a possible explanation for the permineralized cyanobacterial filaments found in the meteorites.

  6. Exploration of new HCC biomarkers

    Directory of Open Access Journals (Sweden)

    Regina M. Santella

    2007-02-01

    Full Text Available

    Analysis of plasma/serum for levels of viral antigens or antibodies to viral proteins has been used extensively as an early biomarker of potential risk of HCC. In addition, detection of elevated levels of alpha-fetoprotein is commonly used for early identification of HCC. Unfortunately, both of these approaches are not highly sensitive or specific. As a result, there is continuing investigation to identify additional biomarkers that may help in the early identification of cases. The use of DNA isolated from plasma or serum for detection of gene specific methylation has been discussed previously. In addition, tumor DNA isolated from blood has been analyzed for the presence of p53 mutations and found in a subset of cases to be present years prior to diagnosis as for methylated DNA. The general level of DNA present in blood has also been suggested as a potential biomarker of cancer.

    Among the newer methods being tested are the detection of specific mutations in HBV. In many cases of HCC in China and Africa a double mutation, an A to T transversion at nucleotide 1762 and a G to A transition at nucleotide 1764 (1762T/1764A have been found. These mutations have been associated with increased severity of HBV infection and cirrhosis suggesting that they might be a useful biomarker for high risk subjects.

    The field of proteomics also holds promise for the development of new biomarkers. A number of groups are developing mass spectrometry methods for the identification of serum/plasma proteomic patterns that will distinguish bloods of HCC cases from those of controls. While some interesting preliminary data have been developed for several cancers, much additional work needs to be done in this area

  7. Liquid chromatography-high resolution mass spectrometry with immunoaffinity clean-up for the determination of the oxidative stress biomarker 8-iso-prostaglandin F2alpha in wastewater.

    Science.gov (United States)

    Ryu, Yeonsuk; Reid, Malcolm J; Thomas, Kevin V

    2015-08-28

    A reliable oxidative stress biomarker, 8-iso-prostaglandin F2α (8-iso-PGF2α), was for the first time quantitatively analysed in wastewater using an analytical method consisting of liquid chromatography-high resolution mass spectrometry coupled to immunoaffinity clean-up (IAC-LC-HRMS). Factors influencing the method's robustness were investigated, including analyte stability in sewage and enzymatic deconjugation with β-glucuronidase. The IAC-LC-HRMS method was linear over the range of 0.1-100ng/mL with correlation coefficient (R(2)) of 0.999. The quantification limits were sufficiently low to detect 8-iso-PGF2α in sewage (method quantification limit of 0.3ng/L) and precision, expressed as relative standard deviation was less than 7% and the accuracy expressed as relative recovery was in the 103-113% range. As a result, the application of the method to 24-h composite wastewater samples from Oslo showed 8-iso-PGF2α concentrations of 18.9-23.3ng/L for 8 days in March 2015. This study demonstrates a standard method to analyse 8-iso-PGF2α in sewage that will contribute to the further investigation of the potential use of 8-iso-PGF2α as a sewage biomarker for assessing the status of community health.

  8. Molecular Techniques Revealed Highly Diverse Microbial Communities in Natural Marine Biofilms on Polystyrene Dishes for Invertebrate Larval Settlement

    KAUST Repository

    Lee, On On

    2014-01-09

    Biofilm microbial communities play an important role in the larval settlement response of marine invertebrates. However, the underlying mechanism has yet to be resolved, mainly because of the uncertainties in characterizing members in the communities using traditional 16S rRNA gene-based molecular methods and in identifying the chemical signals involved. In this study, pyrosequencing was used to characterize the bacterial communities in intertidal and subtidal marine biofilms developed during two seasons. We revealed highly diverse biofilm bacterial communities that varied with season and tidal level. Over 3,000 operational taxonomic units with estimates of up to 8,000 species were recovered in a biofilm sample, which is by far the highest number recorded in subtropical marine biofilms. Nineteen phyla were found, of which Cyanobacteria and Proteobacteria were the most dominant one in the intertidal and subtidal biofilms, respectively. Apart from these, Actinobacteria, Bacteroidetes, and Planctomycetes were the major groups recovered in both intertidal and subtidal biofilms, although their relative abundance varied among samples. Full-length 16S rRNA gene clone libraries were constructed for the four biofilm samples and showed similar bacterial compositions at the phylum level to those revealed by pyrosequencing. Laboratory assays confirmed that cyrids of the barnacle Balanus amphitrite preferred to settle on the intertidal rather than subtidal biofilms. This preference was independent of the biofilm bacterial density or biomass but was probably related to the biofilm community structure, particularly, the Proteobacterial and Cyanobacterial groups. © 2014 Springer Science+Business Media New York.

  9. The spider hemolymph clot proteome reveals high concentrations of hemocyanin and von Willebrand factor-like proteins.

    Science.gov (United States)

    Sanggaard, Kristian W; Dyrlund, Thomas F; Bechsgaard, Jesper S; Scavenius, Carsten; Wang, Tobias; Bilde, Trine; Enghild, Jan J

    2016-02-01

    Arthropods include chelicerates, crustaceans, and insects that all have open circulation systems and thus require different properties of their coagulation system than vertebrates. Although the clotting reaction in the chelicerate horseshoe crab (Family: Limulidae) has been described in details, the overall protein composition of the resulting clot has not been analyzed for any of the chelicerates. The largest class among the chelicerates is the arachnids, which includes spiders, ticks, mites, and scorpions. Here, we use a mass spectrometry-based approach to characterize the spider hemolymph clot proteome from the Brazilian whiteknee tarantula, Acanthoscurria geniculata. We focused on the insoluble part of the clot and demonstrated high concentrations of proteins homologous to the hemostasis-related and multimerization-prone von Willebrand factor. These proteins, which include hemolectins and vitellogenin homologous, were previously identified as essential components of the hemolymph clot in crustaceans and insects. Their presence in the spider hemolymph clot suggests that the origin of these proteins' function in coagulation predates the split between chelicerates and mandibulata. The clot proteome reveals that the major proteinaceous component is the oxygen-transporting and phenoloxidase-displaying abundant hemolymph protein hemocyanin, suggesting that this protein also plays a role in clot biology. Furthermore, quantification of the peptidome after coagulation revealed the simultaneous activation of both the innate immune system and the coagulation system. In general, many of the identified clot-proteins are related to the innate immune system, and our results support the previously suggested crosstalk between immunity and coagulation in arthropods.

  10. A Comparative Analysis of Biomarker Selection Techniques

    Directory of Open Access Journals (Sweden)

    Nicoletta Dessì

    2013-01-01

    Full Text Available Feature selection has become the essential step in biomarker discovery from high-dimensional genomics data. It is recognized that different feature selection techniques may result in different set of biomarkers, that is, different groups of genes highly correlated to a given pathological condition, but few direct comparisons exist which quantify these differences in a systematic way. In this paper, we propose a general methodology for comparing the outcomes of different selection techniques in the context of biomarker discovery. The comparison is carried out along two dimensions: (i measuring the similarity/dissimilarity of selected gene sets; (ii evaluating the implications of these differences in terms of both predictive performance and stability of selected gene sets. As a case study, we considered three benchmarks deriving from DNA microarray experiments and conducted a comparative analysis among eight selection methods, representatives of different classes of feature selection techniques. Our results show that the proposed approach can provide useful insight about the pattern of agreement of biomarker discovery techniques.

  11. Primary Sjӧgren's syndrome: Clinical phenotypes, outcome and the development of biomarkers.

    Science.gov (United States)

    Goules, Andreas V; Tzioufas, Athanasios G

    2016-07-01

    Primary Sjӧgren's syndrome (pSS) is a complex autoimmune disease with distinct clinical phenotypes and variable outcomes. The systemic form of the disease is characterized by immune complex mediated manifestations and is complicated by lymphoma as a result of a polyclonal B cell hyperactivity that is evolving into B cell malignancy. In the past decades, well-established clinical and serological markers have been described in the literature to identify high-risk patients and to predict lymphoma development. However, specific biologic treatments have proven ineffective to control the disease. Significant research effort has been made to reveal the major underlying biological events in this subgroup and identify biomarkers for early diagnosis, prognosis and response to treatment. In this review, we summarize the current data for the proposed histological, molecular and genetic biomarkers.

  12. Relationship between inflammatory and coagulation biomarkers and cardiac autonomic function in HIV-infected individuals

    DEFF Research Database (Denmark)

    Young, Lari C; Roediger, Mollie P; Grandits, Greg;

    2014-01-01

    AIM: To examine the relationship between inflammatory and coagulation biomarkers and cardiac autonomic function (CAF) as measured by heart rate variability in persons with HIV. MATERIALS & METHODS: This analysis included 4073 HIV-infected persons from the Strategies for Management of Antiretroviral...... Therapy study. We examined the association between IL-6, high-sensitivity C-reactive protein (hsCRP) and D-dimer with heart rate variability measures (SDNN and rMSSD), both cross-sectionally and longitudinally. RESULTS: Cross-sectional analysis revealed significant inverse associations between IL-6, hs......CRP and d-dimer with SDNN and rMSSD (p longitudinal analysis failed to show a significant association between baseline IL-6, hsCRP and d-dimer with change in CAF over time. CONCLUSION: Cross-sectionally, higher levels of inflammatory and coagulation biomarkers were...

  13. High-Resolution Profiling of Drosophila Replication Start Sites Reveals a DNA Shape and Chromatin Signature of Metazoan Origins

    Directory of Open Access Journals (Sweden)

    Federico Comoglio

    2015-05-01

    Full Text Available At every cell cycle, faithful inheritance of metazoan genomes requires the concerted activation of thousands of DNA replication origins. However, the genetic and chromatin features defining metazoan replication start sites remain largely unknown. Here, we delineate the origin repertoire of the Drosophila genome at high resolution. We address the role of origin-proximal G-quadruplexes and suggest that they transiently stall replication forks in vivo. We dissect the chromatin configuration of replication origins and identify a rich spatial organization of chromatin features at initiation sites. DNA shape and chromatin configurations, not strict sequence motifs, mark and predict origins in higher eukaryotes. We further examine the link between transcription and origin firing and reveal that modulation of origin activity across cell types is intimately linked to cell-type-specific transcriptional programs. Our study unravels conserved origin features and provides unique insights into the relationship among DNA topology, chromatin, transcription, and replication initiation across metazoa.

  14. High-resolution profiling of Drosophila replication start sites reveals a DNA shape and chromatin signature of metazoan origins.

    Science.gov (United States)

    Comoglio, Federico; Schlumpf, Tommy; Schmid, Virginia; Rohs, Remo; Beisel, Christian; Paro, Renato

    2015-05-05

    At every cell cycle, faithful inheritance of metazoan genomes requires the concerted activation of thousands of DNA replication origins. However, the genetic and chromatin features defining metazoan replication start sites remain largely unknown. Here, we delineate the origin repertoire of the Drosophila genome at high resolution. We address the role of origin-proximal G-quadruplexes and suggest that they transiently stall replication forks in vivo. We dissect the chromatin configuration of replication origins and identify a rich spatial organization of chromatin features at initiation sites. DNA shape and chromatin configurations, not strict sequence motifs, mark and predict origins in higher eukaryotes. We further examine the link between transcription and origin firing and reveal that modulation of origin activity across cell types is intimately linked to cell-type-specific transcriptional programs. Our study unravels conserved origin features and provides unique insights into the relationship among DNA topology, chromatin, transcription, and replication initiation across metazoa.

  15. Visualization of multivalent histone modification in a single cell reveals highly concerted epigenetic changes on differentiation of embryonic stem cells

    DEFF Research Database (Denmark)

    Hattori, Naoko; Niwa, Tohru; Kimura, Kana;

    2013-01-01

    Combinations of histone modifications have significant biological roles, such as maintenance of pluripotency and cancer development, but cannot be analyzed at the single cell level. Here, we visualized a combination of histone modifications by applying the in situ proximity ligation assay, which....... Bivalent modification was clearly visualized by iChmo in wild-type embryonic stem cells (ESCs) known to have it, whereas rarely in Suz12 knockout ESCs and mouse embryonic fibroblasts known to have little of it. iChmo was applied to analysis of epigenetic and phenotypic changes of heterogeneous cell...... population, namely, ESCs at an early stage of differentiation, and this revealed that the bivalent modification disappeared in a highly concerted manner, whereas phenotypic differentiation proceeded with large variations among cells. Also, using this method, we were able to visualize a combination...

