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Sample records for variable multiple gene

  1. Multiple and variable NHEJ-like genes are involved in resistance to DNA damage in Streptomyces ambofaciens

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    Grégory Hoff

    2016-11-01

    Full Text Available Non homologous end-joining (NHEJ is a double strand break (DSB repair pathway which does not require any homologous template and can ligate two DNA ends together. The basic bacterial NHEJ machinery involves two partners: the Ku protein, a DNA end binding protein for DSB recognition and the multifunctional LigD protein composed a ligase, a nuclease and a polymerase domain, for end processing and ligation of the broken ends. In silico analyses performed in the 38 sequenced genomes of Streptomyces species revealed the existence of a large panel of NHEJ-like genes. Indeed, ku genes or ligD domain homologues are scattered throughout the genome in multiple copies and can be distinguished in two categories: the core NHEJ gene set constituted of conserved loci and the variable NHEJ gene set constituted of NHEJ-like genes present in only a part of the species. In Streptomyces ambofaciens ATCC 23877, not only the deletion of core genes but also that of variable genes led to an increased sensitivity to DNA damage induced by electron beam irradiation. Multiple mutants of ku, ligase or polymerase encoding genes showed an aggravated phenotype compared to single mutants. Biochemical assays revealed the ability of Ku-like proteins to protect and to stimulate ligation of DNA ends. RT-qPCR and GFP fusion experiments suggested that ku-like genes show a growth phase dependent expression profile consistent with their involvement in DNA repair during spores formation and/or germination.

  2. A Latent Variable Approach for Meta-Analysis of Gene Expression Data from Multiple Microarray Experiments

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    Chinnaiyan Arul M

    2007-09-01

    Full Text Available Abstract Background With the explosion in data generated using microarray technology by different investigators working on similar experiments, it is of interest to combine results across multiple studies. Results In this article, we describe a general probabilistic framework for combining high-throughput genomic data from several related microarray experiments using mixture models. A key feature of the model is the use of latent variables that represent quantities that can be combined across diverse platforms. We consider two methods for estimation of an index termed the probability of expression (POE. The first, reported in previous work by the authors, involves Markov Chain Monte Carlo (MCMC techniques. The second method is a faster algorithm based on the expectation-maximization (EM algorithm. The methods are illustrated with application to a meta-analysis of datasets for metastatic cancer. Conclusion The statistical methods described in the paper are available as an R package, metaArray 1.8.1, which is at Bioconductor, whose URL is http://www.bioconductor.org/.

  3. A latent variable approach to study gene-environment interactions in the presence of multiple correlated exposures.

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    Sánchez, Brisa N; Kang, Shan; Mukherjee, Bhramar

    2012-06-01

    Many existing cohort studies initially designed to investigate disease risk as a function of environmental exposures have collected genomic data in recent years with the objective of testing for gene-environment interaction (G × E) effects. In environmental epidemiology, interest in G × E arises primarily after a significant effect of the environmental exposure has been documented. Cohort studies often collect rich exposure data; as a result, assessing G × E effects in the presence of multiple exposure markers further increases the burden of multiple testing, an issue already present in both genetic and environment health studies. Latent variable (LV) models have been used in environmental epidemiology to reduce dimensionality of the exposure data, gain power by reducing multiplicity issues via condensing exposure data, and avoid collinearity problems due to presence of multiple correlated exposures. We extend the LV framework to characterize gene-environment interaction in presence of multiple correlated exposures and genotype categories. Further, similar to what has been done in case-control G × E studies, we use the assumption of gene-environment (G-E) independence to boost the power of tests for interaction. The consequences of making this assumption, or the issue of how to explicitly model G-E association has not been previously investigated in LV models. We postulate a hierarchy of assumptions about the LV model regarding the different forms of G-E dependence and show that making such assumptions may influence inferential results on the G, E, and G × E parameters. We implement a class of shrinkage estimators to data adaptively trade-off between the most restrictive to most flexible form of G-E dependence assumption and note that such class of compromise estimators can serve as a benchmark of model adequacy in LV models. We demonstrate the methods with an example from the Early Life Exposures in Mexico City to Neuro-Toxicants Study of lead exposure, iron

  4. Gait Variability and Multiple Sclerosis

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    Michael J. Socie

    2013-01-01

    Full Text Available Gait variability, that is, fluctuations in movement during walking, is an indicator of walking function and has been associated with various adverse outcomes such as falls. In this paper, current research concerning gait variability in persons with multiple sclerosis (MS is discussed. It is well established that persons with MS have greater gait variability compared to age and gender matched controls without MS. The reasons for the increase in gait variability are not completely understood. Evidence indicates that disability level, assistive device use, attentional requirement, and fatigue are related to gait variability in persons with MS. Future research should address the time-evolving structure (i.e., temporal characteristics of gait variability, the clinical importance of gait variability, and underlying mechanisms that drive gait variability in individuals with MS.

  5. Multiple Independent Retroelement Insertions in the Promoter of a Stress Response Gene Have Variable Molecular and Functional Effects in Drosophila.

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    Miriam Merenciano

    2016-08-01

    Full Text Available Promoters are structurally and functionally diverse gene regulatory regions. The presence or absence of sequence motifs and the spacing between the motifs defines the properties of promoters. Recent alternative promoter usage analyses in Drosophila melanogaster revealed that transposable elements significantly contribute to promote diversity. In this work, we analyzed in detail one of the transposable element insertions, named FBti0019985, that has been co-opted to drive expression of CG18446, a candidate stress response gene. We analyzed strains from different natural populations and we found that besides FBti0019985, there are another eight independent transposable elements inserted in the proximal promoter region of CG18446. All nine insertions are solo-LTRs that belong to the roo family. We analyzed the sequence of the nine roo insertions and we investigated whether the different insertions were functionally equivalent by performing 5'-RACE, gene expression, and cold-stress survival experiments. We found that different insertions have different molecular and functional consequences. The exact position where the transposable elements are inserted matters, as they all showed highly conserved sequences but only two of the analyzed insertions provided alternative transcription start sites, and only the FBti0019985 insertion consistently affects CG18446 expression. The phenotypic consequences of the different insertions also vary: only FBti0019985 was associated with cold-stress tolerance. Interestingly, the only previous report of transposable elements inserting repeatedly and independently in a promoter region in D. melanogaster, were also located upstream of a stress response gene. Our results suggest that functional validation of individual structural variants is needed to resolve the complexity of insertion clusters.

  6. High-Throughput GoMiner, an 'industrial-strength' integrative gene ontology tool for interpretation of multiple-microarray experiments, with application to studies of Common Variable Immune Deficiency (CVID

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    Wynn Thomas A

    2005-07-01

    interpretation of altered gene expression patterns in Common Variable Immune Deficiency (CVID. High-Throughput GoMiner will be useful in a wide range of applications, including the study of time-courses, evaluation of multiple drug treatments, comparison of multiple gene knock-outs or knock-downs, and screening of large numbers of chemical derivatives generated from a promising lead compound.

  7. Increased chromosomal breakage in Tourette syndrome predicts the possibility of variable multiple gene involvement in spectrum phenotypes: Preliminary findings and hypothesis

    Energy Technology Data Exchange (ETDEWEB)

    Gericke, G.S.; Simonic, I.; Cloete, E.; Buckle, C. [Univ. of Pretoria (South Africa)] [and others

    1995-10-09

    Increased chromosomal breakage was found in 12 patients with DSM-IV Tourette syndrome (TS) as compared with 10 non-TS control individuals with respect to untreated, modified RPM1-, and BrdU treated lymphocyte cultures (P < 0.001 in each category). A hypothesis is proposed that a major TS gene is probably connected to genetic instability, and associated chromosomal marker sites may be indicative of the localization of secondary genes whose altered expression could be responsible for associated comorbid conditions. This concept implies that genes influencing higher brain functions may be situated at or near highly recombigenic areas allowing enhanced amplification, duplication and recombination following chromosomal strand breakage. Further studies on a larger sample size are required to confirm the findings relating to chromosomal breakage and to analyze the possible implications for a paradigmatic shift in linkage strategy for complex disorders by focusing on areas at or near unstable chromosomal marker sites. 32 refs., 1 tab.

  8. Multiple factor analysis with continuous and dichotomous variables

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    Thanoon, Thanoon Y.; Adnan, Robiah; Saffari, Seyed Ehsan

    2014-12-01

    In this paper, continuous and dichotomous variables are used in multiple factor analysis method. When all variables within the same group are continuous, we use principal component analysis method in factor analysis, if all variables within the same group are dichotomous we use multiple correspondence analysis method in factor analysis. Statistical analyses, which involve Eigen roots, Eigen vectors, multiple factor loadings, correlation coefficient RV, contribution table, are discussed. The proposed procedure is illustrated by a lung cancer data consists of four groups "group of personal variables", "group of therapeutic variables", "group of nutritional variables", "group of genetic variables". Analysis are done by using XLSTAT program.

  9. Mining gene expression data of multiple sclerosis.

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    Pi Guo

    Full Text Available Microarray produces a large amount of gene expression data, containing various biological implications. The challenge is to detect a panel of discriminative genes associated with disease. This study proposed a robust classification model for gene selection using gene expression data, and performed an analysis to identify disease-related genes using multiple sclerosis as an example.Gene expression profiles based on the transcriptome of peripheral blood mononuclear cells from a total of 44 samples from 26 multiple sclerosis patients and 18 individuals with other neurological diseases (control were analyzed. Feature selection algorithms including Support Vector Machine based on Recursive Feature Elimination, Receiver Operating Characteristic Curve, and Boruta algorithms were jointly performed to select candidate genes associating with multiple sclerosis. Multiple classification models categorized samples into two different groups based on the identified genes. Models' performance was evaluated using cross-validation methods, and an optimal classifier for gene selection was determined.An overlapping feature set was identified consisting of 8 genes that were differentially expressed between the two phenotype groups. The genes were significantly associated with the pathways of apoptosis and cytokine-cytokine receptor interaction. TNFSF10 was significantly associated with multiple sclerosis. A Support Vector Machine model was established based on the featured genes and gave a practical accuracy of ∼86%. This binary classification model also outperformed the other models in terms of Sensitivity, Specificity and F1 score.The combined analytical framework integrating feature ranking algorithms and Support Vector Machine model could be used for selecting genes for other diseases.

  10. Dimension reduction of the explanatory variables in multiple linear regression

    OpenAIRE

    Filzmoser, P; Croux, Christophe

    2003-01-01

    2002 Mathematics Subject Classification: 62J05, 62G35. In classical multiple linear regression analysis problems will occur if the regressors are either multicollinear or if the number of regressors is larger than the number of observations. In this note a new method is introduced which constructs orthogonal predictor variables in a way to have a maximal correlation with the dependent variable. The predictor variables are linear combinations of the original regressors. This ...

  11. Genetic variability of the equine casein genes.

    Science.gov (United States)

    Brinkmann, J; Jagannathan, V; Drögemüller, C; Rieder, S; Leeb, T; Thaller, G; Tetens, J

    2016-07-01

    The casein genes are known to be highly variable in typical dairy species, such as cattle and goat, but the knowledge about equine casein genes is limited. Nevertheless, mare milk production and consumption is gaining importance because of its high nutritive value, use in naturopathy, and hypoallergenic properties with respect to cow milk protein allergies. In the current study, the open reading frames of the 4 casein genes CSN1S1 (αS1-casein), CSN2 (β-casein), CSN1S2 (αS2-casein), and CSN3 (κ-casein) were resequenced in 253 horses of 14 breeds. The analysis revealed 21 nonsynonymous nucleotide exchanges, as well as 11 synonymous nucleotide exchanges, leading to a total of 31 putative protein isoforms predicted at the DNA level, 26 of which considered novel. Although the majority of the alleles need to be confirmed at the transcript and protein level, a preliminary nomenclature was established for the equine casein alleles. Copyright © 2016 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

  12. Aberrant gene promoter methylation associated with sporadic multiple colorectal cancer.

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    Victoria Gonzalo

    Full Text Available BACKGROUND: Colorectal cancer (CRC multiplicity has been mainly related to polyposis and non-polyposis hereditary syndromes. In sporadic CRC, aberrant gene promoter methylation has been shown to play a key role in carcinogenesis, although little is known about its involvement in multiplicity. To assess the effect of methylation in tumor multiplicity in sporadic CRC, hypermethylation of key tumor suppressor genes was evaluated in patients with both multiple and solitary tumors, as a proof-of-concept of an underlying epigenetic defect. METHODOLOGY/PRINCIPAL FINDINGS: We examined a total of 47 synchronous/metachronous primary CRC from 41 patients, and 41 gender, age (5-year intervals and tumor location-paired patients with solitary tumors. Exclusion criteria were polyposis syndromes, Lynch syndrome and inflammatory bowel disease. DNA methylation at the promoter region of the MGMT, CDKN2A, SFRP1, TMEFF2, HS3ST2 (3OST2, RASSF1A and GATA4 genes was evaluated by quantitative methylation specific PCR in both tumor and corresponding normal appearing colorectal mucosa samples. Overall, patients with multiple lesions exhibited a higher degree of methylation in tumor samples than those with solitary tumors regarding all evaluated genes. After adjusting for age and gender, binomial logistic regression analysis identified methylation of MGMT2 (OR, 1.48; 95% CI, 1.10 to 1.97; p = 0.008 and RASSF1A (OR, 2.04; 95% CI, 1.01 to 4.13; p = 0.047 as variables independently associated with tumor multiplicity, being the risk related to methylation of any of these two genes 4.57 (95% CI, 1.53 to 13.61; p = 0.006. Moreover, in six patients in whom both tumors were available, we found a correlation in the methylation levels of MGMT2 (r = 0.64, p = 0.17, SFRP1 (r = 0.83, 0.06, HPP1 (r = 0.64, p = 0.17, 3OST2 (r = 0.83, p = 0.06 and GATA4 (r = 0.6, p = 0.24. Methylation in normal appearing colorectal mucosa from patients with multiple and solitary CRC showed no relevant

  13. [Heart rate variability during sleep in children with multiple disabilities].

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    Bouquier, L; Amand, M; Van Eecke, D

    2013-12-01

    To study heart rate variability during sleep in children with multiple disabilities in order to observe the behavior of the autonomic nervous system. The R-R interval variability of 4 to 12 years old children was recorded with a heart rate monitor during one night. Children with multiple disabilities (G1) and healthy children (G2) were compared in time, frequency, and non-linear domains. Temporal (P0.05). The diseases encountered are probably the reason for these findings, but the variety of disorders and medications of the children with multiple disabilities needs to be studied with a larger and more varied sample. Sympathetic predominance during sleep in children with multiple disabilities is associated with a decrease in adaptive abilities of these children's autonomic nervous system. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  14. Variable selection in multiple linear regression: The influence of ...

    African Journals Online (AJOL)

    Akaike's information criterion, influential data cases, Mallows' Cp criterion, multiple linear regression, variable ... may be modified, and hopefully improved, by making use of the influence measures. Four practical ..... information to any practitioner who analyses the fuel data, will surely be helpful in the decision as to whether ...

  15. Variable selection in multiple linear regression: The influence of ...

    African Journals Online (AJOL)

    The influence of individual cases in a data set is studied when variable selection is applied in multiple linear regression. Two different influence measures, based on the Cp criterion and Akaike's information criterion, are introduced. The relative change in the selection criterion when an individual case is omitted is proposed ...

  16. Interpreting Multiple Linear Regression: A Guidebook of Variable Importance

    Science.gov (United States)

    Nathans, Laura L.; Oswald, Frederick L.; Nimon, Kim

    2012-01-01

    Multiple regression (MR) analyses are commonly employed in social science fields. It is also common for interpretation of results to typically reflect overreliance on beta weights, often resulting in very limited interpretations of variable importance. It appears that few researchers employ other methods to obtain a fuller understanding of what…

  17. Simultaneous gene finding in multiple genomes.

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    König, Stefanie; Romoth, Lars W; Gerischer, Lizzy; Stanke, Mario

    2016-11-15

    As the tree of life is populated with sequenced genomes ever more densely, the new challenge is the accurate and consistent annotation of entire clades of genomes. We address this problem with a new approach to comparative gene finding that takes a multiple genome alignment of closely related species and simultaneously predicts the location and structure of protein-coding genes in all input genomes, thereby exploiting negative selection and sequence conservation. The model prefers potential gene structures in the different genomes that are in agreement with each other, or-if not-where the exon gains and losses are plausible given the species tree. We formulate the multi-species gene finding problem as a binary labeling problem on a graph. The resulting optimization problem is NP hard, but can be efficiently approximated using a subgradient-based dual decomposition approach. The proposed method was tested on whole-genome alignments of 12 vertebrate and 12 Drosophila species. The accuracy was evaluated for human, mouse and Drosophila melanogaster and compared to competing methods. Results suggest that our method is well-suited for annotation of (a large number of) genomes of closely related species within a clade, in particular, when RNA-Seq data are available for many of the genomes. The transfer of existing annotations from one genome to another via the genome alignment is more accurate than previous approaches that are based on protein-spliced alignments, when the genomes are at close to medium distances. The method is implemented in C ++ as part of Augustus and available open source at http://bioinf.uni-greifswald.de/augustus/ CONTACT: stefaniekoenig@ymail.com or mario.stanke@uni-greifswald.deSupplementary information: Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  18. Ultrahigh-dimensional variable selection method for whole-genome gene-gene interaction analysis

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    Ueki Masao

    2012-05-01

    Full Text Available Abstract Background Genome-wide gene-gene interaction analysis using single nucleotide polymorphisms (SNPs is an attractive way for identification of genetic components that confers susceptibility of human complex diseases. Individual hypothesis testing for SNP-SNP pairs as in common genome-wide association study (GWAS however involves difficulty in setting overall p-value due to complicated correlation structure, namely, the multiple testing problem that causes unacceptable false negative results. A large number of SNP-SNP pairs than sample size, so-called the large p small n problem, precludes simultaneous analysis using multiple regression. The method that overcomes above issues is thus needed. Results We adopt an up-to-date method for ultrahigh-dimensional variable selection termed the sure independence screening (SIS for appropriate handling of numerous number of SNP-SNP interactions by including them as predictor variables in logistic regression. We propose ranking strategy using promising dummy coding methods and following variable selection procedure in the SIS method suitably modified for gene-gene interaction analysis. We also implemented the procedures in a software program, EPISIS, using the cost-effective GPGPU (General-purpose computing on graphics processing units technology. EPISIS can complete exhaustive search for SNP-SNP interactions in standard GWAS dataset within several hours. The proposed method works successfully in simulation experiments and in application to real WTCCC (Wellcome Trust Case–control Consortium data. Conclusions Based on the machine-learning principle, the proposed method gives powerful and flexible genome-wide search for various patterns of gene-gene interaction.

  19. VariableR Reclustering in Multiple Top Quark and W Boson Events

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    Hyde, Jeremy [SLAC National Accelerator Lab., Menlo Park, CA (United States)

    2015-08-14

    VariableR jet reclustering is an innovative technique that allows for the reconstruction of boosted object over a wide range of kinematic regimes. Such capability enables the efficient identification of events with multiple boosted top quarks which is a typical signature for new physics processes such as the production of the supersymmetric partner of the gluon. In order to evaluate the performance of the algorithm, the VariableR reclustered jets are compared with fixed radius reclustered jets. The flexibility of the algorithm is tested by reconstructing both boosted top quarks and boosted W bosons. The VariableR reclustering method is found to be more efficient than the fixed radius algorithm at identifying top quarks and W bosons in events with four top quarks, therefore enhancing the sensitivity for gluino searches.

  20. VariableR reclustering in multiple top quark events - Oral Presentation

    Energy Technology Data Exchange (ETDEWEB)

    Hyde, Jeremy; /SLAC

    2015-08-22

    VariableR jet reclustering is an innovative technique that allows for the reconstruction of boosted object over a wide range of kinematic regimes. Such capability enables the efficient identification of events with multiple boosted top quarks which is a typical signature for new physics processes such as the production of the supersymmetric partner of the gluon. In order to evaluate the performance of the algorithm, the VariableR reclustered jets are compared with fixed radius reclustered jets. The flexibility of the algorithm is tested by reconstructing both boosted top quarks and boosted W bosons. The VariableR reclustering method is found to be more efficient than the fixed radius algorithm at identifying top quarks and W bosons in events with four top quarks, therefore enhancing the sensitivity for gluino searches.

  1. FPGA implementation of high-frequency multiple PWM for variable voltage variable frequency controller

    Energy Technology Data Exchange (ETDEWEB)

    Boumaaraf, Abdelâali, E-mail: aboumaaraf@yahoo.fr [Université Abbès Laghrour, Laboratoire des capteurs, Instrumentations et procédés (LCIP), Khenchela (Algeria); University of Farhat Abbas Setif1, Sétif, 19000 (Algeria); Mohamadi, Tayeb [University of Farhat Abbas Setif1, Sétif, 19000 (Algeria); Gourmat, Laïd [Université Abbès Laghrour, Khenchela, 40000 (Algeria)

    2016-07-25

    In this paper, we present the FPGA implementation of the multiple pulse width modulation (MPWM) signal generation with repetition of data segments, applied to the variable frequency variable voltage systems and specially at to the photovoltaic water pumping system, in order to generate a signal command very easily between 10 Hz to 60 Hz with a small frequency and reduce the cost of the control system.

  2. Risk score modeling of multiple gene to gene interactions using aggregated-multifactor dimensionality reduction

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    Dai Hongying

    2013-01-01

    Full Text Available Abstract Background Multifactor Dimensionality Reduction (MDR has been widely applied to detect gene-gene (GxG interactions associated with complex diseases. Existing MDR methods summarize disease risk by a dichotomous predisposing model (high-risk/low-risk from one optimal GxG interaction, which does not take the accumulated effects from multiple GxG interactions into account. Results We propose an Aggregated-Multifactor Dimensionality Reduction (A-MDR method that exhaustively searches for and detects significant GxG interactions to generate an epistasis enriched gene network. An aggregated epistasis enriched risk score, which takes into account multiple GxG interactions simultaneously, replaces the dichotomous predisposing risk variable and provides higher resolution in the quantification of disease susceptibility. We evaluate this new A-MDR approach in a broad range of simulations. Also, we present the results of an application of the A-MDR method to a data set derived from Juvenile Idiopathic Arthritis patients treated with methotrexate (MTX that revealed several GxG interactions in the folate pathway that were associated with treatment response. The epistasis enriched risk score that pooled information from 82 significant GxG interactions distinguished MTX responders from non-responders with 82% accuracy. Conclusions The proposed A-MDR is innovative in the MDR framework to investigate aggregated effects among GxG interactions. New measures (pOR, pRR and pChi are proposed to detect multiple GxG interactions.

  3. Identification of genes associated with multiple cancers via integrative analysis

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    Huang Jian

    2009-11-01

    Full Text Available Abstract Background Advancement in gene profiling techniques makes it possible to measure expressions of thousands of genes and identify genes associated with development and progression of cancer. The identified cancer-associated genes can be used for diagnosis, prognosis prediction, and treatment selection. Most existing cancer microarray studies have been focusing on the identification of genes associated with a specific type of cancer. Recent biomedical studies suggest that different cancers may share common susceptibility genes. A comprehensive description of the associations between genes and cancers requires identification of not only multiple genes associated with a specific type of cancer but also genes associated with multiple cancers. Results In this article, we propose the Mc.TGD (Multi-cancer Threshold Gradient Descent, an integrative analysis approach capable of analyzing multiple microarray studies on different cancers. The Mc.TGD is the first regularized approach to conduct "two-dimensional" selection of genes with joint effects on cancer development. Simulation studies show that the Mc.TGD can more accurately identify genes associated with multiple cancers than meta analysis based on "one-dimensional" methods. As a byproduct, identification accuracy of genes associated with only one type of cancer may also be improved. We use the Mc.TGD to analyze seven microarray studies investigating development of seven different types of cancers. We identify one gene associated with six types of cancers and four genes associated with five types of cancers. In addition, we also identify 11, 9, 18, and 17 genes associated with 4 to 1 types of cancers, respectively. We evaluate prediction performance using a Leave-One-Out cross validation approach and find that only 4 (out of 570 subjects cannot be properly predicted. Conclusion The Mc.TGD can identify a short list of genes associated with one or multiple types of cancers. The identified genes

  4. Methods for monitoring multiple gene expression

    Energy Technology Data Exchange (ETDEWEB)

    Berka, Randy [Davis, CA; Bachkirova, Elena [Davis, CA; Rey, Michael [Davis, CA

    2012-05-01

    The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

  5. Methods for monitoring multiple gene expression

    Science.gov (United States)

    Berka, Randy; Bachkirova, Elena; Rey, Michael

    2013-10-01

    The present invention relates to methods for monitoring differential expression of a plurality of genes in a first filamentous fungal cell relative to expression of the same genes in one or more second filamentous fungal cells using microarrays containing Trichoderma reesei ESTs or SSH clones, or a combination thereof. The present invention also relates to computer readable media and substrates containing such array features for monitoring expression of a plurality of genes in filamentous fungal cells.

  6. Active late-appearing variable surface antigen genes in Trypanosoma equiperdum are constructed entirely from pseudogenes.

    Science.gov (United States)

    Roth, C; Bringaud, F; Layden, R E; Baltz, T; Eisen, H

    1989-12-01

    The expression of genes coding for variable surface glycoproteins (VSGs) in Trypanosoma equiperdum is linked to duplicative transpositions of silent, basic copy sequences into telomere-linked expression sites. Examination of three independently derived late-appearing trypanosome clones expressing VSG-78 revealed that the expressed gene in all cases is composed of sequences derived from three or four individual silent genes. The 182 base pairs at the 3' end of the coding sequence are derived from one silent gene, the 3' donor. The remaining 5' segment is a mosaic structure containing variable-length segments derived from two, or perhaps three, related silent genes. All of the silent genes that participate in the construction of the VSG-78 expression-linked copy (ELC) genes contain multiple stop codons and are unable to code for VSGs. Individual silent pseudogenes complement one another in the mosaic structure of the 5' portions of the ELC genes and create functional VSG genes. The joining of the 3' and 5' portions of the composite genes occurs in short regions of homology and suggests a mechanism by which the ordered expression of the VSG genes is generated.

  7. Statistical applications in nutrigenomics : analyzing multiple genes and proteins in relation to complex diseases in humans

    NARCIS (Netherlands)

    Heidema, A.G.

    2008-01-01

    Background The recent advances in technology provide the possibility to obtain large genomic datasets that contain information on large numbers of variables, while the sample sizes are moderate to small. This has lead to statistical challenges in the analysis of multiple genes and proteins in

  8. PDCD10 gene mutations in multiple cerebral cavernous malformations.

    Science.gov (United States)

    Cigoli, Maria Sole; Avemaria, Francesca; De Benedetti, Stefano; Gesu, Giovanni P; Accorsi, Lucio Giordano; Parmigiani, Stefano; Corona, Maria Franca; Capra, Valeria; Mosca, Andrea; Giovannini, Simona; Notturno, Francesca; Ciccocioppo, Fausta; Volpi, Lilia; Estienne, Margherita; De Michele, Giuseppe; Antenora, Antonella; Bilo, Leda; Tavoni, Antonietta; Zamponi, Nelia; Alfei, Enrico; Baranello, Giovanni; Riva, Daria; Penco, Silvana

    2014-01-01

    Cerebral cavernous malformations (CCMs) are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging) with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA) analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

  9. PDCD10 gene mutations in multiple cerebral cavernous malformations.

    Directory of Open Access Journals (Sweden)

    Maria Sole Cigoli

    Full Text Available Cerebral cavernous malformations (CCMs are vascular abnormalities that may cause seizures, intracerebral haemorrhages, and focal neurological deficits. Familial form shows an autosomal dominant pattern of inheritance with incomplete penetrance and variable clinical expression. Three genes have been identified causing familial CCM: KRIT1/CCM1, MGC4607/CCM2, and PDCD10/CCM3. Aim of this study is to report additional PDCD10/CCM3 families poorly described so far which account for 10-15% of hereditary cerebral cavernous malformations. Our group investigated 87 consecutive Italian affected individuals (i.e. positive Magnetic Resonance Imaging with multiple/familial CCM through direct sequencing and Multiplex Ligation-Dependent Probe Amplification (MLPA analysis. We identified mutations in over 97.7% of cases, and PDCD10/CCM3 accounts for 13.1%. PDCD10/CCM3 molecular screening revealed four already known mutations and four novel ones. The mutated patients show an earlier onset of clinical manifestations as compared to CCM1/CCM2 mutated patients. The study of further families carrying mutations in PDCD10/CCM3 may help define a possible correlation between genotype and phenotype; an accurate clinical follow up of the subjects would help define more precisely whether mutations in PDCD10/CCM3 lead to a characteristic phenotype.