  16. A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures.

    Science.gov (United States)

    Wong, Michael Thomas; Ong, David Eng Hui; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Henry Kun Kiaang; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng-Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Curotto de Lafaille, Maria Alicia; Newell, Evan William

    2016-08-16

    Depending on the tissue microenvironment, T cells can differentiate into highly diverse subsets expressing unique trafficking receptors and cytokines. Studies of human lymphocytes have primarily focused on a limited number of parameters in blood, representing an incomplete view of the human immune system. Here, we have utilized mass cytometry to simultaneously analyze T cell trafficking and functional markers across eight different human tissues, including blood, lymphoid, and non-lymphoid tissues. These data have revealed that combinatorial expression of trafficking receptors and cytokines better defines tissue specificity. Notably, we identified numerous T helper cell subsets with overlapping cytokine expression, but only specific cytokine combinations are secreted regardless of tissue type. This indicates that T cell lineages defined in mouse models cannot be clearly distinguished in humans. Overall, our data uncover a plethora of tissue immune signatures and provide a systemic map of how T cell phenotypes are altered throughout the human body.

  17. High-throughput engineering of a mammalian genome reveals building principles of methylation states at CG rich regions.

    Science.gov (United States)

    Krebs, Arnaud R; Dessus-Babus, Sophie; Burger, Lukas; Schübeler, Dirk

    2014-09-26

    The majority of mammalian promoters are CpG islands; regions of high CG density that require protection from DNA methylation to be functional. Importantly, how sequence architecture mediates this unmethylated state remains unclear. To address this question in a comprehensive manner, we developed a method to interrogate methylation states of hundreds of sequence variants inserted at the same genomic site in mouse embryonic stem cells. Using this assay, we were able to quantify the contribution of various sequence motifs towards the resulting DNA methylation state. Modeling of this comprehensive dataset revealed that CG density alone is a minor determinant of their unmethylated state. Instead, these data argue for a principal role for transcription factor binding sites, a prediction confirmed by testing synthetic mutant libraries. Taken together, these findings establish the hierarchy between the two cis-encoded mechanisms that define the DNA methylation state and thus the transcriptional competence of CpG islands.

  18. Structural properties of GaN(0001) epitaxial layers revealed by high resolution X-ray diffraction

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    High-resolution X-ray diffraction has been used to analyze GaN(0001) epitaxial layers on sapphire substrates. Several structural properties of GaN, including the lattice constants, strains, and dislocation densities are revealed by the technique of X-ray dffraction (XRD). Lattice constants calculated from the omega/2theta scan are c=0.5185 nm and a=0.3157 nm. Also, the in-plane strain is -1.003%, while out of the plane, the epitaxial film is almost relaxed. Several methods are used to deduce the mosaicity and dislocation density of GaN, showing that the edge type dislocations are the overwhelming majority.

  19. MicroRNA expression profiling in skeletal muscle reveals different regulatory patterns in high and low responders to resistance training.

    Science.gov (United States)

    Ogasawara, Riki; Akimoto, Takayuki; Umeno, Tokushi; Sawada, Shuji; Hamaoka, Takafumi; Fujita, Satoshi

    2016-04-01

    Large variability exists in muscle adaptive response to resistance exercise (RE) training between individuals. Recent studies have revealed a significant role for microRNAs (miRNAs) in skeletal muscle plasticity. In this study, we investigated how RE affects miRNA expression and whether the variability of muscle hypertrophy to RE training may be attributed to differential miRNA regulation in the skeletal muscle. To screen high and low responders to RE, we had 18 young men perform arm curl exercise training. After screening, all the men performed 12 wk of lower body RE training, but only the high or low responders participated in the acute RE test before training. Muscle biopsies were obtained from the vastus lateralis muscle at baseline, 3 h after acute RE, and after the training period. Total RNA was extracted from the skeletal muscle, and miRNA expression (800 miRNAs) was analyzed. RE training increased the cross-sectional area of the biceps brachii (-1.7-26.1%), quadriceps (2.2-16.8%), and hamstrings (1.6-18.4%). Eighty-five and 102 miRNAs were differentially expressed after acute and chronic RE, respectively (P muscle between high and low responders, indicating that the expression patterns of several miRNAs are altered by acute or chronic RE, and that miRNAs are involved in skeletal muscle adaptation to RE training.

  20. High-throughput cell-based screening reveals a role for ZNF131 as a repressor of ERalpha signaling

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    Du Peige

    2008-10-01

    Full Text Available Abstract Background Estrogen receptor α (ERα is a transcription factor whose activity is affected by multiple regulatory cofactors. In an effort to identify the human genes involved in the regulation of ERα, we constructed a high-throughput, cell-based, functional screening platform by linking a response element (ERE with a reporter gene. This allowed the cellular activity of ERα, in cells cotransfected with the candidate gene, to be quantified in the presence or absence of its cognate ligand E2. Results From a library of 570 human cDNA clones, we identified zinc finger protein 131 (ZNF131 as a repressor of ERα mediated transactivation. ZNF131 is a typical member of the BTB/POZ family of transcription factors, and shows both ubiquitous expression and a high degree of sequence conservation. The luciferase reporter gene assay revealed that ZNF131 inhibits ligand-dependent transactivation by ERα in a dose-dependent manner. Electrophoretic mobility shift assay clearly demonstrated that the interaction between ZNF131 and ERα interrupts or prevents ERα binding to the estrogen response element (ERE. In addition, ZNF131 was able to suppress the expression of pS2, an ERα target gene. Conclusion We suggest that the functional screening platform we constructed can be applied for high-throughput genomic screening candidate ERα-related genes. This in turn may provide new insights into the underlying molecular mechanisms of ERα regulation in mammalian cells.

  1. AstroSat/LAXPC reveals the high energy variability of GRS 1915+105 in the chi class

    CERN Document Server

    Yadav, J S; Chauhan, Jai Verdhan; Agrawal, P C; Antia, H M; Pahari, Mayukh; Dedhia, Dhiraj; Katoch, Tilak; Madhwani, P; Manchanda, R K; Paul, B; Shah, Parag; Ishwara-Chandra, C H

    2016-01-01

    We present the first quick look analysis of data from nine {\\it AstroSat}'s LAXPC observations of GRS 1915+105 during March 2016 when the source had the characteristics of being in Radio-quiet $\\chi$ class. We find that a simple empirical model of a disk blackbody emission, with Comptonization and a broad Gaussian Iron line can fit the time averaged 3--80 keV spectrum with a systematic uncertainty of 1.5\\% and a background flux uncertainty of 4\\%. A simple deadtime-corrected Poisson noise level spectrum matches well with the observed high frequency power spectra till 50 kHz and as expected the data show no significant high frequency ($> 20$ Hz) features. Energy dependent power spectra reveal a strong low frequency (2 - 8 Hz) Quasi-periodic oscillation (LFQPO) and its harmonic along with broad band noise. The QPO frequency changes rapidly with flux (nearly 4 Hz in ~ 5 hours). With increasing QPO frequency, an excess noise component appears significantly in the high energy regime (> 8 keV). At the QPO frequenci...

  2. Not all are free-living: high-throughput DNA metabarcoding reveals a diverse community of protists parasitizing soil metazoa.

    Science.gov (United States)

    Geisen, S; Laros, I; Vizcaíno, A; Bonkowski, M; de Groot, G A

    2015-09-01

    Protists, the most diverse eukaryotes, are largely considered to be free-living bacterivores, but vast numbers of taxa are known to parasitize plants or animals. High-throughput sequencing (HTS) approaches now commonly replace cultivation-based approaches in studying soil protists, but insights into common biases associated with this method are limited to aquatic taxa and samples. We created a mock community of common free-living soil protists (amoebae, flagellates, ciliates), extracted DNA and amplified it in the presence of metazoan DNA using 454 HTS. We aimed at evaluating whether HTS quantitatively reveals true relative abundances of soil protists and at investigating whether the expected protist community structure is altered by the co-amplification of metazoan-associated protist taxa. Indeed, HTS revealed fundamentally different protist communities from those expected. Ciliate sequences were highly over-represented, while those of most amoebae and flagellates were under-represented or totally absent. These results underpin the biases introduced by HTS that prevent reliable quantitative estimations of free-living protist communities. Furthermore, we detected a wide range of nonadded protist taxa probably introduced along with metazoan DNA, which altered the protist community structure. Among those, 20 taxa most closely resembled parasitic, often pathogenic taxa. Therewith, we provide the first HTS data in support of classical observational studies that showed that potential protist parasites are hosted by soil metazoa. Taken together, profound differences in amplification success between protist taxa and an inevitable co-extraction of protist taxa parasitizing soil metazoa obscure the true diversity of free-living soil protist communities.

  3. Association of Lipids with Oxidative Stress Biomarkers in Subclinical Hypothyroidism

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    Adriana Santi

    2012-01-01

    Full Text Available Objective. The aim of the present study was to evaluate the oxidative stress biomarkers in patients with subclinical hypothyroidism (n=20 and health controls (n=20. Subjects and Methods. Total cholesterol (TC, triglycerides (TGs, low-density lipoprotein-cholesterol (LDL-C, high-density lipoprotein cholesterol (HDL-C, thiobarbituric acid reactive substances (TBARSs, catalase (CAT, superoxide dismutase (SOD, and arylesterase (ARE were analyzed. Results. TC, LDL-C, TBARS, and CAT were higher in subclinical hypothyroidism patients, whereas SOD did not change. Arylesterase activity was significantly lower in the SH group, compared with the control group. Correlation analyses revealed the association of lipids (TC and LDL-C with both oxidative stress biomarkers and thyrotropin (TSH. Thyroid hormones were correlated only with triglyceride levels. In addition, TSH was significantly correlated with TBARS, CAT, and SOD. However, no significant correlations were observed after controlling TC levels. Conclusions. We found that SH patients are under increased oxidative stress manifested by reduced ARE activity and elevated lipoperoxidation and CAT activity. Secondary hypercholesterolemia to thyroid dysfunction and not hypothyroidism per se appears to be associated with oxidative stress in subclinical hypothyroidism.

  4. Proteomic profiling of exosomes leads to the identification of novel biomarkers for prostate cancer.

    Directory of Open Access Journals (Sweden)

    Diederick Duijvesz

    Full Text Available BACKGROUND: Current markers for prostate cancer, such as PSA lack specificity. Therefore, novel biomarkers are needed. Unfortunately, the complexity of body fluids often hampers biomarker discovery. An attractive alternative approach is the isolation of small vesicles, i.e. exosomes, ∼100 nm, which contain proteins that are specific to the tissue from which they are derived and therefore can be considered as treasure chests for disease-specific biomarker discovery. MATERIALS AND METHODS: Exosomes were isolated from 2 immortalized primary prostate epithelial cells (PNT2C2 and RWPE-1 and 2 PCa cell lines (PC346C and VCaP by ultracentrifugation. After tryptic digestion, proteomic analyses utilized a nanoLC coupled with an LTQ-Orbitrap operated in tandem MS (MS/MS mode. Accurate Mass and Time (AMT tag approach was employed for peptide identification and quantitation. Candidate biomarkers were validated by Western blotting and Immunohistochemistry. RESULTS: Proteomic characterization resulted in the identification of 248, 233, 169, and 216 proteins by at least 2 peptides in exosomes from PNT2C2, RWPE-1, PC346C, and VCaP, respectively. Statistical analyses revealed 52 proteins differently abundant between PCa and control cells, 9 of which were more abundant in PCa. Validation by Western blotting confirmed a higher abundance of FASN, XPO1 and PDCD6IP (ALIX in PCa exosomes. CONCLUSIONS: Identification of exosomal proteins using high performance LC-FTMS resulted in the discovery of PDCD6IP, FASN, XPO1 and ENO1 as new candidate biomarkers for prostate cancer.