  10. Capturing heterogeneity in gene expression studies by surrogate variable analysis.

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    Jeffrey T Leek

    2007-09-01

    Full Text Available It has unambiguously been shown that genetic, environmental, demographic, and technical factors may have substantial effects on gene expression levels. In addition to the measured variable(s of interest, there will tend to be sources of signal due to factors that are unknown, unmeasured, or too complicated to capture through simple models. We show that failing to incorporate these sources of heterogeneity into an analysis can have widespread and detrimental effects on the study. Not only can this reduce power or induce unwanted dependence across genes, but it can also introduce sources of spurious signal to many genes. This phenomenon is true even for well-designed, randomized studies. We introduce "surrogate variable analysis" (SVA to overcome the problems caused by heterogeneity in expression studies. SVA can be applied in conjunction with standard analysis techniques to accurately capture the relationship between expression and any modeled variables of interest. We apply SVA to disease class, time course, and genetics of gene expression studies. We show that SVA increases the biological accuracy and reproducibility of analyses in genome-wide expression studies.

  11. Genetics of wide compatible gene and variability studies in rice ...

    Indian Academy of Sciences (India)

    ... Discussion Meetings · Public Lectures · Lecture Workshops · Refresher Courses · Symposia. Home; Journals; Journal of Genetics; Volume 95; Issue 2. Genetics of wide compatible gene and variability studies in rice (Oryza sativa L.) S. REVATHI K. SAKTHIVEL S. MANONMANI M. UMADEVI R. USHAKUMARI S. ROBIN.

  12. Phenotypic effects of genetic variability in human clock genes on ...

    Indian Academy of Sciences (India)

    Several mouse models of clock gene null alleles have been demonstrated to have affected sleep homeostasis. Recent findings have shown that the variable number tandem polymorphism in PER3, previously linked to diurnal preference, has profound effects on sleep homeostasis and cognitive performance following sleep ...

  13. What is a Gene? A Question With Variable Answers

    Indian Academy of Sciences (India)

    Home; Journals; Resonance – Journal of Science Education; Volume 2; Issue 4. What is a Gene? A Question With Variable Answers. S C Lakhotia. General Article Volume 2 Issue 4 April 1997 pp 38-47. Fulltext. Click here to view fulltext PDF. Permanent link: http://www.ias.ac.in/article/fulltext/reso/002/04/0038-0047 ...

  14. Gene variants associated with antisocial behaviour: a latent variable approach.

    Science.gov (United States)

    Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V; Lee, Maria; Yrigollen, Carolyn M; Pakstis, Andrew J; Katsovich, Liliya; Olds, David L; Grigorenko, Elena L; Leckman, James F

    2013-10-01

    The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a 15-year follow-up of a randomized trial of a prenatal and infancy nurse-home visitation programme in Elmira, New York. We then investigated, via a novel latent variable approach, 450 informative genetic polymorphisms in 71 genes previously associated with antisocial behaviour, drug use, affiliative behaviours and stress response in 241 consenting individuals for whom DNA was available. Haplotype and Pathway analyses were also performed. Eight single-nucleotide polymorphisms (SNPs) from eight genes contributed to the latent genetic variable that in turn accounted for 16.0% of the variance within the latent antisocial phenotype. The number of risk alleles was linearly related to the latent antisocial variable scores. Haplotypes that included the putative risk alleles for all eight genes were also associated with higher latent antisocial variable scores. In addition, 33 SNPs from 63 of the remaining genes were also significant when added to the final model. Many of these genes interact on a molecular level, forming molecular networks. The results support a role for genes related to dopamine, norepinephrine, serotonin, glutamate, opioid and cholinergic signalling as well as stress response pathways in mediating susceptibility to antisocial behaviour. This preliminary study supports use of relevant behavioural indicators and latent variable approaches to study the potential 'co-action' of gene variants associated with antisocial behaviour. It also underscores the cumulative relevance of common genetic variants for understanding the aetiology of complex behaviour. If replicated in future studies, this approach may allow the identification of a

  15. Cyclotrons with fast variable and/or multiple energy extraction

    Directory of Open Access Journals (Sweden)

    C. Baumgarten

    2013-10-01

    Full Text Available We discuss the possibility in principle of stripping extraction in combination with reverse bends in isochronous separate-sector cyclotrons (and/or fixed field alternating gradient accelerators. If one uses reverse bends between the sectors (instead of or in combination with drifts and places stripper foils at the sector exit edges, the stripped beam has a reduced bending radius and it should be able to leave the cyclotron within the range of the valley—even if the beam is stripped at less than full energy. We are especially interested in stripping of H_{2}^{+}, as it doubles the charge to mass ratio of the ions. However the method could be applied to other ions or ionized molecules as well. For the production of proton beams by stripping extraction of an H_{2}^{+} beam, we discuss possible designs for three types of machines: First, a low-energy cyclotron for the simultaneous production of several beams at multiple energies—for instance 15, 30, and 70 MeV—thus allowing beam delivery on several isotope production targets. In this case it can be an advantage to have a strong energy dependence of the direction of the extracted beam. Second, we consider a fast variable-energy proton machine for cancer therapy that should allow extraction (of the complete beam at all energies in the range of about 70 MeV to about 250 MeV into the same beam line. Third, we consider a high-intensity high-energy machine, where the main design goals are extraction with low losses, low activation of components, and high reliability. Especially if such a machine is considered for an accelerator driven system (ADS, this extraction mechanism has advantages: Beam trips by the failure of electrostatic elements could be avoided and the turn separation would be less critical, which allows operation at lower main cavity voltages. This would in turn reduce the number of rf trips. The price that has to be paid for these advantages is an increase in size and/or field

  16. Genetic Association Test for Multiple Traits at Gene Level

    OpenAIRE

    Guo, Xiaobo; Liu, Zhifa; Wang, Xueqin; Zhang, Heping

    2012-01-01

    Genome-wide association studies (GWASs) at gene level are commonly used to understand biological mechanisms underlying complex diseases. In general, one response or outcome is used to present a disease of interest in such studies. In this study, we consider a multiple traits association test from gene level. We propose and examine a class of test statistics that summarizes the association information between single nucleotide polymorphisms (SNPs) and each of the traits. Our simulation studies...

  17. Restriction genes for retroviruses influence the risk of multiple sclerosis

    DEFF Research Database (Denmark)

    Nexø, Bjørn A; Hansen, Bettina; Nissen, Kari K

    2013-01-01

    known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22......We recently described that the autoimmune, central nervous system disease, multiple sclerosis (MS), is genetically associated with the human endogenous retroviral locus, HERV-Fc1, in Scandinavians. A number of dominant human genes encoding factors that restrict retrovirus replication have been...

  18. Multiple genes encode the major surface glycoprotein of Pneumocystis carinii

    DEFF Research Database (Denmark)

    Kovacs, J A; Powell, F; Edman, J C

    1993-01-01

    this antigen is a good candidate for development as a vaccine to prevent or control P. carinii infection. We have cloned and sequenced seven related but unique genes encoding the major surface glycoprotein of rat P. carinii. Partial amino acid sequencing confirmed the identity of these genes. Based on Southern...... blot studies using chromosomal or restricted DNA, the major surface glycoproteins are the products of a multicopy family of genes. The predicted protein has an M(r) of approximately 123,000, is relatively rich in cysteine residues (5.5%) that are very strongly conserved, and contains a well conserved...... hydrophobic region at the carboxyl terminus. The presence of multiple related msg genes encoding the major surface glycoprotein of P. carinii suggests that antigenic variation is a possible mechanism for evading host defenses. Further characterization of this family of genes should allow the development...

  19. Diagnostic Challenges in Retinitis Pigmentosa: Genotypic Multiplicity and Phenotypic Variability

    Science.gov (United States)

    Chang, Susie; Vaccarella, Leah; Olatunji, Sunday; Cebulla, Colleen; Christoforidis, John

    2011-01-01

    Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders. Diagnosis can be challenging as more than 40 genes are known to cause non-syndromic RP and phenotypic expression can differ significantly resulting in variations in disease severity, age of onset, rate of progression, and clinical findings. We describe the clinical manifestations of RP, the more commonly known causative gene mutations, and the genotypic-phenotypic correlation of RP. PMID:22131872

  20. Association of circadian rhythm genes ARNTL/BMAL1 and CLOCK with multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Polona Lavtar

    Full Text Available Prevalence of multiple sclerosis varies with geographic latitude. We hypothesized that this fact might be partially associated with the influence of latitude on circadian rhythm and consequently that genetic variability of key circadian rhythm regulators, ARNTL and CLOCK genes, might contribute to the risk for multiple sclerosis. Our aim was to analyse selected polymorphisms of ARNTL and CLOCK, and their association with multiple sclerosis. A total of 900 Caucasian patients and 1024 healthy controls were compared for genetic signature at 8 SNPs, 4 for each of both genes. We found a statistically significant difference in genotype (ARNTL rs3789327, P = 7.5·10-5; CLOCK rs6811520 P = 0.02 distributions in patients and controls. The ARNTL rs3789327 CC genotype was associated with higher risk for multiple sclerosis at an OR of 1.67 (95% CI 1.35-2.07, P = 0.0001 and the CLOCK rs6811520 genotype CC at an OR of 1.40 (95% CI 1.13-1.73, P = 0.002. The results of this study suggest that genetic variability in the ARNTL and CLOCK genes might be associated with risk for multiple sclerosis.

  1. A variable gene delivery carrier-biotinylated chitosan/polyethyleneimine

    Energy Technology Data Exchange (ETDEWEB)

    Chung, Yi-Chen; Young, Tai-Horng [Institute of Polymer Science and Engineering, College of Engineering, National Taiwan University, Taipei 106, Taiwan (China); Chang, Fu-Hsiung [Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 100, Taiwan (China); Wei, Ming-Feng, E-mail: thyoung@ntu.edu.t [Institute of Biomedical Engineering, College of Medicine and College of Engineering, National Taiwan University, Taipei 100, Taiwan (China)

    2010-12-15

    A variable gene delivery system has been developed based on conjugating chitosan to biotin through a functionalized poly(ethylene glycol) (PEG) spacer, which can be used to further bind different molecules on the outer layer of a polymer/DNA complex by streptavidin (SA)-biotin linkage. In this study, TAT-conjugated SA was used as the model molecule to prove the conjugation function of the prepared complex. In addition, low-molecular-weight poly(ethyleneimine) (PEI) was added into the polymer/DNA complex to increase the transfection efficiency. The results of the luciferase assay show that the transfection efficiency of the prepared complex was significantly correlated with the amount of PEI and was further enhanced when TAT was conjugated to the complex by SA-biotin linkage. Considered to have negligible cytotoxic effects, the variable gene delivery complex prepared in this study would be of considerable potential as carriers for in vitro applications.

  2. Pediatric Multiple Sclerosis: Genes, Environment, and a Comprehensive Therapeutic Approach.

    Science.gov (United States)

    Cappa, Ryan; Theroux, Liana; Brenton, J Nicholas

    2017-10-01

    Pediatric multiple sclerosis is an increasingly recognized and studied disorder that accounts for 3% to 10% of all patients with multiple sclerosis. The risk for pediatric multiple sclerosis is thought to reflect a complex interplay between environmental and genetic risk factors. Environmental exposures, including sunlight (ultraviolet radiation, vitamin D levels), infections (Epstein-Barr virus), passive smoking, and obesity, have been identified as potential risk factors in youth. Genetic predisposition contributes to the risk of multiple sclerosis, and the major histocompatibility complex on chromosome 6 makes the single largest contribution to susceptibility to multiple sclerosis. With the use of large-scale genome-wide association studies, other non-major histocompatibility complex alleles have been identified as independent risk factors for the disease. The bridge between environment and genes likely lies in the study of epigenetic processes, which are environmentally-influenced mechanisms through which gene expression may be modified. This article will review these topics to provide a framework for discussion of a comprehensive approach to counseling and ultimately treating the pediatric patient with multiple sclerosis. Copyright © 2017 Elsevier Inc. All rights reserved.

  3. Syllidae mitochondrial gene order is unusually variable for Annelida.

    Science.gov (United States)

    Aguado, M Teresa; Richter, Sandy; Sontowski, Rebekka; Golombek, Anja; Struck, Torsten H; Bleidorn, Christoph

    2016-12-05

    Complete mitochondrial genomes of five syllids (Streptosyllis sp., Eusyllis blomstrandi, Myrianida brachycephala, Typosyllis antoni and Typosyllis sp.) have been obtained using Illumina sequencing. Together with two previous studied taxa (Ramisyllis multicaudata and Trypanobia cryptica), the analysed sequences represent most of the main lineages within the family Syllidae (Anoplosyllinae, Eusyllinae, Autolytinae and Syllinae). The genomic features, gene order and phylogenetic relationships are examined. Unusual for annelids, syllid mitochondrial genomes are highly variable in their gene order. Considering genomic features, such as length, skewness, gene content, and codon bias, most similar to the rest of annelids are the genomes of E. blomstrandi and M. brachycephala, while Streptosyllis sp. and the analysed sylline taxa (R. multicaudata, T. cryptica, T. antoni and Typosyllis sp.) are the most dissimilar. Two methionine tRNA's (trnM) have been found in T. antoni and Typosyllis sp. The mt genomes of these latter taxa are the longest with numerous non-coding regions. The 13 protein coding genes, as well as the rRNA's are used to perform phylogenetic analyses that recovered the relationships within the family explored before by previous authors. The gene order in Syllidae shows very different patterns. E. blomstrandi and M. prolifera show a similar pattern to the one found in Pleistoannelida; however this might have changed at least twice within Syllidae: in Streptosyllis sp. and within Syllinae. All analysed Syllinae show different gene orders, thereby illustrating more variability as all other pleistoannelids analysed so far. The information provided herein allows a more accurate reconstruction of the possible evolutionary scenarios in Syllidae. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Cross Validation of Selection of Variables in Multiple Regression.

    Science.gov (United States)

    1979-12-01

    Bomber IBMNAV * BOMNAV Navigation-Cargo * * CARNAV Sensory-Fighter * SF FGTSEN Sensory - Bomber * SB BOMSEN Communication - Fighter IFGCOM CF FGTCOM...of Variables Variable No. Recode FGTNAV 1 0 LESS THAN 1 1 OR OVER BONNAV 2 0 LESS THAN S1 OR OVER CARNAV 3 0 LESS THAN S1 OR OVER FGTSEN 4 0 LESS THAN...cc x x x x x x x CARNAV X X X X X X x XMTR x X X X X x PD X x X X X X UP x- *Those which AID determined. 44 This value was lowered to 3 in the

  5. Gene expression profiles in Finnish twins with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Kaprio Jaakko

    2006-02-01

    Full Text Available Abstract Background Since genetic alterations influencing susceptibility to multiple sclerosis (MS, the most common autoimmune demyelinating disease of the central nervous system (CNS, are as yet poorly understood, the purpose of this study was to identify genes responsible for MS by studying monozygotic (MZ twin pairs discordant for MS. Methods In order to identify genes involved in MS development, the gene expression profiles in blood mononuclear cells obtained from eight MZ twin pairs discordant for MS were analyzed by cDNA microarray technology detecting the expression of 8 300 genes. The twins were collected from the Finnish Twin Cohort Study and both affected subjects and their healthy siblings underwent neurological evaluation and cerebral and spinal magnetic resonance imaging. Gene expressions were confirmed by relative quantitative reverse transcription PCR. Results It appeared that 25 genes were at least two-fold up-regulated and 15 genes down-regulated in 25% (2/8 of twins with MS when compared to their healthy siblings. Moreover, 6/25 genes were up-regulated in 40% of MS twins and one gene, interferon alpha-inducible protein (clone IFI-6-16 (G1P3, in 50% of them. The six most constantly expressed genes are (1 G1P3, (2 POU domain, class 3, transcription factor 1, (3 myxovirus resistance 2, (4 lysosomal-associated multispanning membrane protein-5, (5 hemoglobin alpha 2 and (6 hemoglobin beta. Conclusion Over two-fold up-regulation of these six genes in almost half of MZ twins with MS suggests their role in MS pathogenesis. Studies using MZ MS twins obtained from genetically homogeneous population offer a unique opportunity to explore the genetic nature of MS.

  6. Polycomb target genes are silenced in multiple myeloma.

    Directory of Open Access Journals (Sweden)

    Antonia Kalushkova

    Full Text Available Multiple myeloma (MM is a genetically heterogeneous disease, which to date remains fatal. Finding a common mechanism for initiation and progression of MM continues to be challenging. By means of integrative genomics, we identified an underexpressed gene signature in MM patient cells compared to normal counterpart plasma cells. This profile was enriched for previously defined H3K27-tri-methylated genes, targets of the Polycomb group (PcG proteins in human embryonic fibroblasts. Additionally, the silenced gene signature was more pronounced in ISS stage III MM compared to stage I and II. Using chromatin immunoprecipitation (ChIP assay on purified CD138+ cells from four MM patients and on two MM cell lines, we found enrichment of H3K27me3 at genes selected from the profile. As the data implied that the Polycomb-targeted gene profile would be highly relevant for pharmacological treatment of MM, we used two compounds to chemically revert the H3K27-tri-methylation mediated gene silencing. The S-adenosylhomocysteine hydrolase inhibitor 3-Deazaneplanocin (DZNep and the histone deacetylase inhibitor LBH589 (Panobinostat, reactivated the expression of genes repressed by H3K27me3, depleted cells from the PRC2 component EZH2 and induced apoptosis in human MM cell lines. In the immunocompetent 5T33MM in vivo model for MM, treatment with LBH589 resulted in gene upregulation, reduced tumor load and increased overall survival. Taken together, our results reveal a common gene signature in MM, mediated by gene silencing via the Polycomb repressor complex. The importance of the underexpressed gene profile in MM tumor initiation and progression should be subjected to further studies.

  7. Multiple Testing of Gene Sets from Gene Ontology: Possibilities and Pitfalls

    NARCIS (Netherlands)

    Meijer, R.J.; Goeman, J.J.

    2016-01-01

    The use of multiple testing procedures in the context of gene-set testing is an important but relatively underexposed topic. If a multiple testing method is used, this is usually a standard familywise error rate (FWER) or false discovery rate (FDR) controlling procedure in which the logical

  8. Multiple Criteria Decision Making Based on Discrete Linguistic Stochastic Variables

    OpenAIRE

    Ren, Jian; Gao, Yang; Bian, Can

    2013-01-01

    For solving the discrete linguistic stochastic multiple criteria decision making problems with incomplete information, a new decision making method based on the differences between the superiorities and the inferiorities is proposed. According to the two basic parameters which are the possible outcome and the state probability, the superior decision matrix and the inferior decision matrix of the alternative set under each criterion are first worked out. Then, by the differences between the el...

  9. Gene expression profiling reveals multiple toxicity endpoints induced by hepatotoxicants

    Energy Technology Data Exchange (ETDEWEB)

    Huang Qihong; Jin Xidong; Gaillard, Elias T.; Knight, Brian L.; Pack, Franklin D.; Stoltz, James H.; Jayadev, Supriya; Blanchard, Kerry T

    2004-05-18

    Microarray technology continues to gain increased acceptance in the drug development process, particularly at the stage of toxicology and safety assessment. In the current study, microarrays were used to investigate gene expression changes associated with hepatotoxicity, the most commonly reported clinical liability with pharmaceutical agents. Acetaminophen, methotrexate, methapyrilene, furan and phenytoin were used as benchmark compounds capable of inducing specific but different types of hepatotoxicity. The goal of the work was to define gene expression profiles capable of distinguishing the different subtypes of hepatotoxicity. Sprague-Dawley rats were orally dosed with acetaminophen (single dose, 4500 mg/kg for 6, 24 and 72 h), methotrexate (1 mg/kg per day for 1, 7 and 14 days), methapyrilene (100 mg/kg per day for 3 and 7 days), furan (40 mg/kg per day for 1, 3, 7 and 14 days) or phenytoin (300 mg/kg per day for 14 days). Hepatic gene expression was assessed using toxicology-specific gene arrays containing 684 target genes or expressed sequence tags (ESTs). Principal component analysis (PCA) of gene expression data was able to provide a clear distinction of each compound, suggesting that gene expression data can be used to discern different hepatotoxic agents and toxicity endpoints. Gene expression data were applied to the multiplicity-adjusted permutation test and significantly changed genes were categorized and correlated to hepatotoxic endpoints. Repression of enzymes involved in lipid oxidation (acyl-CoA dehydrogenase, medium chain, enoyl CoA hydratase, very long-chain acyl-CoA synthetase) were associated with microvesicular lipidosis. Likewise, subsets of genes associated with hepatotocellular necrosis, inflammation, hepatitis, bile duct hyperplasia and fibrosis have been identified. The current study illustrates that expression profiling can be used to: (1) distinguish different hepatotoxic endpoints; (2) predict the development of toxic endpoints; and

  10. Variability of the Transferrin Receptor 2 Gene in AMD

    Directory of Open Access Journals (Sweden)

    Daniel Wysokinski

    2014-01-01

    Full Text Available Oxidative stress is a major factor in the pathogenesis of age-related macular degeneration (AMD. Iron may catalyze the Fenton reaction resulting in overproduction of reactive oxygen species. Transferrin receptor 2 plays a critical role in iron homeostasis and variability in its gene may influence oxidative stress and AMD occurrence. To verify this hypothesis we assessed the association between polymorphisms of the TFR2 gene and AMD. A total of 493 AMD patients and 171 matched controls were genotyped for the two polymorphisms of the TFR2 gene: c.1892C>T (rs2075674 and c.−258+123T>C (rs4434553. We also assessed the modulation of some AMD risk factors by these polymorphisms. The CC and TT genotypes of the c.1892C>T were associated with AMD occurrence but the latter only in obese patients. The other polymorphism was not associated with AMD occurrence, but the CC genotype was correlated with an increasing AMD frequency in subjects with BMIT and c.−258+123T>C polymorphisms of the TRF2 gene may be associated with AMD occurrence, either directly or by modulation of risk factors.

  11. Sequence Variability in Staphylococcal Enterotoxin Genes seb, sec, and sed

    Directory of Open Access Journals (Sweden)

    Sophia Johler

    2016-06-01

    Full Text Available Ingestion of staphylococcal enterotoxins preformed by Staphylococcus aureus in food leads to staphylococcal food poisoning, the most prevalent foodborne intoxication worldwide. There are five major staphylococcal enterotoxins: SEA, SEB, SEC, SED, and SEE. While variants of these toxins have been described and were linked to specific hosts or levels or enterotoxin production, data on sequence variation is still limited. In this study, we aim to extend the knowledge on promoter and gene variants of the major enterotoxins SEB, SEC, and SED. To this end, we determined seb, sec, and sed promoter and gene sequences of a well-characterized set of enterotoxigenic Staphylococcus aureus strains originating from foodborne outbreaks, human infections, human nasal colonization, rabbits, and cattle. New nucleotide sequence variants were detected for all three enterotoxins and a novel amino acid sequence variant of SED was detected in a strain associated with human nasal colonization. While the seb promoter and gene sequences exhibited a high degree of variability, the sec and sed promoter and gene were more conserved. Interestingly, a truncated variant of sed was detected in all tested sed harboring rabbit strains. The generated data represents a further step towards improved understanding of strain-specific differences in enterotoxin expression and host-specific variation in enterotoxin sequences.

  12. Sequence Variability in Staphylococcal Enterotoxin Genes seb, sec, and sed.

    Science.gov (United States)

    Johler, Sophia; Sihto, Henna-Maria; Macori, Guerrino; Stephan, Roger

    2016-06-01

    Ingestion of staphylococcal enterotoxins preformed by Staphylococcus aureus in food leads to staphylococcal food poisoning, the most prevalent foodborne intoxication worldwide. There are five major staphylococcal enterotoxins: SEA, SEB, SEC, SED, and SEE. While variants of these toxins have been described and were linked to specific hosts or levels or enterotoxin production, data on sequence variation is still limited. In this study, we aim to extend the knowledge on promoter and gene variants of the major enterotoxins SEB, SEC, and SED. To this end, we determined seb, sec, and sed promoter and gene sequences of a well-characterized set of enterotoxigenic Staphylococcus aureus strains originating from foodborne outbreaks, human infections, human nasal colonization, rabbits, and cattle. New nucleotide sequence variants were detected for all three enterotoxins and a novel amino acid sequence variant of SED was detected in a strain associated with human nasal colonization. While the seb promoter and gene sequences exhibited a high degree of variability, the sec and sed promoter and gene were more conserved. Interestingly, a truncated variant of sed was detected in all tested sed harboring rabbit strains. The generated data represents a further step towards improved understanding of strain-specific differences in enterotoxin expression and host-specific variation in enterotoxin sequences.

  13. Polymorphism of Genetic variability of gene in sheep

    Directory of Open Access Journals (Sweden)

    R. Rasero

    2010-01-01

    Full Text Available MUC1 gene encodes the polypeptide of a mucin present on the apical surface of the secreting mammary cells during lactation and on the surface of the milk fat globules (Mather, 2000. MUC1 contains a minisatellite region: the sequence, coding for the extracellular protein domain, consists mostly of a motif of 60 bp that in human, cattle and goat is tandemly repeated a variable number of times (VNTR polymorphism, giving rise to molecular variants of different size (Patton et al., 1995.

  14. Surrogate variable analysis using partial least squares (SVA-PLS) in gene expression studies.

    Science.gov (United States)

    Chakraborty, Sutirtha; Datta, Somnath; Datta, Susmita

    2012-03-15

    In a typical gene expression profiling study, our prime objective is to identify the genes that are differentially expressed between the samples from two different tissue types. Commonly, standard analysis of variance (ANOVA)/regression is implemented to identify the relative effects of these genes over the two types of samples from their respective arrays of expression levels. But, this technique becomes fundamentally flawed when there are unaccounted sources of variability in these arrays (latent variables attributable to different biological, environmental or other factors relevant in the context). These factors distort the true picture of differential gene expression between the two tissue types and introduce spurious signals of expression heterogeneity. As a result, many genes which are actually differentially expressed are not detected, whereas many others are falsely identified as positives. Moreover, these distortions can be different for different genes. Thus, it is also not possible to get rid of these variations by simple array normalizations. This both-way error can lead to a serious loss in sensitivity and specificity, thereby causing a severe inefficiency in the underlying multiple testing problem. In this work, we attempt to identify the hidden effects of the underlying latent factors in a gene expression profiling study by partial least squares (PLS) and apply ANCOVA technique with the PLS-identified signatures of these hidden effects as covariates, in order to identify the genes that are truly differentially expressed between the two concerned tissue types. We compare the performance of our method SVA-PLS with standard ANOVA and a relatively recent technique of surrogate variable analysis (SVA), on a wide variety of simulation settings (incorporating different effects of the hidden variable, under situations with varying signal intensities and gene groupings). In all settings, our method yields the highest sensitivity while maintaining relatively

  15. Restriction genes for retroviruses influence the risk of multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Bjørn A Nexø

    Full Text Available We recently described that the autoimmune, central nervous system disease, multiple sclerosis (MS, is genetically associated with the human endogenous retroviral locus, HERV-Fc1, in Scandinavians. A number of dominant human genes encoding factors that restrict retrovirus replication have been known for a long time. Today human restriction genes for retroviruses include amongst others TRIMs, APOBEC3s, BST2 and TREXs. We have therefore looked for a role of these retroviral restriction genes in MS using genetic epidemiology. We here report that markers in two TRIMs, TRIM5 and TRIM22 and a marker in BST2, associated statistically with the risk of getting MS, while markers in or near APOBEC3s and TREXs showed little or no effect. This indicates that the two TRIMs and BST2 influence the risk of disease and thus supports the hypothesis of a viral involvement.