  5. Preservation of hydrocarbons and biomarkers in oil trapped inside fluid inclusions for >2 billion years

    Science.gov (United States)

    George, Simon C.; Volk, Herbert; Dutkiewicz, Adriana; Ridley, John; Buick, Roger

    2008-02-01

    Oil-bearing fluid inclusions occur in a ca. 2.45 Ga fluvial metaconglomerate of the Matinenda Formation at Elliot Lake, Canada. The oil, most likely derived from the conformably overlying deltaic McKim Formation, was trapped in quartz and feldspar during diagenesis and early metamorphism of the host rock, probably before ca. 2.2 Ga. Molecular geochemical analyses of the oil reveal a wide range of compounds, including CH 4, CO 2, n-alkanes, isoprenoids, monomethylalkanes, aromatic hydrocarbons, low molecular weight cyclic hydrocarbons, and trace amounts of complex multi-ring biomarkers. Maturity ratios show that the oil was generated in the oil window, with no evidence of extensive thermal cracking. This is remarkable, given that the oils were exposed to upper prehnite-pumpellyite facies metamorphism (280-350 °C) either during migration or after entrapment. The fluid inclusions are closed systems, with high fluid pressures, and contain no clays or other minerals or metals that might catalyse oil-to-gas cracking. These three attributes may all contribute to the thermal stability of the included oil and enable survival of biomarkers and molecular ratios over billions of years. The biomarker geochemistry of the oil in the Matinenda Formation fluid inclusions enables inferences about the organisms that contributed to the organic matter deposited in the Palaeoproterozoic source rocks from which the analysed oil was generated and expelled. The presence of biomarkers produced by cyanobacteria and eukaryotes that are derived from and trapped in rocks deposited before ca. 2.2 Ga is consistent with an earlier evolution of oxygenic photosynthesis and suggests that some aquatic settings had become sufficiently oxygenated for sterol biosynthesis by this time. The extraction of biomarker molecules from Palaeoproterozoic oil-bearing fluid inclusions thus establishes a new method, using low detection limits and system blank levels, to trace evolution through Earth's early history

  6. Early biomarkers of joint damage in rheumatoid and psoriatic arthritis.

    Science.gov (United States)

    Mc Ardle, Angela; Flatley, Brian; Pennington, Stephen R; FitzGerald, Oliver

    2015-06-01

    Joint destruction, as evidenced by radiographic findings, is a significant problem for patients suffering from rheumatoid arthritis and psoriatic arthritis. Inherently irreversible and frequently progressive, the process of joint damage begins at and even before the clinical onset of disease. However, rheumatoid and psoriatic arthropathies are heterogeneous in nature and not all patients progress to joint damage. It is therefore important to identify patients susceptible to joint destruction in order to initiate more aggressive treatment as soon as possible and thereby potentially prevent irreversible joint damage. At the same time, the high cost and potential side effects associated with aggressive treatment mean it is also important not to over treat patients and especially those who, even if left untreated, would not progress to joint destruction. It is therefore clear that a protein biomarker signature that could predict joint damage at an early stage would support more informed clinical decisions on the most appropriate treatment regimens for individual patients. Although many candidate biomarkers for rheumatoid and psoriatic arthritis have been reported in the literature, relatively few have reached clinical use and as a consequence the number of prognostic biomarkers used in rheumatology has remained relatively static for several years. It has become evident that a significant challenge in the transition of biomarker candidates to clinical diagnostic assays lies in the development of suitably robust biomarker assays, especially multiplexed assays, and their clinical validation in appropriate patient sample cohorts. Recent developments in mass spectrometry-based targeted quantitative protein measurements have transformed our ability to rapidly develop multiplexed protein biomarker assays. These advances are likely to have a significant impact on the validation of biomarkers in the future. In this review, we have comprehensively compiled a list of candidate

  7. Early biomarkers of joint damage in rheumatoid and psoriatic arthritis.

    LENUS (Irish Health Repository)

    Mc Ardle, Angela

    2015-01-01

    Joint destruction, as evidenced by radiographic findings, is a significant problem for patients suffering from rheumatoid arthritis and psoriatic arthritis. Inherently irreversible and frequently progressive, the process of joint damage begins at and even before the clinical onset of disease. However, rheumatoid and psoriatic arthropathies are heterogeneous in nature and not all patients progress to joint damage. It is therefore important to identify patients susceptible to joint destruction in order to initiate more aggressive treatment as soon as possible and thereby potentially prevent irreversible joint damage. At the same time, the high cost and potential side effects associated with aggressive treatment mean it is also important not to over treat patients and especially those who, even if left untreated, would not progress to joint destruction. It is therefore clear that a protein biomarker signature that could predict joint damage at an early stage would support more informed clinical decisions on the most appropriate treatment regimens for individual patients. Although many candidate biomarkers for rheumatoid and psoriatic arthritis have been reported in the literature, relatively few have reached clinical use and as a consequence the number of prognostic biomarkers used in rheumatology has remained relatively static for several years. It has become evident that a significant challenge in the transition of biomarker candidates to clinical diagnostic assays lies in the development of suitably robust biomarker assays, especially multiplexed assays, and their clinical validation in appropriate patient sample cohorts. Recent developments in mass spectrometry-based targeted quantitative protein measurements have transformed our ability to rapidly develop multiplexed protein biomarker assays. These advances are likely to have a significant impact on the validation of biomarkers in the future. In this review, we have comprehensively compiled a list of candidate

  8. Biomarkers in canine parvovirus enteritis.

    Science.gov (United States)

    Schoeman, J P; Goddard, A; Leisewitz, A L

    2013-07-01

    Canine parvovirus (CPV) enteritis has, since its emergence in 1978, remained a common and important cause of morbidity and mortality in young dogs. The continued incidence of parvoviral enteritis is partly due to the virus' capability to evolve into more virulent and resistant variants with significant local gastrointestinal and systemic inflammatory sequelae. This paper reviews current knowledge on historical-, signalment-, and clinical factors as well as several haematological-, biochemical- and endocrine parameters that can be used as diagnostic and prognostic biomarkers in CPV enteritis. These factors include season of presentation, purebred nature, bodyweight, vomiting, leukopaenia, lymphopaenia, thrombocytopaenia, hypercoagulability, hypercortisolaemia, hypothyroxinaemia, hypoalbuminaemia, elevated C-reactive protein and tumour necrosis factor, hypocholesterolaemia and hypocitrullinaemia. Factors contributing to the manifestations of CPV infection are multiple with elements of host, pathogen, secondary infections, underlying stressors and environment affecting severity and outcome. The availability of several prognosticators has made identification of patients at high risk of death and their subsequent targeted management more rewarding.

  9. Astrosat/LAXPC Reveals the High-energy Variability of GRS 1915+105 in the X Class

    Science.gov (United States)

    Yadav, J. S.; Misra, Ranjeev; Verdhan Chauhan, Jai; Agrawal, P. C.; Antia, H. M.; Pahari, Mayukh; Dedhia, Dhiraj; Katoch, Tilak; Madhwani, P.; Manchanda, R. K.; Paul, B.; Shah, Parag; Ishwara-Chandra, C. H.

    2016-12-01

    We present the first quick look analysis of data from nine AstroSat's Large Area X-ray Proportional Counter (LAXPC) observations of GRS 1915+105 during 2016 March when the source had the characteristics of being in the Radio-quiet χ class. We find that a simple empirical model of a disk blackbody emission, with Comptonization and a broad Gaussian Iron line can fit the time-averaged 3-80 keV spectrum with a systematic uncertainty of 1.5% and a background flux uncertainty of 4%. A simple dead time corrected Poisson noise level spectrum matches well with the observed high-frequency power spectra till 50 kHz and as expected the data show no significant high-frequency (\\gt 20 {Hz}) features. Energy dependent power spectra reveal a strong low-frequency (2-8 Hz) quasi-periodic oscillation and its harmonic along with broadband noise. The QPO frequency changes rapidly with flux (nearly 4 Hz in ˜5 hr). With increasing QPO frequency, an excess noise component appears significantly in the high-energy regime (\\gt 8 keV). At the QPO frequencies, the time-lag as a function of energy has a non-monotonic behavior such that the lags decrease with energy till about 15-20 keV and then increase for higher energies. These first-look results benchmark the performance of LAXPC at high energies and confirms that its data can be used for more sophisticated analysis such as flux or frequency-resolved spectro-timing studies.

  10. Transcriptomic profiling of soybean in response to high-intensity UV-B irradiation reveals stress defense signaling

    Directory of Open Access Journals (Sweden)

    Min Young Yoon

    2016-12-01

    Full Text Available The depletion of the ozone layer in the stratosphere has led to a dramatic spike in ultraviolet B (UV-B intensity and increased UV-B light levels. The direct absorption of high-intensity UV-B induces complex abiotic stresses in plants, including excessive light exposure, heat, and dehydration. However, UV-B stress signaling mechanisms in plants including soybean (Glycine max [L.] remain poorly understood. Here, we surveyed the overall transcriptional responses of two soybean genotypes, UV-B-sensitive Cheongja 3 and UV-B-resistant Buseok, to continuous UV-B irradiation for 0 (control, 0.5, and 6 h using RNA-seq analysis. Homology analysis using UV-B-related genes from Arabidopsis thaliana revealed differentially expressed genes (DEGs likely involved in UV-B stress responses. Functional classification of the DEGs showed that the categories of immune response, stress defense signaling, and reactive oxygen species (ROS metabolism were over-represented. UV-B-resistant Buseok utilized phosphatidic acid-dependent signaling pathways (based on subsequent reactions of phospholipase C and diacylglycerol kinase rather than phospholipase D in response to UV-B exposure at high fluence rates, and genes involved in its downstream pathways, such as ABA signaling, mitogen-activated protein kinase cascades, and ROS overproduction, were upregulated in this genotype. In addition, the DEGs for TIR-NBS-LRR and heat shock proteins are positively activated. These results suggest that defense mechanisms against UV-B stress at high fluence rates are separate from the photomorphogenic responses utilized by plants to adapt to low-level UV light. Our study provides valuable information for deep understanding of UV-B stress defense mechanisms and for the development of resistant soybean genotypes that survive under high-intensity UV-B stress.

  11. Sample phenotype clusters in high-density oligonucleotide microarray data sets are revealed using Isomap, a nonlinear algorithm

    Directory of Open Access Journals (Sweden)

    Malyj Wasyl

    2005-08-01

    Full Text Available Abstract Background Life processes are determined by the organism's genetic profile and multiple environmental variables. However the interaction between these factors is inherently non-linear 1. Microarray data is one representation of the nonlinear interactions among genes and genes and environmental factors. Still most microarray studies use linear methods for the interpretation of nonlinear data. In this study, we apply Isomap, a nonlinear method of dimensionality reduction, to analyze three independent large Affymetrix high-density oligonucleotide microarray data sets. Results Isomap discovered low-dimensional structures embedded in the Affymetrix microarray data sets. These structures correspond to and help to interpret biological phenomena present in the data. This analysis provides examples of temporal, spatial, and functional processes revealed by the Isomap algorithm. In a spinal cord injury data set, Isomap discovers the three main modalities of the experiment – location and severity of the injury and the time elapsed after the injury. In a multiple tissue data set, Isomap discovers a low-dimensional structure that corresponds to anatomical locations of the source tissues. This model is capable of describing low- and high-resolution differences in the same model, such as kidney-vs.-brain and differences between the nuclei of the amygdala, respectively. In a high-throughput drug screening data set, Isomap discovers the monocytic and granulocytic differentiation of myeloid cells and maps several chemical compounds on the two-dimensional model. Conclusion Visualization of Isomap models provides useful tools for exploratory analysis of microarray data sets. In most instances, Isomap models explain more of the variance present in the microarray data than PCA or MDS. Finally, Isomap is a promising new algorithm for class discovery and class prediction in high-density oligonucleotide data sets.

  12. A biomarker panel (Bioscore incorporating monocytic surface and soluble TREM-1 has high discriminative value for ventilator-associated pneumonia: a prospective observational study.