  16. Multiple Criteria Decision Making Based on Discrete Linguistic Stochastic Variables

    Directory of Open Access Journals (Sweden)

    Jian Ren

    2013-01-01

    Full Text Available For solving the discrete linguistic stochastic multiple criteria decision making problems with incomplete information, a new decision making method based on the differences between the superiorities and the inferiorities is proposed. According to the two basic parameters which are the possible outcome and the state probability, the superior decision matrix and the inferior decision matrix of the alternative set under each criterion are first worked out. Then, by the differences between the elements on the appropriate locations of these matrices, the corresponding dominant decision matrices are formed. Subsequently, with the help of the weight vector of the criterion set, the weighted integrated dominant decision matrix of the alternative set is built. Consequently, the weighted integrated dominant indices' sum of each alternative is calculated. Thus, the rank of the alternatives comes out. Finally, a numerical example is given. The result shows the superiority of the method.

  17. Integrative analysis of multiple cancer prognosis studies with gene expression measurements

    Science.gov (United States)

    Ma, Shuangge; Huang, Jian; Wei, Fengrong; Xie, Yang; Fang, Kuangnan

    2012-01-01

    Although in cancer research microarray gene profiling studies have been successful in identifying genetic variants predisposing to the development and progression of cancer, the identified markers from analysis of single datasets often suffer low reproducibility. Among multiple possible causes, the most important one is the small sample size hence the lack of power of single studies. Integrative analysis jointly considers multiple heterogeneous studies, has a significantly larger sample size, and can improve reproducibility. In this article, we focus on cancer prognosis studies, where the response variables are progression-free, overall, or other types of survival. A group minimax concave penalty (GMCP) penalized integrative analysis approach is proposed for analyzing multiple heterogeneous cancer prognosis studies with microarray gene expression measurements. An efficient group coordinate descent algorithm is developed. The GMCP can automatically accommodate the heterogeneity across multiple datasets, and the identified markers have consistent effects across multiple studies. Simulation studies show that the GMCP provides significantly improved selection results as compared with the existing meta-analysis approaches, intensity approaches, and group Lasso penalized integrative analysis. We apply the GMCP to four microarray studies and identify genes associated with the prognosis of breast cancer. PMID:22105693

  18. Direct Multiple Shooting Optimization with Variable Problem Parameters

    Science.gov (United States)

    Whitley, Ryan J.; Ocampo, Cesar A.

    2009-01-01

    Taking advantage of a novel approach to the design of the orbital transfer optimization problem and advanced non-linear programming algorithms, several optimal transfer trajectories are found for problems with and without known analytic solutions. This method treats the fixed known gravitational constants as optimization variables in order to reduce the need for an advanced initial guess. Complex periodic orbits are targeted with very simple guesses and the ability to find optimal transfers in spite of these bad guesses is successfully demonstrated. Impulsive transfers are considered for orbits in both the 2-body frame as well as the circular restricted three-body problem (CRTBP). The results with this new approach demonstrate the potential for increasing robustness for all types of orbit transfer problems.

  19. Genes and Environment in Multiple Sclerosis project: A platform to investigate multiple sclerosis risk.

    Science.gov (United States)

    Xia, Zongqi; White, Charles C; Owen, Emily K; Von Korff, Alina; Clarkson, Sarah R; McCabe, Cristin A; Cimpean, Maria; Winn, Phoebe A; Hoesing, Ashley; Steele, Sonya U; Cortese, Irene C M; Chitnis, Tanuja; Weiner, Howard L; Reich, Daniel S; Chibnik, Lori B; De Jager, Philip L

    2016-02-01

    The Genes and Environment in Multiple Sclerosis project establishes a platform to investigate the events leading to multiple sclerosis (MS) in at-risk individuals. It has recruited 2,632 first-degree relatives from across the USA. Using an integrated genetic and environmental risk score, we identified subjects with twice the MS risk when compared to the average family member, and we report an initial incidence rate in these subjects that is 30 times greater than that of sporadic MS. We discuss the feasibility of large-scale studies of asymptomatic at-risk subjects that leverage modern tools of subject recruitment to execute collaborative projects. © 2015 American Neurological Association.

  20. Motivational and Volitional Variables Associated with Stages of Change for Exercise in Multiple Sclerosis: A Multiple Discriminant Analysis

    Science.gov (United States)

    Chiu, Chung-Yi; Fitzgerald, Sandra D.; Strand, David M.; Muller, Veronica; Brooks, Jessica; Chan, Fong

    2012-01-01

    The main objective of this study was to determine whether motivational and volitional variables identified in the health action process approach (HAPA) model can be used to successfully differentiate people with multiple sclerosis (MS) in different stages of change for exercise and physical activity. Ex-post-facto design using multiple…

  1. Gene Expression Variability in Human Hepatic Drug Metabolizing Enzymes and Transporters

    Science.gov (United States)

    Yang, Lun; Price, Elvin T.; Chang, Ching-Wei; Li, Yan; Huang, Ying; Guo, Li-Wu; Guo, Yongli; Kaput, Jim; Shi, Leming; Ning, Baitang

    2013-01-01

    Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs) in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications. PMID:23637747

  2. Functional analysis of sirtuin genes in multiple Plasmodium falciparum strains.

    Directory of Open Access Journals (Sweden)

    Catherine J Merrick

    Full Text Available Plasmodium falciparum, the causative agent of severe human malaria, employs antigenic variation to avoid host immunity. Antigenic variation is achieved by transcriptional switching amongst polymorphic var genes, enforced by epigenetic modification of chromatin. The histone-modifying 'sirtuin' enzymes PfSir2a and PfSir2b have been implicated in this process. Disparate patterns of var expression have been reported in patient isolates as well as in cultured strains. We examined var expression in three commonly used laboratory strains (3D7, NF54 and FCR-3 in parallel. NF54 parasites express significantly lower levels of var genes compared to 3D7, despite the fact that 3D7 was originally a clone of the NF54 strain. To investigate whether this was linked to the expression of sirtuins, genetic disruption of both sirtuins was attempted in all three strains. No dramatic changes in var gene expression occurred in NF54 or FCR-3 following PfSir2b disruption, contrasting with previous observations in 3D7. In 3D7, complementation of the PfSir2a genetic disruption resulted in a significant decrease in previously-elevated var gene expression levels, but with the continued expression of multiple var genes. Finally, rearranged chromosomes were observed in the 3D7 PfSir2a knockout line. Our results focus on the potential for parasite genetic background to contribute to sirtuin function in regulating virulence gene expression and suggest a potential role for sirtuins in maintaining genome integrity.

  3. Functional analysis of sirtuin genes in multiple Plasmodium falciparum strains.

    Science.gov (United States)

    Merrick, Catherine J; Jiang, Rays H Y; Skillman, Kristen M; Samarakoon, Upeka; Moore, Rachel M; Dzikowski, Ron; Ferdig, Michael T; Duraisingh, Manoj T

    2015-01-01

    Plasmodium falciparum, the causative agent of severe human malaria, employs antigenic variation to avoid host immunity. Antigenic variation is achieved by transcriptional switching amongst polymorphic var genes, enforced by epigenetic modification of chromatin. The histone-modifying 'sirtuin' enzymes PfSir2a and PfSir2b have been implicated in this process. Disparate patterns of var expression have been reported in patient isolates as well as in cultured strains. We examined var expression in three commonly used laboratory strains (3D7, NF54 and FCR-3) in parallel. NF54 parasites express significantly lower levels of var genes compared to 3D7, despite the fact that 3D7 was originally a clone of the NF54 strain. To investigate whether this was linked to the expression of sirtuins, genetic disruption of both sirtuins was attempted in all three strains. No dramatic changes in var gene expression occurred in NF54 or FCR-3 following PfSir2b disruption, contrasting with previous observations in 3D7. In 3D7, complementation of the PfSir2a genetic disruption resulted in a significant decrease in previously-elevated var gene expression levels, but with the continued expression of multiple var genes. Finally, rearranged chromosomes were observed in the 3D7 PfSir2a knockout line. Our results focus on the potential for parasite genetic background to contribute to sirtuin function in regulating virulence gene expression and suggest a potential role for sirtuins in maintaining genome integrity.

  4. Comparison of multiple regression to two latent variable techniques for estimation and prediction.

    Science.gov (United States)

    Wall, Melanie M; Li, Ruifeng

    2003-12-15

    In the areas of epidemiology, psychology, sociology, and other social and behavioural sciences, researchers often encounter situations where there are not only many variables contributing to a particular phenomenon, but there are also strong relationships among many of the predictor variables of interest. By using the traditional multiple regression on all the predictor variables, it is possible to have problems with interpretation and multicollinearity. As an alternative to multiple regression, we explore the use of a latent variable model that can address the relationship among the predictor variables. We consider two different methods for estimation and prediction for this model: one that uses multiple regression on factor score estimates and the other that uses structural equation modelling. The first method uses multiple regression but on a set of predicted underlying factors (i.e. factor scores), and the second method is a full-information maximum-likelihood technique that incorporates the complete covariance structure of the data. In this tutorial, we will explain the model and each estimation method, including how to carry out prediction. A data example will be used for demonstration, where respiratory disease death rates by county in Minnesota are predicted by five county-level census variables. A simulation study is performed to evaluate the efficiency of prediction using the two latent variable modelling techniques compared to multiple regression. Copyright 2003 John Wiley & Sons, Ltd.

  5. Influence of Coding Variability in APP-Aβ Metabolism Genes in Sporadic Alzheimer's Disease.

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    Celeste Sassi

    Full Text Available The cerebral deposition of Aβ42, a neurotoxic proteolytic derivate of amyloid precursor protein (APP, is a central event in Alzheimer's disease (AD(Amyloid hypothesis. Given the key role of APP-Aβ metabolism in AD pathogenesis, we selected 29 genes involved in APP processing, Aβ degradation and clearance. We then used exome and genome sequencing to investigate the single independent (single-variant association test and cumulative (gene-based association test effect of coding variants in these genes as potential susceptibility factors for AD, in a cohort composed of 332 sporadic and mainly late-onset AD cases and 676 elderly controls from North America and the UK. Our study shows that common coding variability in these genes does not play a major role for the disease development. In the single-variant association analysis, the main hits, none of which statistically significant after multiple testing correction (1.9e-4genes mainly involved in Aβ extracellular degradation (TTR, ACE, clearance (LRP1 and APP trafficking and recycling (SORL1. These results were partially replicated in the gene-based analysis (c-alpha and SKAT tests, that reports ECE1, LYZ and TTR as nominally associated to AD (1.7e-3 variability in APP-Aβ genes is not a critical factor for AD development and 2 Aβ degradation and clearance, rather than Aβ production, may play a key role in the etiology of sporadic AD.

  6. Multiple-source multiple-harmonic active vibration control of variable section cylindrical structures: A numerical study

    Science.gov (United States)

    Liu, Jinxin; Chen, Xuefeng; Gao, Jiawei; Zhang, Xingwu

    2016-12-01

    Air vehicles, space vehicles and underwater vehicles, the cabins of which can be viewed as variable section cylindrical structures, have multiple rotational vibration sources (e.g., engines, propellers, compressors and motors), making the spectrum of noise multiple-harmonic. The suppression of such noise has been a focus of interests in the field of active vibration control (AVC). In this paper, a multiple-source multiple-harmonic (MSMH) active vibration suppression algorithm with feed-forward structure is proposed based on reference amplitude rectification and conjugate gradient method (CGM). An AVC simulation scheme called finite element model in-loop simulation (FEMILS) is also proposed for rapid algorithm verification. Numerical studies of AVC are conducted on a variable section cylindrical structure based on the proposed MSMH algorithm and FEMILS scheme. It can be seen from the numerical studies that: (1) the proposed MSMH algorithm can individually suppress each component of the multiple-harmonic noise with an unified and improved convergence rate; (2) the FEMILS scheme is convenient and straightforward for multiple-source simulations with an acceptable loop time. Moreover, the simulations have similar procedure to real-life control and can be easily extended to physical model platform.

  7. Multiple-locus variable-number tandem-repeat analysis of Streptococcus pneumoniae and comparison with multiple loci sequence typing

    Directory of Open Access Journals (Sweden)

    van Cuyck Hélène

    2012-10-01

    Full Text Available Abstract Background Streptococcus pneumoniae infections remain a major cause of morbidity and mortality worldwide. The diversity of pneumococci was first evidenced by serotyping of their capsular polysaccharides, responsible of virulence, resolving into more than 93 serotypes. Molecular tools have been developed to track the emergence and the spread of resistant, hyper virulent or non-vaccine type clones, particularly DNA-based methods using genetic polymorphism. Pulsed-Field Gel Electrophoresis analysis (PFGE and Multiple Loci Sequence Typing (MLST are the most frequently used genotyping techniques for S. pneumoniae. MLST is based on sequence comparison of housekeeping genes clustering isolates within sequence types. The availability of genome sequence data from different S. pneumoniae strains facilitated the search for other class of genetic markers as polymorphic DNA sequences for a Multiple-Locus Variable-Number Tandem-Repeat Analysis (MLVA. This study aims at confirming the relevance of MLVA of S. pneumoniae, comparing MLST and MLVA performances when discriminating subgroups of strains belonging to the same Sequence Type (ST, and defining a restricted but universal set of MLVA markers that has at least the same discriminatory power as MLST for S. pneumoniae by applying marker sets used by different authors on 331 isolates selected in UK. Results A minimum spanning tree was built including the serotypes distribution and comparing MLVA and MLST results. 220 MLVA types were determined grouped in 10 Sequence Types (ST. MLVA differentiated ST162 in two clonal complexes. A minimal set was defined: ms 25 and ms37, ms17, ms19, ms33, ms39, and ms40 including two universal markers. The selection was based on MLVA markers with a Diversity Index >0.8 and a selection of others depending of the population tested and the aim of the study. This set of 7 MLVA markers yields strain clusters similar to those obtained by MLST. Conclusions MLVA can discriminate

  8. Variables Associated with Communicative Participation in People with Multiple Sclerosis: A Regression Analysis

    Science.gov (United States)

    Baylor, Carolyn; Yorkston, Kathryn; Bamer, Alyssa; Britton, Deanna; Amtmann, Dagmar

    2010-01-01

    Purpose: To explore variables associated with self-reported communicative participation in a sample (n = 498) of community-dwelling adults with multiple sclerosis (MS). Method: A battery of questionnaires was administered online or on paper per participant preference. Data were analyzed using multiple linear backward stepwise regression. The…

  9. The Detection and Interpretation of Interaction Effects between Continuous Variables in Multiple Regression.

    Science.gov (United States)

    Jaccard, James; And Others

    1990-01-01

    Issues in the detection and interpretation of interaction effects between quantitative variables in multiple regression analysis are discussed. Recent discussions associated with problems of multicollinearity are reviewed in the context of the conditional nature of multiple regression with product terms. (TJH)

  10. Cascading the multiple stages of optical fractional Fourier transforms under different variable scales.

    Science.gov (United States)

    Liu, S; Wu, J; Li, C

    1995-06-15

    A simple but necessary condition for cascading the multiple stages of an optical fractional Fourier transform with different variable scales is presented. That condition permits more flexibility in the design of optical information-processing systems that use optical fractional Fourier transforms. We have expanded the optical applications of fractional Fourier transforms with adjustable variable scales.

  11. Horizontal acquisition of multiple mitochondrial genes from a parasitic plant followed by gene conversion with host mitochondrial genes

    Directory of Open Access Journals (Sweden)

    Hao Weilong

    2010-12-01

    Full Text Available Abstract Background Horizontal gene transfer (HGT is relatively common in plant mitochondrial genomes but the mechanisms, extent and consequences of transfer remain largely unknown. Previous results indicate that parasitic plants are often involved as either transfer donors or recipients, suggesting that direct contact between parasite and host facilitates genetic transfer among plants. Results In order to uncover the mechanistic details of plant-to-plant HGT, the extent and evolutionary fate of transfer was investigated between two groups: the parasitic genus Cuscuta and a small clade of Plantago species. A broad polymerase chain reaction (PCR survey of mitochondrial genes revealed that at least three genes (atp1, atp6 and matR were recently transferred from Cuscuta to Plantago. Quantitative PCR assays show that these three genes have a mitochondrial location in the one species line of Plantago examined. Patterns of sequence evolution suggest that these foreign genes degraded into pseudogenes shortly after transfer and reverse transcription (RT-PCR analyses demonstrate that none are detectably transcribed. Three cases of gene conversion were detected between native and foreign copies of the atp1 gene. The identical phylogenetic distribution of the three foreign genes within Plantago and the retention of cytidines at ancestral positions of RNA editing indicate that these genes were probably acquired via a single, DNA-mediated transfer event. However, samplings of multiple individuals from two of the three species in the recipient Plantago clade revealed complex and perplexing phylogenetic discrepancies and patterns of sequence divergence for all three of the foreign genes. Conclusions This study reports the best evidence to date that multiple mitochondrial genes can be transferred via a single HGT event and that transfer occurred via a strictly DNA-level intermediate. The discovery of gene conversion between co-resident foreign and native

  12. Horizontal acquisition of multiple mitochondrial genes from a parasitic plant followed by gene conversion with host mitochondrial genes

    Science.gov (United States)

    2010-01-01

    Background Horizontal gene transfer (HGT) is relatively common in plant mitochondrial genomes but the mechanisms, extent and consequences of transfer remain largely unknown. Previous results indicate that parasitic plants are often involved as either transfer donors or recipients, suggesting that direct contact between parasite and host facilitates genetic transfer among plants. Results In order to uncover the mechanistic details of plant-to-plant HGT, the extent and evolutionary fate of transfer was investigated between two groups: the parasitic genus Cuscuta and a small clade of Plantago species. A broad polymerase chain reaction (PCR) survey of mitochondrial genes revealed that at least three genes (atp1, atp6 and matR) were recently transferred from Cuscuta to Plantago. Quantitative PCR assays show that these three genes have a mitochondrial location in the one species line of Plantago examined. Patterns of sequence evolution suggest that these foreign genes degraded into pseudogenes shortly after transfer and reverse transcription (RT)-PCR analyses demonstrate that none are detectably transcribed. Three cases of gene conversion were detected between native and foreign copies of the atp1 gene. The identical phylogenetic distribution of the three foreign genes within Plantago and the retention of cytidines at ancestral positions of RNA editing indicate that these genes were probably acquired via a single, DNA-mediated transfer event. However, samplings of multiple individuals from two of the three species in the recipient Plantago clade revealed complex and perplexing phylogenetic discrepancies and patterns of sequence divergence for all three of the foreign genes. Conclusions This study reports the best evidence to date that multiple mitochondrial genes can be transferred via a single HGT event and that transfer occurred via a strictly DNA-level intermediate. The discovery of gene conversion between co-resident foreign and native mitochondrial copies suggests

  13. Interleukin VII Receptor Gene Polymorphism in Multiple Sclerosis Patients

    Directory of Open Access Journals (Sweden)

    M Ahmadzadeh Raji

    2011-10-01

    Full Text Available Introduction: Multiple Sclerosis is a chronic disease of central nervous system. Disease is more common in young adults and females and causes neurologic symptoms and signs. Cytokine IL-7 is a 25– kDa glycoprotein that has an important role in Lymphopoiesis. Interleukin VII receptor gene has been identified to be associated with multiple sclerosis, so its assessment is important. Methods: We investigated 60 Iranian patients with clinically definite MS and 60 normal healthy controls with negative family history for MS. After blood sampling, DNA was extracted from the whole blood, then we used 2 sets of primers for promoter and exon 4 of IL-VII gene. These fragments were amplified by PCR technique and early screening was performed by SSCP technic in the presence of control samples. Then different patterns with control samples were sent for DNA sequencing. Results: We observed one SNP in promoter. Most of the alleles of the patients were homozygote. There were two 2 SNPs and two sequence variations in exon 4 as P.H165H and P.V138I, which has been submitted in European Bioinformatics Institute under the access number of FR863587. Conclusion: Further studies on control group will be required to reveal the effects of these SNPs on the ILVII-R α protein and they can probably be useed as a biomarker for early diagnosis of MS.

  14. Adaptive Horizontal Gene Transfers between Multiple Cheese-Associated Fungi.

    Science.gov (United States)

    Ropars, Jeanne; Rodríguez de la Vega, Ricardo C; López-Villavicencio, Manuela; Gouzy, Jérôme; Sallet, Erika; Dumas, Émilie; Lacoste, Sandrine; Debuchy, Robert; Dupont, Joëlle; Branca, Antoine; Giraud, Tatiana

    2015-10-05

    Domestication is an excellent model for studies of adaptation because it involves recent and strong selection on a few, identified traits [1-5]. Few studies have focused on the domestication of fungi, with notable exceptions [6-11], despite their importance to bioindustry [12] and to a general understanding of adaptation in eukaryotes [5]. Penicillium fungi are ubiquitous molds among which two distantly related species have been independently selected for cheese making-P. roqueforti for blue cheeses like Roquefort and P. camemberti for soft cheeses like Camembert. The selected traits include morphology, aromatic profile, lipolytic and proteolytic activities, and ability to grow at low temperatures, in a matrix containing bacterial and fungal competitors [13-15]. By comparing the genomes of ten Penicillium species, we show that adaptation to cheese was associated with multiple recent horizontal transfers of large genomic regions carrying crucial metabolic genes. We identified seven horizontally transferred regions (HTRs) spanning more than 10 kb each, flanked by specific transposable elements, and displaying nearly 100% identity between distant Penicillium species. Two HTRs carried genes with functions involved in the utilization of cheese nutrients or competition and were found nearly identical in multiple strains and species of cheese-associated Penicillium fungi, indicating recent selective sweeps; they were experimentally associated with faster growth and greater competitiveness on cheese and contained genes highly expressed in the early stage of cheese maturation. These findings have industrial and food safety implications and improve our understanding of the processes of adaptation to rapid environmental changes. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. Antibody Heavy Chain Variable Domains of Different Germline Gene Origins Diversify through Different Paths

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    Ufuk Kirik

    2017-11-01

    Full Text Available B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes.

  16. Antibody Heavy Chain Variable Domains of Different Germline Gene Origins Diversify through Different Paths

    Science.gov (United States)

    Kirik, Ufuk; Persson, Helena; Levander, Fredrik; Greiff, Lennart; Ohlin, Mats

    2017-01-01

    B cells produce antibodies, key effector molecules in health and disease. They mature their properties, including their affinity for antigen, through hypermutation events; processes that involve, e.g., base substitution, codon insertion and deletion, often in association with an isotype switch. Investigations of antibody evolution define modes whereby particular antibody responses are able to form, and such studies provide insight important for instance for development of efficient vaccines. Antibody evolution is also used in vitro for the design of antibodies with improved properties. To better understand the basic concepts of antibody evolution, we analyzed the mutational paths, both in terms of amino acid substitution and insertions and deletions, taken by antibodies of the IgG isotype. The analysis focused on the evolution of the heavy chain variable domain of sets of antibodies, each with an origin in 1 of 11 different germline genes representing six human heavy chain germline gene subgroups. Investigated genes were isolated from cells of human bone marrow, a major site of antibody production, and characterized by next-generation sequencing and an in-house bioinformatics pipeline. Apart from substitutions within the complementarity determining regions, multiple framework residues including those in protein cores were targets of extensive diversification. Diversity, both in terms of substitutions, and insertions and deletions, in antibodies is focused to different positions in the sequence in a germline gene-unique manner. Altogether, our findings create a framework for understanding patterns of evolution of antibodies from defined germline genes. PMID:29180996

  17. EBV-positive primary central nervous system lymphomas in monozygote twins with common variable immunodeficiency and suspected multiple sclerosis.

    Science.gov (United States)

    Jensen, M K; Koch-Henriksen, N; Johansen, P; Varming, K; Christiansen, C B; Knudsen, F

    1997-12-01

    Common variable immunodeficiency represents the most frequently occurring primary immunodeficiency disorder and is usually detected sporadically in patients with no family history of immunodeficiency. We present the case stories of two monozygote twins, who following a period of decreasing serum immunoglobulins developed primary central nervous system lymphomas. One twin had clinical and paraclinical features mimicking multiple sclerosis. Immunohistochemical investigations on biopsy tissue showed expression of the bcl-2 and p53 gene products, and Epstein-Barr virus (EBV) encoded small RNA's (EBER) indicating latent infection were detected in lymphoma cells using in situ hybridisation techniques. The pathogenetic role of EBV in oncogenesis is discussed.

  18. Walking on multiple disease-gene networks to prioritize candidate genes.

    Science.gov (United States)

    Jiang, Rui

    2015-06-01

    Uncovering causal genes for human inherited diseases, as the primary step toward understanding the pathogenesis of these diseases, requires a combined analysis of genetic and genomic data. Although bioinformatics methods have been designed to prioritize candidate genes resulting from genetic linkage analysis or association studies, the coverage of both diseases and genes in existing methods is quite limited, thereby preventing the scan of causal genes for a significant proportion of diseases at the whole-genome level. To overcome this limitation, we propose a method named pgWalk to prioritize candidate genes by integrating multiple phenomic and genomic data. We derive three types of phenotype similarities among 7719 diseases and nine types of functional similarities among 20327 genes. Based on a pair of phenotype and gene similarities, we construct a disease-gene network and then simulate the process that a random walker wanders on such a heterogeneous network to quantify the strength of association between a candidate gene and a query disease. A weighted version of the Fisher's method with dependent correction is adopted to integrate 27 scores obtained in this way, and a final q-value is calibrated for prioritizing candidate genes. A series of validation experiments are conducted to demonstrate the superior performance of this approach. We further show the effectiveness of this method in exome sequencing studies of autism and epileptic encephalopathies. An online service and the standalone software of pgWalk can be found at http://bioinfo.au.tsinghua.edu.cn/jianglab/pgwalk. © The Author (2015). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS. All rights reserved.

  19. Visualising disease progression on multiple variables with vector plots and path plots

    Directory of Open Access Journals (Sweden)

    Michell Andrew W

    2009-05-01

    Full Text Available Abstract Background It is often desirable to observe how a disease progresses over time in individual patients, rather than graphing group averages; and since multiple outcomes are typically recorded on each patient, it would be advantageous to visualise disease progression on multiple variables simultaneously. Methods A variety of vector plots and a path plot have been developed for this purpose, and data from a longitudinal Huntington's disease study are used to illustrate the utility of these graphical methods for exploratory data analysis. Results Initial and final values for three outcome variables can be easily visualised per patient, along with the change in these variables over time. In addition to the disease trajectory, the path individual patients take from initial to final observation can be traced. Categorical variables can be coded with different types of vectors or paths (e.g. different colours, line types, line thickness and separate panels can be used to include further categorical or continuous variables, allowing clear visualisation of further information for each individual. In addition, summary statistics such as mean vectors, bivariate interquartile ranges and convex polygons can be included to assist in interpreting trajectories, comparing groups, and detecting multivariate outliers. Conclusion Vector and path plots are useful graphical methods for exploratory data analysis when individual-level information on multiple variables over time is desired, and they have several advantages over plotting each variable separately.

  20. The interaction between smoking and HLA genes in multiple sclerosis

    DEFF Research Database (Denmark)

    Hedström, Anna Karin; Katsoulis, Michail; Hössjer, Ola

    2017-01-01

    Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used...... populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each...... combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared...

  1. Identification of single- and multiple-class specific signature genes from gene expression profiles by group marker index.