    Directory of Open Access Journals (Sweden)

    Vimal Grover

    Full Text Available Ventilator-associated pneumonia (VAP increases mortality in critical illness. However, clinical diagnostic uncertainty persists. We hypothesised that measuring cell-surface and soluble inflammatory markers, incorporating Triggering Receptor Expressed by Myeloid cells (TREM-1, would improve diagnostic accuracy.A single centre prospective observational study, set in a University Hospital medical-surgical intensive Care unit, recruited 91 patients into 3 groups: 27 patients with VAP, 33 ventilated controls without evidence of pulmonary sepsis (non-VAP, and 31 non-ventilated controls (NVC, without clinical infection, attending for bronchoscopy. Paired samples of Bronchiolo-alveolar lavage fluid (BALF and blood from each subject were analysed for putative biomarkers of infection: Cellular (TREM-1, CD11b and CD62L and soluble (IL-1β, IL-6, IL-8, sTREM-1, Procalcitonin. Expression of cellular markers on monocytes and neutrophils were measured by flow cytometry. Soluble inflammatory markers were determined by ELISA. A biomarker panel ('Bioscore', was constructed, tested and validated, using Fisher's discriminant function analysis, to assess its value in distinguishing VAP from non VAP.The expression of TREM-1 on monocytes (mTREM-1 and neutrophils (nTREM-1 and concentrations of IL-1β, IL-8, and sTREM-1 in BALF were significantly higher in VAP compared with non-VAP and NVC (p<0.001. The BALF/blood mTREM-1 was significantly higher in VAP patients compared to non-VAP and NVC (0.8 v 0.4 v 0.3 p<0.001. A seven marker Bioscore (BALF/blood ratio mTREM-1 and mCD11b, BALF sTREM-1, IL-8 and IL-1β, and serum CRP and IL-6 correctly identified 88.9% of VAP cases and 100% of non-VAP cases.A 7-marker bioscore, incorporating cellular and soluble TREM-1, accurately discriminates VAP from non-pulmonary infection.

  13. Towards Improved Biomarker Research

    DEFF Research Database (Denmark)

    Kjeldahl, Karin

    This thesis takes a look at the data analytical challenges associated with the search for biomarkers in large-scale biological data such as transcriptomics, proteomics and metabolomics data. These studies aim to identify genes, proteins or metabolites which can be associated with e.g. a diet, dis...... is used both for regression and classification purposes. This method has proven its strong worth in the multivariate data analysis throughout an enormous range of applications; a very classic data type is near infrared (NIR) data, but many similar data types have also be very successful...

  14. High-throughput sequencing reveals differing immune responses in the intestinal mucosa of two inbred lines afflicted with necrotic enteritis.

    Science.gov (United States)

    Truong, Anh Duc; Hong, Yeong Ho; Lillehoj, Hyun S

    2015-08-15

    We investigated the necrotic enteritis (NE)-induced transcripts of immune-related genes in the intestinal mucosa of two highly inbred White Leghorn chicken lines, line 6.3 and line 7.2, which share the same MHC haplotype and show different levels of NE susceptibility using high-throughput RNA sequencing (RNA-Seq) technology. NE was induced by the previously described co-infection model using Eimeria maxima and Clostridium perfringens. The RNA-Seq generated over 38 million sequence reads for Marek's disease (MD)-resistant line 6.3 and over 40 million reads for the MD-susceptible line 7.2. Alignment of these sequences with the Gallus gallus genome database revealed the expression of over 29,900 gene transcripts induced by NE in these two lines, among which 7,841 genes were significantly upregulated and 2,919 genes were downregulated in line 6.3 chickens and 6,043 genes were significantly upregulated and 2,764 genes were downregulated in NE-induced line 7.2 compared with their uninfected controls. Analysis of 560 differentially expressed genes (DEGs) using the gene ontology database revealed annotations for 246 biological processes, 215 molecular functions, and 81 cellular components. Among the 53 cytokines and 96 cytokine receptors, 15 cytokines and 29 cytokine receptors were highly expressed in line 6.3, whereas the expression of 15 cytokines and 15 cytokine receptors was higher in line 7.2 than in line 6.3 (fold change ≥ 2, p<0.01). In a hierarchical cluster analysis of novel mRNAs, the novel mRNA transcriptome showed higher expression in line 6.3 than in line 7.2, which is consistent with the expression profile of immune-related target genes. In qRT-PCR and RNA-Seq analysis, all the genes examined showed similar responses to NE (correlation coefficient R=0.85-0.89, p<0.01) in both lines 6.3 and 7.2. This study is the first report describing NE-induced DEGs and novel transcriptomes using RNA-seq data from two inbred chicken lines showing different levels of NE

  15. Pyrosequencing reveals high-temperature cellulolytic microbial consortia in Great Boiling Spring after in situ lignocellulose enrichment.

    Directory of Open Access Journals (Sweden)

    Joseph P Peacock

    Full Text Available To characterize high-temperature cellulolytic microbial communities, two lignocellulosic substrates, ammonia fiber-explosion-treated corn stover and aspen shavings, were incubated at average temperatures of 77 and 85°C in the sediment and water column of Great Boiling Spring, Nevada. Comparison of 109,941 quality-filtered 16S rRNA gene pyrosequences (pyrotags from eight enrichments to 37,057 quality-filtered pyrotags from corresponding natural samples revealed distinct enriched communities dominated by phylotypes related to cellulolytic and hemicellulolytic Thermotoga and Dictyoglomus, cellulolytic and sugar-fermenting Desulfurococcales, and sugar-fermenting and hydrogenotrophic Archaeoglobales. Minor enriched populations included close relatives of hydrogenotrophic Thermodesulfobacteria, the candidate bacterial phylum OP9, and candidate archaeal groups C2 and DHVE3. Enrichment temperature was the major factor influencing community composition, with a negative correlation between temperature and richness, followed by lignocellulosic substrate composition. This study establishes the importance of these groups in the natural degradation of lignocellulose at high temperatures and suggests that a substantial portion of the diversity of thermophiles contributing to consortial cellulolysis may be contained within lineages that have representatives in pure culture.

  16. Large-Scale Structure of the Molecular Gas in Taurus Revealed by High Linear Dynamic Range Spectral Line Mapping

    CERN Document Server

    Goldsmith, Paul F; Narayanan, Gopal; Snell, Ronald; Li, Di; Brunt, Chris

    2008-01-01

    We report the results of a 100 square degree survey of the Taurus Molecular Cloud region in the J = 1-0 transition of 12CO and 13CO. The image of the cloud in each velocity channel includes ~ 3 million Nyquist sampled pixels on a 20" grid. The high sensitivity and large linear dynamic range of the maps in both isotopologues reveal a very complex, highly structured cloud morphology. There are large scale correlated structures evident in 13CO emission having very fine dimensions, including filaments, cavities, and rings. The 12CO emission shows a quite different structure, with particularly complex interfaces between regions of greater and smaller column density defining the boundaries of the largest-scale cloud structures. The axes of the striations seen in the 12CO emission from relatively diffuse gas are aligned with the direction of the magnetic field. Using a column density-dependent model for the CO fractional abundance, we derive the mass of the region mapped to be 24,000 solar masses, a factor of three ...

  17. Microbial diversity in uranium mining-impacted soils as revealed by high-density 16S microarray and clone library.

    Science.gov (United States)

    Rastogi, Gurdeep; Osman, Shariff; Vaishampayan, Parag A; Andersen, Gary L; Stetler, Larry D; Sani, Rajesh K

    2010-01-01

    Microbial diversity was characterized in mining-impacted soils collected from two abandoned uranium mine sites, the Edgemont and the North Cave Hills, South Dakota, using a high-density 16S microarray (PhyloChip) and clone libraries. Characterization of the elemental compositions of soils by X-ray fluorescence spectroscopy revealed higher metal contamination including uranium at the Edgemont than at the North Cave Hills mine site. Microarray data demonstrated extensive phylogenetic diversity in soils and confirmed nearly all clone-detected taxonomic levels. Additionally, the microarray exhibited greater diversity than clone libraries at each taxonomic level at both the mine sites. Interestingly, the PhyloChip detected the largest number of taxa in Proteobacteria phylum for both the mine sites. However, clone libraries detected Acidobacteria and Bacteroidetes as the most numerically abundant phyla in the Edgemont and North Cave Hills mine sites, respectively. Several 16S rDNA signatures found in both the microarrays and clone libraries displayed sequence similarities with yet-uncultured bacteria representing a hitherto unidentified diversity. Results from this study demonstrated that highly diverse microbial populations were present in these uranium mine sites. Diversity indices indicated that microbial communities at the North Cave Hills mine site were much more diverse than those at the Edgemont mine site.

  18. Changes in bone macro- and microstructure in diabetic obese mice revealed by high resolution microfocus X-ray computed tomography

    Science.gov (United States)

    Kerckhofs, G.; Durand, M.; Vangoitsenhoven, R.; Marin, C.; van der Schueren, B.; Carmeliet, G.; Luyten, F. P.; Geris, L.; Vandamme, K.

    2016-10-01

    High resolution microfocus X-ray computed tomography (HR-microCT) was employed to characterize the structural alterations of the cortical and trabecular bone in a mouse model of obesity-driven type 2 diabetes (T2DM). C57Bl/6J mice were randomly assigned for 14 weeks to either a control diet-fed (CTRL) or a high fat diet (HFD)-fed group developing obesity, hyperglycaemia and insulin resistance. The HFD group showed an increased trabecular thickness and a decreased trabecular number compared to CTRL animals. Midshaft tibia intracortical porosity was assessed at two spatial image resolutions. At 2 μm scale, no change was observed in the intracortical structure. At 1 μm scale, a decrease in the cortical vascular porosity of the HFD bone was evidenced. The study of a group of 8 week old animals corresponding to animals at the start of the diet challenge revealed that the decreased vascular porosity was T2DM-dependant and not related to the ageing process. Our results offer an unprecedented ultra-characterization of the T2DM compromised skeletal micro-architecture and highlight an unrevealed T2DM-related decrease in the cortical vascular porosity, potentially affecting the bone health and fragility. Additionally, it provides some insights into the technical challenge facing the assessment of the rodent bone structure using HR-microCT imaging.

  19. Unbiased K-mer Analysis Reveals Changes in Copy Number of Highly Repetitive Sequences During Maize Domestication and Improvement

    Science.gov (United States)

    Liu, Sanzhen; Zheng, Jun; Migeon, Pierre; Ren, Jie; Hu, Ying; He, Cheng; Liu, Hongjun; Fu, Junjie; White, Frank F.; Toomajian, Christopher; Wang, Guoying

    2017-01-01

    The major component of complex genomes is repetitive elements, which remain recalcitrant to characterization. Using maize as a model system, we analyzed whole genome shotgun (WGS) sequences for the two maize inbred lines B73 and Mo17 using k-mer analysis to quantify the differences between the two genomes. Significant differences were identified in highly repetitive sequences, including centromere, 45S ribosomal DNA (rDNA), knob, and telomere repeats. Genotype specific 45S rDNA sequences were discovered. The B73 and Mo17 polymorphic k-mers were used to examine allele-specific expression of 45S rDNA in the hybrids. Although Mo17 contains higher copy number than B73, equivalent levels of overall 45S rDNA expression indicates that transcriptional or post-transcriptional regulation mechanisms operate for the 45S rDNA in the hybrids. Using WGS sequences of B73xMo17 doubled haploids, genomic locations showing differential repetitive contents were genetically mapped, which displayed different organization of highly repetitive sequences in the two genomes. In an analysis of WGS sequences of HapMap2 lines, including maize wild progenitor, landraces, and improved lines, decreases and increases in abundance of additional sets of k-mers associated with centromere, 45S rDNA, knob, and retrotransposons were found among groups, revealing global evolutionary trends of genomic repeats during maize domestication and improvement. PMID:28186206

  20. The Double-Reduction Landscape in Tetraploid Potato as Revealed by a High-Density Linkage Map.

    Science.gov (United States)

    Bourke, Peter M; Voorrips, Roeland E; Visser, Richard G F; Maliepaard, Chris

    2015-11-01

    The creation of genetic linkage maps in polyploid species has been a long-standing problem for which various approaches have been proposed. In the case of autopolyploids, a commonly used simplification is that random bivalents form during meiosis. This leads to relatively straightforward estimation of recombination frequencies using maximum likelihood, from which a genetic map can be derived. However, autopolyploids such as tetraploid potato (Solanum tuberosum L.) may exhibit additional features, such as double reduction, not normally encountered in diploid or allopolyploid species. In this study, we produced a high-density linkage map of tetraploid potato and used it to identify regions of double reduction in a biparental mapping population. The frequency of multivalents required to produce this degree of double reduction was determined through simulation. We also determined the effect that multivalents or preferential pairing between homologous chromosomes has on linkage mapping. Low levels of multivalents or preferential pairing do not adversely affect map construction when highly informative marker types and phases are used. We reveal the double-reduction landscape in tetraploid potato, clearly showing that this phenomenon increases with distance from the centromeres.

  1. Bacterial pathogens and community composition in advanced sewage treatment systems revealed by metagenomics analysis based on high-throughput sequencing.

    Science.gov (United States)

    Lu, Xin; Zhang, Xu-Xiang; Wang, Zhu; Huang, Kailong; Wang, Yuan; Liang, Weigang; Tan, Yunfei; Liu, Bo; Tang, Junying

    2015-01-01

    This study used 454 pyrosequencing, Illumina high-throughput sequencing and metagenomic analysis to investigate bacterial pathogens and their potential virulence in a sewage treatment plant (STP) applying both conventional and advanced treatment processes. Pyrosequencing and Illumina sequencing consistently demonstrated that Arcobacter genus occupied over 43.42% of total abundance of potential pathogens in the STP. At species level, potential pathogens Arcobacter butzleri, Aeromonas hydrophila and Klebsiella pneumonia dominated in raw sewage, which was also confirmed by quantitative real time PCR. Illumina sequencing also revealed prevalence of various types of pathogenicity islands and virulence proteins in the STP. Most of the potential pathogens and virulence factors were eliminated in the STP, and the removal efficiency mainly depended on oxidation ditch. Compared with sand filtration, magnetic resin seemed to have higher removals in most of the potential pathogens and virulence factors. However, presence of the residual A. butzleri in the final effluent still deserves more concerns. The findings indicate that sewage acts as an important source of environmental pathogens, but STPs can effectively control their spread in the environment. Joint use of the high-throughput sequencing technologies is considered a reliable method for deep and comprehensive overview of environmental bacterial virulence.

  2. Fine-scale planktonic habitat partitioning at a shelf-slope front revealed by a high-resolution imaging system

    Science.gov (United States)

    Greer, Adam T.; Cowen, Robert K.; Guigand, Cedric M.; Hare, Jonathan A.

    2015-02-01

    Ocean fronts represent productive regions of the ocean, but predator-prey interactions within these features are poorly understood partially due to the coarse-scale and biases of net-based sampling methods. We used the In Situ Ichthyoplankton Imaging System (ISIIS) to sample across a front near the Georges Bank shelf edge on two separate sampling days in August 2010. Salinity characterized the transition from shelf to slope water, with isopycnals sloping vertically, seaward, and shoaling at the thermocline. A frontal feature defined by the convergence of isopycnals and a surface temperature gradient was sampled inshore of the shallowest zone of the shelf-slope front. Zooplankton and larval fishes were abundant on the shelf side of the front and displayed taxon-dependent depth distributions but were rare in the slope waters. Supervised automated particle counting showed small particles with high solidity, verified to be zooplankton (copepods and appendicularians), aggregating near surface above the front. Salps were most abundant in zones of intermediate chlorophyll-a fluorescence, distinctly separate from high abundances of other grazers and found almost exclusively in colonial form (97.5%). Distributions of gelatinous zooplankton differed among taxa but tended to follow isopycnals. Fine-scale sampling revealed distinct habitat partitioning of various planktonic taxa, resulting from a balance of physical and biological drivers in relation to the front.

  3. Amplicon-Based Pyrosequencing Reveals High Diversity of Protistan Parasites in Ships' Ballast Water: Implications for Biogeography and Infectious Diseases.

    Science.gov (United States)

    Pagenkopp Lohan, K M; Fleischer, R C; Carney, K J; Holzer, K K; Ruiz, G M

    2016-04-01

    Ships' ballast water (BW) commonly moves macroorganisms and microorganisms across the world's oceans and along coasts; however, the majority of these microbial transfers have gone undetected. We applied high-throughput sequencing methods to identify microbial eukaryotes, specifically emphasizing the protistan parasites, in ships' BW collected from vessels calling to the Chesapeake Bay (Virginia and Maryland, USA) from European and Eastern Canadian ports. We utilized tagged-amplicon 454 pyrosequencing with two general primer sets, amplifying either the V4 or V9 domain of the small subunit (SSU) of the ribosomal RNA (rRNA) gene complex, from total DNA extracted from water samples collected from the ballast tanks of bulk cargo vessels. We detected a diverse group of protistan taxa, with some known to contain important parasites in marine systems, including Apicomplexa (unidentified apicomplexans, unidentified gregarines, Cryptosporidium spp.), Dinophyta (Blastodinium spp., Euduboscquella sp., unidentified syndinids, Karlodinium spp., Syndinium spp.), Perkinsea (Parvilucifera sp.), Opisthokonta (Ichthyosporea sp., Pseudoperkinsidae, unidentified ichthyosporeans), and Stramenopiles (Labyrinthulomycetes). Further characterization of groups with parasitic taxa, consisting of phylogenetic analyses for four taxa (Cryptosporidium spp., Parvilucifera spp., Labyrinthulomycetes, and Ichthyosporea), revealed that sequences were obtained from both known and novel lineages. This study demonstrates that high-throughput sequencing is a viable and sensitive method for detecting parasitic protists when present and transported in the ballast water of ships. These data also underscore the potential importance of human-aided dispersal in the biogeography of these microbes and emerging diseases in the world's oceans.

  4. Bacterial pathogens and community composition in advanced sewage treatment systems revealed by metagenomics analysis based on high-throughput sequencing.

    Directory of Open Access Journals (Sweden)

    Xin Lu

    Full Text Available This study used 454 pyrosequencing, Illumina high-throughput sequencing and metagenomic analysis to investigate bacterial pathogens and their potential virulence in a sewage treatment plant (STP applying both conventional and advanced treatment processes. Pyrosequencing and Illumina sequencing consistently demonstrated that Arcobacter genus occupied over 43.42% of total abundance of potential pathogens in the STP. At species level, potential pathogens Arcobacter butzleri, Aeromonas hydrophila and Klebsiella pneumonia dominated in raw sewage, which was also confirmed by quantitative real time PCR. Illumina sequencing also revealed prevalence of various types of pathogenicity islands and virulence proteins in the STP. Most of the potential pathogens and virulence factors were eliminated in the STP, and the removal efficiency mainly depended on oxidation ditch. Compared with sand filtration, magnetic resin seemed to have higher removals in most of the potential pathogens and virulence factors. However, presence of the residual A. butzleri in the final effluent still deserves more concerns. The findings indicate that sewage acts as an important source of environmental pathogens, but STPs can effectively control their spread in the environment. Joint use of the high-throughput sequencing technologies is considered a reliable method for deep and comprehensive overview of environmental bacterial virulence.

  5. Biomarkers in Pediatric ARDS: Future Directions

    Directory of Open Access Journals (Sweden)

    Benjamin E Orwoll

    2016-06-01

    Full Text Available Acute respiratory distress syndrome (ARDS is common among mechanically ventilated children, and accompanies up to 30% of all PICU deaths. Though ARDS diagnosis is based on clinical criteria, biological markers of acute lung damage have been extensively studied in adults and children. Biomarkers of inflammation, alveolar epithelial and capillary endothelial disruption, disordered coagulation, and associated derangements measured in the circulation and other body fluids such as brochoalveolar lavage have improved our understanding of pathobiology of ARDS. The biochemical signature of ARDS has been increasingly well described in adult populations, and this has led to the identification of molecular phenotypes to augment clinical classifications. However, there is a paucity of data from pediatric ARDS patients. Biomarkers and molecular phenotypes have the potential to identify patients at high risk of poor outcomes, and perhaps inform the development of targeted therapies for specific groups of patients. Additionally, because of the lower incidence of and mortality from ARDS in pediatric patients relative to adults and lack of robust clinical predictors of outcome, there is an ongoing interest in biological markers as surrogate outcome measures. The recent definition of pediatric ARDS (pARDS provides additional impetus for measurement of established and novel biomarkers in future pediatric studies in order to further characterize this disease process. This chapter will review the currently available literature and discuss potential future directions for investigation into biomarkers in ARDS among children.

  6. Potential Serological Biomarkers of Cerebral Malaria

    Directory of Open Access Journals (Sweden)

    Naomi W. Lucchi

    2011-01-01

    Full Text Available Biomarkers have been used to diagnose and prognosticate the progress and outcome of many chronic diseases such as neoplastic and non communicable diseases. However, only recently did the field of malaria research move in the direction of actively identifying biomarkers that can accurately discriminate the severe forms of malaria. Malaria continues to be a deadly disease, killing close to a million people (mostly children every year. One life-threatening complication of malaria is cerebral malaria (CM. Studies carried out in Africa have demonstrated that even with the best treatment, as high as 15–30% of CM patients die and about 10–24% of CM survivors suffer short-or long-term neurological impairment. The transition from mild malaria to CM can be sudden and requires immediate intervention. Currently, there is no biological test available to confirm the diagnosis of CM and its complications. It is hoped that development of biomarkers to identify CM patients and potential risk for adverse outcomes would greatly enhance better intervention and clinical management to improve the outcomes. We review here what is currently known regarding biomarkers for CM outcomes.

  7. Characterization of polymorphisms and isoforms of the Clostridium perfringens phospholipase C gene (plc) reveals high genetic diversity.

    Science.gov (United States)

    Siqueira, Flávia F; Almeida, Marcelle O; Barroca, Tatiana M; Horta, Carolina C R; Carmo, Anderson O; Silva, Rodrigo O S; Pires, Prhiscylla S; Lobato, Francisco C F; Kalapothakis, Evanguedes

    2012-10-12

    Clostridium perfringens phospholipase C (Cp-PLC), also called alpha-toxin, is encoded by the plc gene and has been implicated in several diseases; however, only a few studies have described polymorphisms in this gene. The aim of this study was to analyze polymorphisms in the Cp-PLC nucleotide and amino acid sequences obtained from isolates from different regions and to compare them to Clostridium phospholipase C sequences deposited in the NCBI database. Environmental samples (sediment, poultry feed, sawdust) and stool samples (from poultry, bovine, swine, horse, caprine, bird, dog, rabbit, toucan) were collected from healthy and sick animals. A total of 73 isolates were analyzed with the majority of samples belonging to the toxin type A subtype and possessing the gene encoding for the beta-2 toxin. Comparison of plc gene sequences from respective isolates revealed a high genetic diversity in the nucleotide sequences of mature Cp-PLC. Sequence comparisons identified 30 amino acid substitutions and 34 isoforms including some isoforms with substitutions in amino acids critical to toxin function. Comparison of sequences obtained in this study to Cp-PLC sequences obtained from the NCBI database resulted in the identification of 11 common haplotypes and 22 new isoforms. Phylogenetic analysis of phospholipase C sequences obtained from other Clostridium species identified relationships previously described. This report describes a broad characterization of the genetic diversity in the C. perfringens plc gene resulting in the identification of various isoforms. A better understanding of sequences encoding phospholipase C isoforms may reveal changes associated with protein function and C. perfringens virulence.