    Directory of Open Access Journals (Sweden)

    Yu-Shuen Tsai

    Full Text Available Informative genes from microarray data can be used to construct prediction model and investigate biological mechanisms. Differentially expressed genes, the main targets of most gene selection methods, can be classified as single- and multiple-class specific signature genes. Here, we present a novel gene selection algorithm based on a Group Marker Index (GMI, which is intuitive, of low-computational complexity, and efficient in identification of both types of genes. Most gene selection methods identify only single-class specific signature genes and cannot identify multiple-class specific signature genes easily. Our algorithm can detect de novo certain conditions of multiple-class specificity of a gene and makes use of a novel non-parametric indicator to assess the discrimination ability between classes. Our method is effective even when the sample size is small as well as when the class sizes are significantly different. To compare the effectiveness and robustness we formulate an intuitive template-based method and use four well-known datasets. We demonstrate that our algorithm outperforms the template-based method in difficult cases with unbalanced distribution. Moreover, the multiple-class specific genes are good biomarkers and play important roles in biological pathways. Our literature survey supports that the proposed method identifies unique multiple-class specific marker genes (not reported earlier to be related to cancer in the Central Nervous System data. It also discovers unique biomarkers indicating the intrinsic difference between subtypes of lung cancer. We also associate the pathway information with the multiple-class specific signature genes and cross-reference to published studies. We find that the identified genes participate in the pathways directly involved in cancer development in leukemia data. Our method gives a promising way to find genes that can involve in pathways of multiple diseases and hence opens up the possibility of

  2. Communicative participation restrictions in multiple sclerosis: associated variables and correlation with social functioning.

    Science.gov (United States)

    Yorkston, Kathryn M; Baylor, Carolyn; Amtmann, Dagmar

    2014-01-01

    Individuals with multiple sclerosis (MS) are at risk for communication problems that may restrict their ability to take participation in important life roles such as maintenance of relationships, work, or household management. The aim of this project is to examine selected demographic and symptom-related variables that may contribute to participation restrictions. This examination is intended to aid clinicians in predicting who might be at risk for such restrictions and what variables may be targeted in interventions. Community-dwelling adults with MS (n=216) completed a survey either online or using paper forms. The survey included the 46-item version of the Communicative Participation Item Bank, demographics (age, sex, living situation, employment status, education, and time since onset of diagnosis of MS), and self-reported symptom-related variables (physical activity, emotional problems, fatigue, pain, speech severity, and cognitive/communication skills). In order to identify predictors of restrictions in communicative participation, these variables were entered into a backwards stepwise multiple linear regression analysis. Five variables (cognitive/communication skills, speech severity, speech usage, physical activity, and education) were statistically significant predictors of communication participation. In order to examine the relationship of communicative participation and social role variables, bivariate Spearman correlations were conducted. Results suggest only a fair to moderate relationship between communicative participation and measures of social roles. Communicative participation is a complex construct associated with a number of self-reported variables. Clinicians should be alert to risk factors for reduced communicative participation including reduced cognitive and speech skills, lower levels of speech usage, limitations in physical activities and higher levels of education. The reader will be able to: (a) describe the factors that may restrict

  3. A study of variability of capsid protein genes of Radish mosaic virus

    OpenAIRE

    HOLÁ, Marcela

    2008-01-01

    The part of RNA2 genome segment of several isolates of Radish mosaic virus (RaMV) including capsid protein genes was sequenced. Variability of capsid protein genes among the isolates of Radish mosaic virus was studied.

  4. Response of Fish Communities to Various Environmental Variables across Multiple Spatial Scales

    Science.gov (United States)

    Kwon, Yong-Su; Li, Fengqing; Chung, Namil; Bae, Mi-Jung; Hwang, Soon-Jin; Byoen, Myeong-Seop; Park, Sang-Jung; Park, Young-Seuk

    2012-01-01

    A better understanding of the relative importance of different spatial scale determinants on fish communities will eventually increase the accuracy and precision of their bioassessments. Many studies have described the influence of environmental variables on fish communities on multiple spatial scales. However, there is very limited information available on this topic for the East Asian monsoon region, including Korea. In this study, we evaluated the relationship between fish communities and environmental variables at multiple spatial scales using self-organizing map (SOM), random forest, and theoretical path models. The SOM explored differences among fish communities, reflecting environmental gradients, such as a longitudinal gradient from upstream to downstream, and differences in land cover types and water quality. The random forest model for predicting fish community patterns that used all 14 environmental variables was more powerful than a model using any single variable or other combination of environmental variables, and the random forest model was effective at predicting the occurrence of species and evaluating the contribution of environmental variables to that prediction. The theoretical path model described the responses of different species to their environment at multiple spatial scales, showing the importance of altitude, forest, and water quality factors to fish assemblages. PMID:23202766

  5. Whole exome sequencing reveals concomitant mutations of multiple FA genes in individual Fanconi anemia patients.

    Science.gov (United States)

    Chang, Lixian; Yuan, Weiping; Zeng, Huimin; Zhou, Quanquan; Wei, Wei; Zhou, Jianfeng; Li, Miaomiao; Wang, Xiaomin; Xu, Mingjiang; Yang, Fengchun; Yang, Yungui; Cheng, Tao; Zhu, Xiaofan

    2014-05-15

    Fanconi anemia (FA) is a rare inherited genetic syndrome with highly variable clinical manifestations. Fifteen genetic subtypes of FA have been identified. Traditional complementation tests for grouping studies have been used generally in FA patients and in stepwise methods to identify the FA type, which can result in incomplete genetic information from FA patients. We diagnosed five pediatric patients with FA based on clinical manifestations, and we performed exome sequencing of peripheral blood specimens from these patients and their family members. The related sequencing data were then analyzed by bioinformatics, and the FANC gene mutations identified by exome sequencing were confirmed by PCR re-sequencing. Homozygous and compound heterozygous mutations of FANC genes were identified in all of the patients. The FA subtypes of the patients included FANCA, FANCM and FANCD2. Interestingly, four FA patients harbored multiple mutations in at least two FA genes, and some of these mutations have not been previously reported. These patients' clinical manifestations were vastly different from each other, as were their treatment responses to androstanazol and prednisone. This finding suggests that heterozygous mutation(s) in FA genes could also have diverse biological and/or pathophysiological effects on FA patients or FA gene carriers. Interestingly, we were not able to identify de novo mutations in the genes implicated in DNA repair pathways when the sequencing data of patients were compared with those of their parents. Our results indicate that Chinese FA patients and carriers might have higher and more complex mutation rates in FANC genes than have been conventionally recognized. Testing of the fifteen FANC genes in FA patients and their family members should be a regular clinical practice to determine the optimal care for the individual patient, to counsel the family and to obtain a better understanding of FA pathophysiology.

  6. Harmonisation of variables names prior to conducting statistical analyses with multiple datasets: an automated approach

    Science.gov (United States)

    2011-01-01

    Background Data requirements by governments, donors and the international community to measure health and development achievements have increased in the last decade. Datasets produced in surveys conducted in several countries and years are often combined to analyse time trends and geographical patterns of demographic and health related indicators. However, since not all datasets have the same structure, variables definitions and codes, they have to be harmonised prior to submitting them to the statistical analyses. Manually searching, renaming and recoding variables are extremely tedious and prone to errors tasks, overall when the number of datasets and variables are large. This article presents an automated approach to harmonise variables names across several datasets, which optimises the search of variables, minimises manual inputs and reduces the risk of error. Results Three consecutive algorithms are applied iteratively to search for each variable of interest for the analyses in all datasets. The first search (A) captures particular cases that could not be solved in an automated way in the search iterations; the second search (B) is run if search A produced no hits and identifies variables the labels of which contain certain key terms defined by the user. If this search produces no hits, a third one (C) is run to retrieve variables which have been identified in other surveys, as an illustration. For each variable of interest, the outputs of these engines can be (O1) a single best matching variable is found, (O2) more than one matching variable is found or (O3) not matching variables are found. Output O2 is solved by user judgement. Examples using four variables are presented showing that the searches have a 100% sensitivity and specificity after a second iteration. Conclusion Efficient and tested automated algorithms should be used to support the harmonisation process needed to analyse multiple datasets. This is especially relevant when the numbers of datasets

  7. Improved detection of differentially expressed genes in microarray experiments through multiple scanning and image integration

    Science.gov (United States)

    Romualdi, Chiara; Trevisan, Silvia; Celegato, Barbara; Costa, Germano; Lanfranchi, Gerolamo

    2003-01-01

    The variability of results in microarray technology is in part due to the fact that independent scans of a single hybridised microarray give spot images that are not quite the same. To solve this problem and turn it to our advantage, we introduced the approach of multiple scanning and of image integration of microarrays. To this end, we have developed specific software that creates a virtual image that statistically summarises a series of consecutive scans of a microarray. We provide evidence that the use of multiple imaging (i) enhances the detection of differentially expressed genes; (ii) increases the image homogeneity; and (iii) reveals false-positive results such as differentially expressed genes that are detected by a single scan but not confirmed by successive scanning replicates. The increase in the final number of differentially expressed genes detected in a microarray experiment with this approach is remarkable; 50% more for microarrays hybridised with targets labelled by reverse transcriptase, and 200% more for microarrays developed with the tyramide signal amplification (TSA) technique. The results have been confirmed by semi-quantitative RT–PCR tests. PMID:14627839

  8. A multiplicative reinforcement learning model capturing learning dynamics and interindividual variability in mice

    Science.gov (United States)

    Bathellier, Brice; Tee, Sui Poh; Hrovat, Christina; Rumpel, Simon

    2013-01-01

    Both in humans and in animals, different individuals may learn the same task with strikingly different speeds; however, the sources of this variability remain elusive. In standard learning models, interindividual variability is often explained by variations of the learning rate, a parameter indicating how much synapses are updated on each learning event. Here, we theoretically show that the initial connectivity between the neurons involved in learning a task is also a strong determinant of how quickly the task is learned, provided that connections are updated in a multiplicative manner. To experimentally test this idea, we trained mice to perform an auditory Go/NoGo discrimination task followed by a reversal to compare learning speed when starting from naive or already trained synaptic connections. All mice learned the initial task, but often displayed sigmoid-like learning curves, with a variable delay period followed by a steep increase in performance, as often observed in operant conditioning. For all mice, learning was much faster in the subsequent reversal training. An accurate fit of all learning curves could be obtained with a reinforcement learning model endowed with a multiplicative learning rule, but not with an additive rule. Surprisingly, the multiplicative model could explain a large fraction of the interindividual variability by variations in the initial synaptic weights. Altogether, these results demonstrate the power of multiplicative learning rules to account for the full dynamics of biological learning and suggest an important role of initial wiring in the brain for predispositions to different tasks. PMID:24255115

  9. Within-day variability on short and long walking tests in persons with multiple sclerosis

    NARCIS (Netherlands)

    Feys, P.; Bibby, B.; Romberg, A.; Santoyo, C.; Gebara, B.; de Noordhout, B.M.; Knuts, K.; Bethoux, F.; Skjerbaek, A.; Jensen, E.; Baert, I.; Vaney, C.; de Groot, V.; Dalgas, U.

    2014-01-01

    Objective To compare within-day variability of short (10 m walking test at usual and fastest speed; 10MWT) and long (2 and 6-minute walking test; 2MWT/6MWT) tests in persons with multiple sclerosis. Design Observational study. Setting MS rehabilitation and research centers in Europe and US within

  10. Binary variable multiple-model multiple imputation to address missing data mechanism uncertainty: application to a smoking cessation trial.

    Science.gov (United States)

    Siddique, Juned; Harel, Ofer; Crespi, Catherine M; Hedeker, Donald

    2014-07-30

    The true missing data mechanism is never known in practice. We present a method for generating multiple imputations for binary variables, which formally incorporates missing data mechanism uncertainty. Imputations are generated from a distribution of imputation models rather than a single model, with the distribution reflecting subjective notions of missing data mechanism uncertainty. Parameter estimates and standard errors are obtained using rules for nested multiple imputation. Using simulation, we investigate the impact of missing data mechanism uncertainty on post-imputation inferences and show that incorporating this uncertainty can increase the coverage of parameter estimates. We apply our method to a longitudinal smoking cessation trial where nonignorably missing data were a concern. Our method provides a simple approach for formalizing subjective notions regarding nonresponse and can be implemented using existing imputation software. Copyright © 2014 John Wiley & Sons, Ltd.

  11. Variable Speed Wind Turbine Based on Multiple Generators Drive-Train Configuration

    DEFF Research Database (Denmark)

    Deng, Fujin; Chen, Zhe

    2010-01-01

    A variable speed wind turbine is presented in this paper, where multiple permanent magnet synchronous generators (MPMSGs) drive-train configuration is employed in the wind turbine. A cascaded multilevel converter interface based on the MPMSGs is developed to synthesize a desired high ac sinusoidal...... reduce the fluctuation of the electromagnetic torque sum and results in a good performance for the MPMSGs structure. The simulation study is conducted using PSCAD/EMTDC, and the results verify the feasibility of this variable speed wind turbine based on multiple generators drive-train configuration....... output voltage, which could be directly connected to the grids. What is more, such arrangement has been made so that the output ac voltage having a selected phase angle difference among the stator windings of multiple generators. A phase angle shift strategy is proposed in this paper, which effectively...

  12. Heart rate variability is differentially altered in multiple sclerosis: implications for acute, worsening and progressive disability.

    Science.gov (United States)

    Studer, Valeria; Rocchi, Camilla; Motta, Caterina; Lauretti, Benedetta; Perugini, Jacopo; Brambilla, Laura; Pareja-Gutierrez, Lorena; Camera, Giorgia; Barbieri, Francesca Romana; Marfia, Girolama A; Centonze, Diego; Rossi, Silvia

    2017-01-01

    Sympathovagal imbalance has been associated with poor prognosis in chronic diseases, but there is conflicting evidence in multiple sclerosis. The objective of this study was to investigate the autonomic nervous system dysfunction correlation with inflammation and progression in multiple sclerosis. Heart rate variability was analysed in 120 multiple sclerosis patients and 60 healthy controls during supine rest and head-up tilt test; the normalised units of low frequency and high frequency power were considered to assess sympathetic and vagal components, respectively. Correlation analyses with clinical and radiological markers of disease activity and progression were performed. Sympathetic dysfunction was closely related to the progression of disability in multiple sclerosis: progressive patients showed altered heart rate variability with respect to healthy controls and relapsing-remitting patients, with higher rest low frequency power and lacking the expected low frequency power increase during the head-up tilt test. In relapsing-remitting patients, disease activity, even subclinical, was associated with lower rest low frequency power, whereas stable relapsing-remitting patients did not differ from healthy controls. Less sympathetic reactivity and higher low frequency power at rest were associated with incomplete recovery from relapse. Autonomic balance appears to be intimately linked with both the inflammatory activity of multiple sclerosis, which is featured by an overall hypoactivity of the sympathetic nervous system, and its compensatory plastic processes, which appear inefficient in case of worsening and progressive multiple sclerosis.