  8. Metatranscriptomic analysis of a high-sulfide aquatic spring reveals insights into sulfur cycling and unexpected aerobic metabolism

    Directory of Open Access Journals (Sweden)

    Anne M. Spain

    2015-09-01

    Full Text Available Zodletone spring is a sulfide-rich spring in southwestern Oklahoma characterized by shallow, microoxic, light-exposed spring water overlaying anoxic sediments. Previously, culture-independent 16S rRNA gene based diversity surveys have revealed that Zodletone spring source sediments harbor a highly diverse microbial community, with multiple lineages putatively involved in various sulfur-cycling processes. Here, we conducted a metatranscriptomic survey of microbial populations in Zodletone spring source sediments to characterize the relative prevalence and importance of putative phototrophic, chemolithotrophic, and heterotrophic microorganisms in the sulfur cycle, the identity of lineages actively involved in various sulfur cycling processes, and the interaction between sulfur cycling and other geochemical processes at the spring source. Sediment samples at the spring’s source were taken at three different times within a 24-h period for geochemical analyses and RNA sequencing. In depth mining of datasets for sulfur cycling transcripts revealed major sulfur cycling pathways and taxa involved, including an unexpected potential role of Actinobacteria in sulfide oxidation and thiosulfate transformation. Surprisingly, transcripts coding for the cyanobacterial Photosystem II D1 protein, methane monooxygenase, and terminal cytochrome oxidases were encountered, indicating that genes for oxygen production and aerobic modes of metabolism are actively being transcribed, despite below-detectable levels (<1 µM of oxygen in source sediment. Results highlight transcripts involved in sulfur, methane, and oxygen cycles, propose that oxygenic photosynthesis could support aerobic methane and sulfide oxidation in anoxic sediments exposed to sunlight, and provide a viewpoint of microbial metabolic lifestyles under conditions similar to those seen during late Archaean and Proterozoic eons.

  9. Metatranscriptomic analysis of a high-sulfide aquatic spring reveals insights into sulfur cycling and unexpected aerobic metabolism

    Science.gov (United States)

    Elshahed, Mostafa S.; Najar, Fares Z.; Krumholz, Lee R.

    2015-01-01

    Zodletone spring is a sulfide-rich spring in southwestern Oklahoma characterized by shallow, microoxic, light-exposed spring water overlaying anoxic sediments. Previously, culture-independent 16S rRNA gene based diversity surveys have revealed that Zodletone spring source sediments harbor a highly diverse microbial community, with multiple lineages putatively involved in various sulfur-cycling processes. Here, we conducted a metatranscriptomic survey of microbial populations in Zodletone spring source sediments to characterize the relative prevalence and importance of putative phototrophic, chemolithotrophic, and heterotrophic microorganisms in the sulfur cycle, the identity of lineages actively involved in various sulfur cycling processes, and the interaction between sulfur cycling and other geochemical processes at the spring source. Sediment samples at the spring’s source were taken at three different times within a 24-h period for geochemical analyses and RNA sequencing. In depth mining of datasets for sulfur cycling transcripts revealed major sulfur cycling pathways and taxa involved, including an unexpected potential role of Actinobacteria in sulfide oxidation and thiosulfate transformation. Surprisingly, transcripts coding for the cyanobacterial Photosystem II D1 protein, methane monooxygenase, and terminal cytochrome oxidases were encountered, indicating that genes for oxygen production and aerobic modes of metabolism are actively being transcribed, despite below-detectable levels (oxygen in source sediment. Results highlight transcripts involved in sulfur, methane, and oxygen cycles, propose that oxygenic photosynthesis could support aerobic methane and sulfide oxidation in anoxic sediments exposed to sunlight, and provide a viewpoint of microbial metabolic lifestyles under conditions similar to those seen during late Archaean and Proterozoic eons. PMID:26417542

  10. Profiling serologic biomarkers in cirrhotic patients via high-throughput Fourier transform infrared spectroscopy: toward a new diagnostic tool of hepatocellular carcinoma.

    Science.gov (United States)

    Zhang, Xiaoqing; Thiéfin, Gérard; Gobinet, Cyril; Untereiner, Valérie; Taleb, Imane; Bernard-Chabert, Brigitte; Heurgué, Alexandra; Truntzer, Caroline; Ducoroy, Patrick; Hillon, Patrick; Sockalingum, Ganesh D

    2013-11-01

    Identification of novel serum biomarkers of hepatocellular carcinoma (HCC) is needed for early-stage disease detection and to improve patients' survival. The aim of this study was to evaluate the potential of serum Fourier transform infrared (FTIR) spectroscopy for differentiating sera from cirrhotic patients with and without HCC. Serum samples were collected from 2 sets of patients: cirrhotic patients with HCC (n = 39) and without HCC (n = 40). The FTIR spectra (10 per sample) were acquired in the transmission mode, and data homogeneity was tested by cluster analysis to exclude outliers. After data preprocessing by extended multiplicative signal correction and principal component analysis, the Support Vector Machine (SVM) method was applied using a leave-one-out cross-validation algorithm to classify the spectra into 2 classes of cirrhotic patients with and without HCC. When SVM was applied to all spectra (n = 790), the sensitivity and the specificity for the diagnosis of HCC were, respectively, 82.02% and 82.5%. When applied to the subset of spectra excluding the outliers (n = 739), SVM classification led to a sensitivity and specificity of 87.18% and 85%, respectively. Using median spectra for each patient instead of all replicates, the sensitivity and specificity were 84.62% and 82.50%, respectively. The overall accuracy rate was 82%-86%. In conclusion, this study suggests that FTIR spectroscopy combined with advanced methods of pattern analysis shows potential for differentiating sera from cirrhotic patients with and without HCC.

  11. Clinical states model for biomarkers in bladder cancer.

    Science.gov (United States)

    Apolo, Andrea B; Milowsky, Matthew; Bajorin, Dean F

    2009-09-01

    Bladder cancer is a significant healthcare problem in the USA, with a high recurrence rate, the need for expensive continuous surveillance and limited treatment options for patients with advanced disease. Research has contributed to an understanding of the molecular pathways involved in the development and progression of bladder cancer, and that understanding has led to the discovery of potentially diagnostic, predictive and prognostic biomarkers. In this review, a clinical states model of bladder cancer is introduced and integrated into a paradigm for biomarker development. Biomarkers are systematically incorporated with predefined end points to aid in clinical management.

  12. Cardiac Biomarkers and Cycling Race

    Directory of Open Access Journals (Sweden)

    Caroline Le Goff, Jean-François Kaux, Sébastien Goffaux, Etienne Cavalier

    2015-06-01

    Full Text Available In cycling as in other types of strenuous exercise, there exists a risk of sudden death. It is important both to understand its causes and to see if the behavior of certain biomarkers might highlight athletes at risk. Many reports describe changes in biomarkers after strenuous exercise (Nie et al., 2011, but interpreting these changes, and notably distinguishing normal physiological responses from pathological changes, is not easy. Here we have focused on the kinetics of different cardiac biomarkers: creatin kinase (CK, creating kinase midbrain (CK-MB, myoglobin (MYO, highly sensitive troponin T (hs-TnT and N-terminal brain natriuretic peptide (NT-proBNP. The population studied was a group of young trained cyclists participating in a 177-km cycling race. The group of individuals was selected for maximal homogeneity. Their annual training volume was between 10,000 and 16,000 kilometers. The rhythm of races is comparable and averages 35 km/h, depending on the race’s difficulty. The cardiac frequency was recorded via a heart rate monitor. Three blood tests were taken. The first blood test, T0, was taken approximately 2 hours before the start of the race and was intended to gather values which would act as references for the following tests. The second blood test, T1, was realized within 5 minutes of their arrival. The third and final blood test, T3, was taken 3 hours following their arrival. The CK, CK-MB, MYO, hs-TnT and NT-proBNP were measured on the Roche Diagnostic modular E (Manhein, Germany. For the statistical analysis, an ANOVA and post hoc test of Scheffé were calculated with the Statistica Software version 9.1. We noticed an important significant variation in the cardiac frequency between T0 and T1 (p < 0.0001, T0 and T3 (p < 0.0001, and T1 and T3 (p < 0.01. Table 1 shows the results obtained for the different biomarkers. CK and CK-MB showed significant variation between T0-T1 and T0-T3 (p < 0.0001. Myoglobin increased significantly

  13. High-resolution crystal structure of Streptococcus pyogenes β-NAD{sup +} glycohydrolase in complex with its endogenous inhibitor IFS reveals a highly water-rich interface

    Energy Technology Data Exchange (ETDEWEB)

    Yoon, Ji Young; An, Doo Ri; Yoon, Hye-Jin [Seoul National University, Seoul 151-747 (Korea, Republic of); Kim, Hyoun Sook [Seoul National University, Seoul 151-747 (Korea, Republic of); Seoul National University, Seoul 151-742 (Korea, Republic of); Lee, Sang Jae [Seoul National University, Seoul 151-742 (Korea, Republic of); Im, Ha Na; Jang, Jun Young [Seoul National University, Seoul 151-747 (Korea, Republic of); Suh, Se Won, E-mail: sewonsuh@snu.ac.kr [Seoul National University, Seoul 151-747 (Korea, Republic of); Seoul National University, Seoul 151-747 (Korea, Republic of)

    2013-11-01

    The crystal structure of the complex between the C-terminal domain of Streptococcus pyogenes β-NAD{sup +} glycohydrolase and an endogenous inhibitor for SPN was determined at 1.70 Å. It reveals that the interface between the two proteins is highly rich in water molecules. One of the virulence factors produced by Streptococcus pyogenes is β-NAD{sup +} glycohydrolase (SPN). S. pyogenes injects SPN into the cytosol of an infected host cell using the cytolysin-mediated translocation pathway. As SPN is toxic to bacterial cells themselves, S. pyogenes possesses the ifs gene that encodes an endogenous inhibitor for SPN (IFS). IFS is localized intracellularly and forms a complex with SPN. This intracellular complex must be dissociated during export through the cell envelope. To provide a structural basis for understanding the interactions between SPN and IFS, the complex was overexpressed between the mature SPN (residues 38–451) and the full-length IFS (residues 1–161), but it could not be crystallized. Therefore, limited proteolysis was used to isolate a crystallizable SPN{sub ct}–IFS complex, which consists of the SPN C-terminal domain (SPN{sub ct}; residues 193–451) and the full-length IFS. Its crystal structure has been determined by single anomalous diffraction and the model refined at 1.70 Å resolution. Interestingly, our high-resolution structure of the complex reveals that the interface between SPN{sub ct} and IFS is highly rich in water molecules and many of the interactions are water-mediated. The wet interface may facilitate the dissociation of the complex for translocation across the cell envelope.

  14. Comprehensive profiling of mercapturic acid metabolites from dietary acrylamide as short-term exposure biomarkers for evaluation of toxicokinetics in rats and daily internal exposure in humans using isotope dilution ultra-high performance liquid chromatography tandem mass spectrometry.

    Science.gov (United States)

    Zhang, Yu; Wang, Qiao; Cheng, Jun; Zhang, Jingshun; Xu, Jiaojiao; Ren, Yiping

    2015-09-24

    Mercapturic acid metabolites from dietary acrylamide are important short-term exposure biomarkers for evaluating the in vivo toxicity of acrylamide. Most of studies have focused on the measurement of two metabolites, N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA) and N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA). Thus, the comprehensive profile of acrylamide urinary metabolites cannot be fully understood. We developed an isotope dilution ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for the simultaneous determination of all four mercapturic acid adducts of acrylamide and its primary metabolite glycidamide under the electroscopy ionization negative (ESI-) mode in the present study. The limit of detection (LOD) and limit of quantification (LOQ) of the analytes ranged 0.1-0.3 ng/mL and 0.4-1.0 ng/mL, respectively. The recovery rates with low, intermediate and high spiking levels were calculated as 95.5%-105.4%, 98.2%-114.0% and 92.2%-108.9%, respectively. Acceptable within-laboratory reproducibility (RSDrats. Meanwhile, results of human urine analysis indicated that the levels of N-acetyl-S-(2-carbamoylethyl)-L-cysteine-sulfoxide (AAMA-sul), which did not appear in the mercapturic acid metabolites in rodents, were more than the sum of GAMA and N-acetyl-S-(1-carbamoyl-2-hydroxyethyl)-L-cysteine (iso-GAMA). Thus, AAMA-sul may alternatively become a specific biomarker for investigating the acrylamide exposure in humans. Current proposed method provides a substantial methodology support for comprehensive profiling of toxicokinetics and daily internal exposure evaluations of acrylamide in vivo.

  15. Uncovering precision phenotype-biomarker associations in traumatic brain injury using topological data analysis

    Science.gov (United States)

    Nielson, Jessica L.; Cooper, Shelly R.; Sorani, Marco D.; Inoue, Tomoo; Yuh, Esther L.; Mukherjee, Pratik; Petrossian, Tanya C.; Lum, Pek Y.; Lingsma, Hester F.; Gordon, Wayne A.; Okonkwo, David O.; Manley, Geoffrey T.

    2017-01-01

    Background Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented opportunities for improved TBI precision medicine, incorporating patho-anatomical and molecular mechanisms. Complete integration of these diverse data for TBI diagnosis and patient stratification remains an unmet challenge. Methods and findings The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes. We then applied topology-based data-driven discovery to identify natural subgroups of patients, based on the TBI-CDEs collected. Our hypothesis was two-fold: 1) A machine learning tool known as topological data analysis (TDA) would reveal data-driven patterns in patient outcomes to identify candidate biomarkers of recovery, and 2) TDA-identified biomarkers would significantly predict patient outcome recovery after TBI using more traditional methods of univariate statistical tests. TDA algorithms organized and mapped the data of TBI patients in multidimensional space, identifying a subset of mild TBI patients with a specific multivariate phenotype associated with unfavorable outcome at 3 and 6 months after injury. Further analyses revealed that this patient subset had high rates of post-traumatic stress disorder (PTSD), and enrichment in several distinct genetic polymorphisms associated with cellular responses to stress and DNA damage (PARP1), and in striatal dopamine processing (ANKK1, COMT, DRD2). Conclusions TDA identified a unique diagnostic subgroup of patients with unfavorable outcome after mild TBI that were significantly predicted by the presence of specific genetic polymorphisms. Machine learning methods such as TDA may provide a robust

  16. Epigenetic biomarkers in liver cancer.

    Science.gov (United States)

    Banaudha, Krishna K; Verma, Mukesh

    2015-01-01

    Liver cancer (hepatocellular carcinoma or HCC) is a major cancer worldwide. Research in this field is needed to identify biomarkers that can be used for early detection of the disease as well as new approaches to its treatment. Epigenetic biomarkers provide an opportunity to understand liver cancer etiology and evaluate novel epigenetic inhibitors for treatment. Traditionally, liver cirrhosis, proteomic biomarkers, and the presence of hepatitis viruses have been used for the detection and diagnosis of liver cancer. Promising results from microRNA (miRNA) profiling and hypermethylation of selected genes have raised hopes of identifying new biomarkers. Some of these epigenetic biomarkers may be useful in risk assessment and for screening populations to identify who is likely to develop cancer. Challenges and opportunities in the field are discussed in this chapter.

  17. Biomarkers in inflammatory bowel diseases

    DEFF Research Database (Denmark)

    Bennike, Tue; Birkelund, Svend; Stensballe, Allan

    2014-01-01

    with medications with the concomitant risk of adverse events. In addition, identification of disease and course specific biomarker profiles can be used to identify biological pathways involved in the disease development and treatment. Knowledge of disease mechanisms in general can lead to improved future...... development of preventive and treatment strategies. Thus, the clinical use of a panel of biomarkers represents a diagnostic and prognostic tool of potentially great value. The technological development in recent years within proteomic research (determination and quantification of the complete protein content......) has made the discovery of novel biomarkers feasible. Several IBD-associated protein biomarkers are known, but none have been successfully implemented in daily use to distinguish CD and UC patients. The intestinal tissue remains an obvious place to search for novel biomarkers, which blood, urine...

  18. Circulating Biomarker Panels in Alzheimer's Disease.

    Science.gov (United States)

    Zafari, Sachli; Backes, Christina; Meese, Eckart; Keller, Andreas

    2015-01-01

    The early diagnosis of diseases frequently represents an important unmet clinical need supporting in-time treatment of pathologies. This also applies to neurodegenerative diseases such as Alzheimer's disease (AD), the most common form of dementia, estimated to affect millions of individuals worldwide. The respective diagnostic and prognostic markers, especially for the preclinical stages of AD, are expected to improve patients' outcome significantly. In the last decades, many approaches to detecting AD have been developed, including markers to discover changes in amyloid-β levels [from cerebrospinal fluid (CSF) or using positron emission tomography] or other brain imaging technologies such as structural magnetic resonance imaging (MRI), functional-connectivity MRI or task-related functional MRI. A major challenge is the detection of AD using minimally or even noninvasive biomarkers from body fluids such as plasma or serum. Circulating biomarker candidates based on mRNAs or proteins measured from blood cells, plasma or serum have been proposed for various pathologies including AD. As for other diseases, there is a tendency to use marker signatures obtained by high-throughput approaches, which allow the generation of profiles of hundreds to thousands of biomarkers simultaneously [microarrays, mass spectrometry or next-generation sequencing (NGS)]. Beyond mRNAs and proteins, recent approaches have measured small noncoding RNA (so-called microRNA) profiles in AD patients' blood samples using NGS or array-based technologies. Generally, the development of marker panels is in its early stages and requires further, substantial clinical validation. In this review, we provide an overview of different circulating AD biomarkers, starting with a brief summary of CSF markers and focusing on novel biomarker signatures such as small noncoding RNA profiles.

  19. An Infrared Fiber-Optic Raman Sensor for Field Detecting of Organic Biomarkers Project

    Data.gov (United States)

    National Aeronautics and Space Administration — High throughput, fast detection and characterization of inorganic and organic biomarkers have become important challenge for future lunar robotic rover exploration...

  20. The role of metabolic biomarkers in drug toxicity studies.

    Science.gov (United States)

    Schnackenberg, Laura K; Beger, Richard D

    2008-01-01

    ABSTRACT Metabolic profiling is a technique that can potentially provide more sensitive and specific biomarkers of toxicity than the current clinical measures benefiting preclinical and clinical drug studies. Both nuclear magnetic resonance (NMR) and mass spectrometry (MS) platforms have been used for metabolic profiling studies of drug toxicity. Not only can both techniques provide novel biomarker(s) of toxicity but the combination of both techniques gives a broader range of metabolites evaluated. Changes in metabolic patterns can provide insight into mechanism(s) of toxicity and help to eliminate a potentially toxic new chemical entity earlier in the developmental process. Metabolic profiling offers numerous advantages in toxicological research and screening as sample collection and preparation are relatively simple. Further, sample throughput, reproducibility, and accuracy are high. The area of drug toxicity of therapeutic compounds has already been impacted by metabolic profiling studies and will continue to be impacted as new, more specific biomarker(s) are found. In order for a biomarker or pattern of biomarkers to be accepted, it must be shown that they originate from the target tissue of interest. Metabolic profiling studies are amenable to any biofluid or tissue sample making it possible to link the changes noted in urine for instance as originating from renal injury. Additionally, the ease of sample collection makes it possible to follow a single animal or subject over time in order to determine whether and when the toxicity resolves itself. This review focuses on the advantages of metabolic profiling for drug toxicity studies.

  1. Crystal Structures of Lys-63-linked tri- and di-ubiquitin Reveal a Highly Extended Chain Architecture

    Energy Technology Data Exchange (ETDEWEB)

    Weeks, S.; Grasty, K; Hernandez-Cuebas, L; Loll, P

    2009-01-01

    The covalent attachment of different types of poly-ubiquitin chains signal different outcomes for the proteins so targeted. For example, a protein modified with Lys-48-linked poly-ubiquitin chains is targeted for proteasomal degradation, whereas Lys-63-linked chains encode nondegradative signals. The structural features that enable these different types of chains to encode different signals have not yet been fully elucidated. We report here the X-ray crystal structures of Lys-63-linked tri- and di-ubiquitin at resolutions of 2.3 and 1.9 {angstrom}, respectively. The tri- and di-ubiquitin species adopt essentially identical structures. In both instances, the ubiquitin chain assumes a highly extended conformation with a left-handed helical twist; the helical chain contains four ubiquitin monomers per turn and has a repeat length of {approx}110 {angstrom}. Interestingly, Lys-48 ubiquitin chains also adopt a left-handed helical structure with a similar repeat length. However, the Lys-63 architecture is much more open than that of Lys-48 chains and exposes much more of the ubiquitin surface for potential recognition events. These new crystal structures are consistent with the results of solution studies of Lys-63 chain conformation, and reveal the structural basis for differential recognition of Lys-63 versus Lys-48 chains.

  2. High-resolution CO observation of the carbon star CIT 6 revealing the spiral structure and a nascent bipolar outflow

    CERN Document Server

    Kim, Hyosun; Hirano, Naomi; Zhao-Geisler, Ronny; Trejo, Alfonso; Yen, Hsi-Wei; Taam, Ronald E; Kemper, Francisca; Kim, Jongsoo; Byun, Do-Young; Liu, Tie

    2015-01-01

    CIT 6 is a carbon star in the transitional phase from the asymptotic giant branch (AGB) to the protoplanetary nebulae (pPN). Observational evidences of two point sources in the optical, circumstellar arc segments in an HC$_3$N line emission, and a bipolar nebula in near-infrared provide strong support for the presence of a binary companion. Hence, CIT 6 is very attractive for studying the role of companions in the AGB-pPN transition. We have carried out high resolution $^{12}$CO $J=2-1$ and $^{13}$CO $J=2-1$ observations of CIT 6 with the Submillimeter Array combined with the Submillimeter Telescope (single-dish) data. The $^{12}$CO channel maps reveal a spiral-shell pattern connecting the HC$_3$N segments in a continuous form, and an asymmetric outflow corresponding to the near-infrared bipolar nebula. Rotation of the $^{12}$CO channel peak position may be related to the inner spiral winding and/or the bipolar outflow. An eccentric orbit binary is suggested for the presences of an anisotropic mass loss to th...

  3. Single nucleotide polymorphism typing of Mycobacterium ulcerans reveals focal transmission of buruli ulcer in a highly endemic region of Ghana.

    Directory of Open Access Journals (Sweden)

    Katharina Röltgen

    Full Text Available Buruli ulcer (BU is an emerging necrotizing disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. While proximity to stagnant or slow flowing water bodies is a risk factor for acquiring BU, the epidemiology and mode of M. ulcerans transmission is poorly understood. Here we have used high-throughput DNA sequencing and comparisons of the genomes of seven M. ulcerans isolates that appeared monomorphic by existing typing methods. We identified a limited number of single nucleotide polymorphisms (SNPs and developed a real-time PCR SNP typing method based on these differences. We then investigated clinical isolates of M. ulcerans on which we had detailed information concerning patient location and time of diagnosis. Within the Densu river basin of Ghana we observed dominance of one clonal complex and local clustering of some of the variants belonging to this complex. These results reveal focal transmission and demonstrate, that micro-epidemiological analyses by SNP typing has great potential to help us understand how M. ulcerans is transmitted.

  4. Suzaku Observations of Luminous Quasars: Revealing the Nature of High-Energy Blazar Emission in Quiescent States

    CERN Document Server

    Abdo, A A; Sikora, M; Schady, P; Roming, P; Chester, M M; Maraschi, L

    2010-01-01

    We present the results from the Suzaku X-ray observations of five flat-spectrum radio quasars (FSRQs), namely PKS0208-512, Q0827+243, PKS1127-145, PKS1510-089 and 3C 454.3. All these sources were additionally monitored simultaneously or quasi-simultaneously by the Fermi satellite in gamma-rays and the Swift UVOT in the UV and optical bands, respectively. We constructed their broad-band spectra covering the frequency range from 10^14 Hz up to 10^25 Hz, and those reveal the nature of high-energy emission of luminous blazars in their low-activity states. The analyzed X-ray spectra are well fitted by a power-law model with photoelectric absorption. In the case of PKS0208-512, PKS1127-145, and 3C 454.3, the X-ray continuum showed indication of hard-ening at low-energies. Moreover, when compared with the previous X-ray observations, we see a significantly increasing contribution of low-energy photons to the total X-ray fluxes when the sources are getting fainter. The same behavior can be noted in the Suzaku data al...

  5. Comparative genomics analysis of Streptococcus isolates from the human small intestine reveals their adaptation to a highly dynamic ecosystem.

    Directory of Open Access Journals (Sweden)

    Bartholomeus Van den Bogert

    Full Text Available The human small-intestinal microbiota is characterised by relatively large and dynamic Streptococcus populations. In this study, genome sequences of small-intestinal streptococci from S. mitis, S. bovis, and S. salivarius species-groups were determined and compared with those from 58 Streptococcus strains in public databases. The Streptococcus pangenome consists of 12,403 orthologous groups of which 574 are shared among all sequenced streptococci and are defined as the Streptococcus core genome. Genome mining of the small-intestinal streptococci focused on functions playing an important role in the interaction of these streptococci in the small-intestinal ecosystem, including natural competence and nutrient-transport and metabolism. Analysis of the small-intestinal Streptococcus genomes predicts a high capacity to synthesize amino acids and various vitamins as well as substantial divergence in their carbohydrate transport and metabolic capacities, which is in agreement with observed physiological differences between these Streptococcus strains. Gene-specific PCR-strategies enabled evaluation of conservation of Streptococcus populations in intestinal samples from different human individuals, revealing that the S. salivarius strains were frequently detected in the small-intestine microbiota, supporting the representative value of the genomes provided in this study. Finally, the Streptococcus genomes allow prediction of the effect of dietary substances on Streptococcus population dynamics in the human small-intestine.

  6. Decapitation of high-altitude glaciers on the Tibetan Plateau revealed by ice core tritium and mercury records

    Directory of Open Access Journals (Sweden)

    S. C. Kang

    2015-01-01

    Full Text Available Two ice cores were retrieved from high elevations (~ 5800 m a.s.l. at Mt. Nyainqentanglha and Mt. Geladaindong in the southern to inland Tibetan Plateau. The combined analysis of tritium (3H, 210Pb, mercury tracers, along with other chemical records, revealed that the two coring sites had not received net ice accumulation since at least the 1950s and 1980s, respectively, implying an annual ice loss rate of more than several hundred millimeter water equivalent over these periods. Both mass balance modeling at the sites and in situ data from nearby glaciers confirmed a continuously negative mass balance (or mass loss in the region due to the dramatic warming in the last decades. Along with a recent report on Naimona'nyi Glacier in the Himalaya, the findings suggest that glacier decapitation (i.e., the loss of the accumulation zone is a wide-spread phenomenon from the southern to inland Tibetan Plateau even at the summit regions. This raises concerns over the rapid rate of glacier ice loss and associated changes in surface glacier runoff, water availability, and sea levels.

  7. High Species Richness of Scinax Treefrogs (Hylidae) in a Threatened Amazonian Landscape Revealed by an Integrative Approach.

    Science.gov (United States)

    Ferrão, Miquéias; Colatreli, Olavo; de Fraga, Rafael; Kaefer, Igor L; Moravec, Jiří; Lima, Albertina P

    2016-01-01

    Rising habitat loss is one of the main drivers of the global amphibian decline. Nevertheless, knowledge of amphibian diversity needed for effective habitat protection is still highly inadequate in remote tropical regions, the greater part of the Amazonia. In this study we integrated molecular, morphological and bioacoustic evidence to evaluate the species richness of the treefrogs genus Scinax over a 1000 km transect across rainforest of the Purus-Madeira interfluve, and along the east bank of the upper Madeira river, Brazilian Amazonia. Analysis revealed that 82% of the regional species richness of Scinax is still undescribed; two nominal species, seven confirmed candidate species, two unconfirmed candidate species, and one deep conspecific lineage were detected in the study area. DNA barcoding based analysis of the 16s rRNA gene indicates possible existence of three discrete species groups within the genus Scinax, in addition to the already-known S. rostratus species Group. Quantifying and characterizing the number of undescribed Scinax taxa on a regional scale, we provide a framework for future taxonomic study in Amazonia. These findings indicate that the level to which Amazonian anura species richness has been underestimated is far greater than expected. Consequently, special attention should be paid both to taxonomic studies and protection of the still-neglected Amazonian Scinax treefrogs.

  8. Assessing subaqueous mudslide hazard on the Mississippi River delta front, Part 2: Insights revealed through high-resolution geophysical surveying

    Science.gov (United States)

    Obelcz, J.; Xu, K.; Bentley, S. J.; Georgiou, I. Y.; Maloney, J. M.; Miner, M. D.; Hanegan, K.; Keller, G.

    2014-12-01

    The northern Gulf of Mexico, including the subaqueous Mississippi River delta front (MRDF), has been productive for oil and gas development since the early 1900s. In 1969 cyclic seafloor wave loading associated with the passage of Hurricane Camille triggered subaqueous mudflows across the MRDF, destroying several offshore oil platforms. This incident spurred geophysical and geotechnical studies of the MRDF, which found that the delta front is prone to mass failures on gentle gradients (survey area can be classified into four primary sedimentary facies: mudflow gullies, mudflow lobes, undisturbed prodelta, and undisturbed delta front. Subbottom profiles reveal extensive biogenic gas from 20 to about 80 m water depths on the delta front; sidescan data show a variety of bottleneck slides, mudflow gullies and mudflow noses. Previous studies have attempted to constrain the periodicity and magnitude of subaqueous mudslides on the MRDF. However, large age gaps and varied resolution between datasets result in ambiguity regarding the cause and magnitude of observed bathymetric changes. We present high-temporal resolution MRDF bathymetric variations from 2005 (post Hurricane Katrina), 2009 (relatively quiescent storm period), and 2014 (post 2011 Mississippi River flood). These data yield better magnitude and timing estimates of mass movements. This exercise represents a first step towards (1) assembling a comprehensive geologic dataset upon which future MRDF geohazard assessments can be founded, and (2) understanding the dynamics of a massive passive margin deltaic lobe entering a phase of decline.

  9. High throughput sequencing analysis of RNA libraries reveals the influences of initial library and PCR methods on SELEX efficiency.

    Science.gov (United States)

    Takahashi, Mayumi; Wu, Xiwei; Ho, Michelle; Chomchan, Pritsana; Rossi, John J; Burnett, John C; Zhou, Jiehua

    2016-09-22

    The systemic evolution of ligands by exponential enrichment (SELEX) technique is a powerful and effective aptamer-selection procedure. However, modifications to the process can dramatically improve selection efficiency and aptamer performance. For example, droplet digital PCR (ddPCR) has been recently incorporated into SELEX selection protocols to putatively reduce the propagation of byproducts and avoid selection bias that result from differences in PCR efficiency of sequences within the random library. However, a detailed, parallel comparison of the efficacy of conventional solution PCR versus the ddPCR modification in the RNA aptamer-selection process is needed to understand effects on overall SELEX performance. In the present study, we took advantage of powerful high throughput sequencing technology and bioinformatics analysis coupled with SELEX (HT-SELEX) to thoroughly investigate the effects of initial library and PCR methods in the RNA aptamer identification. Our analysis revealed that distinct "biased sequences" and nucleotide composition existed in the initial, unselected libraries purchased from two different manufacturers and that the fate of the "biased sequences" was target-dependent during selection. Our comparison of solution PCR- and ddPCR-driven HT-SELEX demonstrated that PCR method affected not only the nucleotide composition of the enriched sequences, but also the overall SELEX efficiency and aptamer efficacy.

  10. Compositional variability on the surface of 4 Vesta revealed through GRaND measurements of high-energy gamma rays

    Science.gov (United States)

    Peplowski, Patrick N.; Lawrence, David J.; Prettyman, Thomas H.; Yamashita, Naoyuki; Bazell, Dave; Feldman, William C.; Le Corre, Lucille; McCoy, Timothy J.; Reddy, Vishnu; Reedy, Robert C.; Russell, Chris T.; Toplis, Michael J.

    2013-11-01

    Measurements of the high-energy gamma-ray flux emanating from asteroid 4 Vesta by the Dawn Gamma-Ray and Neutron Detector (GRaND) have revealed variability in the near-surface elemental composition of the Vestan surface. These observations are consistent with the presence of large (≥8 × 104 km2) regions with distinct, HED-like elemental compositions. The results agree broadly with other global measurements, such as the macroscopic neutron absorption cross section and spectral reflectance-derived mineralogic maps. Two distinct regions with eucrite-like elemental compositions have been identified, the first located primarily within the Lucaria and Marcia quadrangles and the second within Oppia quadrangle. The former region is collocated with some of the oldest, most heavily cratered terrain on Vesta. The interior of the 500 km diameter Rheasilvia impact basin is found to have a composition that is consistent with diogenite-like material. Taken together, these observations support the hypothesis that Vesta's original crust was composed of basaltic outflows in the form of eucritic-like material and that the Rheasilvia-basin-forming impact exposed lower-crustal, diogenite-like material. These measurements also constrain the maximum amount of mesosiderite-like material to <10% for each 15 × 15° surface element.

  11. ALMA reveals optically thin, highly excited CO gas in the jet-driven winds of the galaxy IC5063

    CERN Document Server

    Dasyra, K M; Oosterloo, T; Oonk, J B R; Morganti, R; Salome, P; Vlahakis, N

    2016-01-01

    Using CO (4-3) and (2-1) Atacama Large Millimeter Array (ALMA) data, we prove that the molecular gas in the jet-driven winds of the galaxy IC5063 is more highly excited than the rest of the molecular gas in the disk of the same galaxy. On average, the CO (4-3) / CO (2-1) flux ratio is 1 for the disk and 5 for the jet accelerated or impacted gas. Spatially-resolved maps reveal that in regions associated with winds, the CO (4-3) / CO (2-1) flux ratio significantly exceeds the upper limit of 4 for optically thick gas. It frequently takes values between 5 and 11, and it occasionally further approaches the upper limit of 16 for optically thin gas. Excitation temperatures of 30-100 K are common for the molecules in these regions. If all of the outflowing molecular gas is optically thin, at 30-50 K, then its mass is 2*10^6 M_sun. This lower mass limit is an order of magnitude below the mass derived from the CO (2-1) flux in case of optically thick gas. Our result suggests that molecular wind masses may be overestima...

  12. Swift reveals the eclipsing nature of the high mass X-ray binary IGR~J16195-4945

    CERN Document Server

    Cusumano, G; Segreto, A; D'Aì, A

    2016-01-01

    IGR J16195-4945 is a hard X-ray source discovered by INTEGRAL during the Core Program observations performed in 2003. We analyzed the X-ray emission of this source exploiting the Swift-BAT survey data from December 2004 to March 2015, and all the available Swift-XRT pointed observations. The source is detected at a high significance level in the 123-month BAT survey data, with an average 15-150 keV flux of the source of ~1.6 mCrab. The timing analysis on the BAT data reveals with a significance higher than 6 standard deviations the presence of a modulated signal with a period of 3.945 d, that we interpret as the orbital period of the binary system. The folded light curve shows a flat profile with a narrow full eclipse lasting ~3.5% of the orbital period. We requested phase-constrained XRT observations to obtain a more detailed characterization of the eclipse in the soft X-ray range. Adopting resonable guess values for the mass and radius of the companion star, we derive a semi-major orbital axis of ~31 R_sun,...

  13. High spatial dynamics-photoluminescence imaging reveals the metallurgy of the earliest lost-wax cast object

    Science.gov (United States)

    Thoury, M.; Mille, B.; Séverin-Fabiani, T.; Robbiola, L.; Réfrégiers, M.; Jarrige, J.-F.; Bertrand, L.

    2016-11-01

    Photoluminescence spectroscopy is a key method to monitor defects in semiconductors from nanophotonics to solar cell systems. Paradoxically, its great sensitivity to small variations of local environment becomes a handicap for heterogeneous systems, such as are encountered in environmental, medical, ancient materials sciences and engineering. Here we demonstrate that a novel full-field photoluminescence imaging approach allows accessing the spatial distribution of crystal defect fluctuations at the crystallite level across centimetre-wide fields of view. This capacity is illustrated in archaeology and material sciences. The coexistence of two hitherto indistinguishable non-stoichiometric cuprous oxide phases is revealed in a 6,000-year-old amulet from Mehrgarh (Baluchistan, Pakistan), identified as the oldest known artefact made by lost-wax casting and providing a better understanding of this fundamental invention. Low-concentration crystal defect fluctuations are readily mapped within ZnO nanowires. High spatial dynamics-photoluminescence imaging holds great promise for the characterization of bulk heterogeneous systems across multiple disciplines.