  13. Epstein-Barr virus candidate genes and multiple sclerosis.

    Science.gov (United States)

    Claire Simon, Kelly; Schmidt, Hollie; Loud, Sara; Ascherio, Alberto

    2015-01-01

    Previous infection with Epstein-Barr virus (EBV) and a history of infectious mononucleosis (IM) have been previously associated with an increased risk of multiple sclerosis (MS). Whether there are common genetic factors that may partially explain these associations has not been thoroughly explored. To investigate whether select polymorphisms in genes associated with IM susceptibility are related to MS risk-a self-reported history of IM or antibody titer against Epstein-Barr virus nuclear antigen 1 (anti-EBNA1). A case-control study including 1213 MS cases and 454 controls enrolled in the Accelerated Cure Project for MS (ACP) Repository. Select polymorphisms in HLA-A, SH2D1A and IL15RA and anti-EBNA1 Ab titers were measured using stored blood samples provided by participants. Generalized linear models were used to assess the associations between select polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titers. No significant associations were observed between the selected polymorphisms and odds of MS, odds of IM or anti-EBNA1 Ab titer. It is unlikely that any of the studied polymorphisms contribute to the explaining the association between anti-EBNA1 Ab titer or history of IM and MS. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Multiple secretoglobin 1A1 genes are differentially expressed in horses

    Directory of Open Access Journals (Sweden)

    Côté Olivier

    2012-12-01

    Full Text Available Abstract Background Secretoglobin 1A1 (SCGB 1A1, also called Clara cell secretory protein, is the most abundantly secreted protein of the airway. The SCGB1A1 gene has been characterized in mammals as a single copy in the genome. However, analysis of the equine genome suggested that horses might have multiple SCGB1A1 gene copies. Non-ciliated lung epithelial cells produce SCGB 1A1 during inhalation of noxious substances to counter airway inflammation. Airway fluid and lung tissue of horses with recurrent airway obstruction (RAO, a chronic inflammatory lung disease affecting mature horses similar to environmentally induced asthma of humans, have reduced total SCGB 1A1 concentration. Herein, we investigated whether horses have distinct expressed SCGB1A1 genes; whether the transcripts are differentially expressed in tissues and in inflammatory lung disease; and whether there is cell specific protein expression in tissues. Results We identified three SCGB1A1 gene copies on equine chromosome 12, contained within a 512-kilobase region. Bioinformatic analysis showed that SCGB1A1 genes differ from each other by 8 to 10 nucleotides, and that they code for different proteins. Transcripts were detected for SCGB1A1 and SCGB1A1A, but not for SCGB1A1P. The SCGB1A1P gene had most inter-individual variability and contained a non-sense mutation in many animals, suggesting that SCGB1A1P has evolved into a pseudogene. Analysis of SCGB1A1 and SCGB1A1A sequences by endpoint-limiting dilution PCR identified a consistent difference affecting 3 bp within exon 2, which served as a gene-specific “signature”. Assessment of gene- and organ-specific expression by semiquantitative RT-PCR of 33 tissues showed strong expression of SCGB1A1 and SCGB1A1A in lung, uterus, Fallopian tube and mammary gland, which correlated with detection of SCGB 1A1 protein by immunohistochemistry. Significantly altered expression of the ratio of SCGB1A1A to SCGB1A1 was detected in RAO

  15. Gene Expression Variability as a Unifying Element of the Pluripotency Network

    Directory of Open Access Journals (Sweden)

    Elizabeth A. Mason

    2014-08-01

    Full Text Available Heterogeneity is a hallmark of stem cell populations, in part due to the molecular differences between cells undergoing self-renewal and those poised to differentiate. We examined phenotypic and molecular heterogeneity in pluripotent stem cell populations, using public gene expression data sets. A high degree of concordance was observed between global gene expression variability and the reported heterogeneity of different human pluripotent lines. Network analysis demonstrated that low-variability genes were the most highly connected, suggesting that these are the most stable elements of the gene regulatory network and are under the highest regulatory constraints. Known drivers of pluripotency were among these, with lowest expression variability of POU5F1 in cells with the highest capacity for self-renewal. Variability of gene expression provides a reliable measure of phenotypic and molecular heterogeneity and predicts those genes with the highest degree of regulatory constraint within the pluripotency network.

  16. Variables associated with communicative participation in people with multiple sclerosis: a regression analysis.

    Science.gov (United States)

    Baylor, Carolyn; Yorkston, Kathryn; Bamer, Alyssa; Britton, Deanna; Amtmann, Dagmar

    2010-05-01

    To explore variables associated with self-reported communicative participation in a sample (n = 498) of community-dwelling adults with multiple sclerosis (MS). A battery of questionnaires was administered online or on paper per participant preference. Data were analyzed using multiple linear backward stepwise regression. The dependent variable was an item response theory score of communicative participation measured by a subset of items from the Communicative Participation Item Bank asking respondents to rate how much their health condition interfered with participation in real-life speech communication situations. Thirteen independent variables were included in the model as self-reported symptoms: problems thinking, slurred speech, vision loss, pain, mobility, depression, fatigue, perceived social support, age, education level, employment status, gender, and MS duration. Fatigue, slurred speech, depression, problems thinking, employment status, and social support were significantly associated with communicative participation, accounting for 48.7% of the variance. Communicative participation is significantly associated with multiple variables, only some of which reflect communication disorders. If the goal of intervention is to improve communicative participation, intervention may need to extend beyond traditional speech-language pathology boundaries to include other health symptoms as well as personal, social, and physical environments.

  17. Variability of monthly nitrogen multiple-breath washout during one year in children with cystic fibrosis

    DEFF Research Database (Denmark)

    Green, Kent; Kongstad, Thomas; Skov, Marianne

    2017-01-01

    Background: Knowledge of between-session variability of nitrogen multiple-breath washout (N2MBW) indices is crucial when designing longitudinal interventional studies and in disease monitoring using N2MBW as end-point. Such information is currently sparse. Methods: Monthly triplets of N2MBW were...... prospectively obtained from 14 children with CF during one year. Linear mixed models were used to analyze variability. Our aim was to assess between-session variability of N2MBW indices from repeated measurements and compare LCI derived from different software packages currently in use (TestPoint® vs. Spiroware......®). Results: Baseline LCI (median; range) was 9.37 (6.82; 12.08). Between-session differences in LCI measurements were up to 25%. Intra Class Correlation-Coefficient was 0.82. There was no systematic difference between LCI measurements derived from the two software packages (p = 0.18); however, variability...

  18. An Extended TOPSIS Method for Multiple Attribute Decision Making based on Interval Neutrosophic Uncertain Linguistic Variables

    Directory of Open Access Journals (Sweden)

    Said Broumi

    2015-03-01

    Full Text Available The interval neutrosophic uncertain linguistic variables can easily express the indeterminate and inconsistent information in real world, and TOPSIS is a very effective decision making method more and more extensive applications. In this paper, we will extend the TOPSIS method to deal with the interval neutrosophic uncertain linguistic information, and propose an extended TOPSIS method to solve the multiple attribute decision making problems in which the attribute value takes the form of the interval neutrosophic uncertain linguistic variables and attribute weight is unknown. Firstly, the operational rules and properties for the interval neutrosophic variables are introduced. Then the distance between two interval neutrosophic uncertain linguistic variables is proposed and the attribute weight is calculated by the maximizing deviation method, and the closeness coefficients to the ideal solution for each alternatives. Finally, an illustrative example is given to illustrate the decision making steps and the effectiveness of the proposed method.

  19. Gene Variants Associated with Antisocial Behaviour: A Latent Variable Approach

    Science.gov (United States)

    Bentley, Mary Jane; Lin, Haiqun; Fernandez, Thomas V.; Lee, Maria; Yrigollen, Carolyn M.; Pakstis, Andrew J.; Katsovich, Liliya; Olds, David L.; Grigorenko, Elena L.; Leckman, James F.

    2013-01-01

    Objective: The aim of this study was to determine if a latent variable approach might be useful in identifying shared variance across genetic risk alleles that is associated with antisocial behaviour at age 15 years. Methods: Using a conventional latent variable approach, we derived an antisocial phenotype in 328 adolescents utilizing data from a…

  20. FIRE: an SPSS program for variable selection in multiple linear regression analysis via the relative importance of predictors

    National Research Council Canada - National Science Library

    Lorenzo-Seva, Urbano; Ferrando, Pere J

    2011-01-01

    We provide an SPSS program that implements currently recommended techniques and recent developments for selecting variables in multiple linear regression analysis via the relative importance of predictors...

  1. Multiple Milia as an Isolated Skin Manifestation of Dominant Dystrophic Epidermolysis Bullosa: Evidence of Phenotypic Variability.

    Science.gov (United States)

    Akasaka, Eijiro; Nakano, Hajime; Takagi, Yuriko; Toyomaki, Yuka; Sawamura, Daisuke

    2017-03-01

    We report a Japanese pedigree with dominant dystrophic epidermolysis bullosa (DDEB) harboring the p.G2251E mutation of COL7A1. The proband of this pedigree presented with multiple milia as an isolated skin manifestation without a history of blistering and subsequently developed generalized intractable blisters, suggesting that multiple milia could be a primary manifestation of DDEB. Her mother exhibited nail dystrophy and pruritic nodules and her elder sister was unaffected, despite having the same COL7A1 mutation. Inter- and intrafamilial clinical variability are often observed in DDEB, so we should be aware of this factor to provide appropriate genetic counselling. © 2016 Wiley Periodicals, Inc.

  2. Stride-Time Variability and Fall Risk in Persons with Multiple Sclerosis.

    Science.gov (United States)

    Moon, Yaejin; Wajda, Douglas A; Motl, Robert W; Sosnoff, Jacob J

    2015-01-01

    Gait variability is associated with falls in clinical populations. However, gait variability's link to falls in persons with Multiple Sclerosis (PwMS) is not well established. This investigation examined the relationship between stride-time variability, fall risk, and physiological fall risk factors in PwMS. 17 PwMS (62.8 ± 7.4 years) and 17 age-matched controls (62.8 ± 5.9 years) performed the 6-minute walk test. Stride-time was assessed with accelerometers attached to the participants' shanks. Stride-time variability was measured by interstride coefficient of variation (CV) of stride-time. The participant's fall risk was measured by the short form physiological profile assessment (PPA). A Spearman correlation analysis was used to determine the relationship between variables. Increased fall risk was strongly associated with increased stride-time CV in both PwMS (ρ = 0.71, p 0.05). In PwMS, stride-time CV was related to postural sway (ρ = 0.74, p < 0.01) while in the control group, it was related to proprioception (ρ = 0.61, p < 0.01) and postural sway (ρ = 0.78, p < 0.01). Current observations suggest that gait variability is maybe more sensitive marker of fall risk than average gait parameters in PwMS. It was also noted that postural sway may be potentially targeted to modify gait variability in PwMS.

  3. Simultaneous Optimization of Multiple Response Variables for the Gelatin-chitosan Microcapsules Containing Angelica Essential Oil.

    Science.gov (United States)

    Li, Qiang; Sun, Li-Jian; Gong, Xian-Feng; Wang, Yang; Zhao, Xue-Ling

    2017-01-01

    Angelica essential oil (AO), a major pharmacologically active component of Angelica sinensis (Oliv.) Diels, possesses hemogenesis, analgesic activities, and sedative effect. The application of AO in pharmaceutical systems had been limited because of its low oxidative stability. The AO-loaded gelatin-chitosan microcapsules with prevention from oxidation were developed and optimized using response surface methodology. The effects of formulation variables (pH at complex coacervation, gelatin concentration, and core/wall ratio) on multiple response variables (yield, encapsulation efficiency, antioxidation rate, percent of drug released in 1 h, and time to 85% drug release) were systemically investigated. A desirability function that combined these five response variables was constructed. All response variables investigated were found to be highly dependent on the formulation variables, with strong interactions observed between the formulation variables. It was found that optimum overall desirability of AO microcapsules could be obtained at pH 6.20, gelatin concentration 25.00%, and core/wall ratio 40.40%. The experimental values of the response variables highly agreed with the predicted values. The antioxidation rate of optimum formulation was approximately 8 times higher than that of AO. The in-vitro drug release from microcapsules was followed Higuchi model with super case-II transport mechanism.

  4. Simultaneous mapping of multiple gene loci with pooled segregants.

    Directory of Open Access Journals (Sweden)

    Jürgen Claesen

    Full Text Available The analysis of polygenic, phenotypic characteristics such as quantitative traits or inheritable diseases remains an important challenge. It requires reliable scoring of many genetic markers covering the entire genome. The advent of high-throughput sequencing technologies provides a new way to evaluate large numbers of single nucleotide polymorphisms (SNPs as genetic markers. Combining the technologies with pooling of segregants, as performed in bulked segregant analysis (BSA, should, in principle, allow the simultaneous mapping of multiple genetic loci present throughout the genome. The gene mapping process, applied here, consists of three steps: First, a controlled crossing of parents with and without a trait. Second, selection based on phenotypic screening of the offspring, followed by the mapping of short offspring sequences against the parental reference. The final step aims at detecting genetic markers such as SNPs, insertions and deletions with next generation sequencing (NGS. Markers in close proximity of genomic loci that are associated to the trait have a higher probability to be inherited together. Hence, these markers are very useful for discovering the loci and the genetic mechanism underlying the characteristic of interest. Within this context, NGS produces binomial counts along the genome, i.e., the number of sequenced reads that matches with the SNP of the parental reference strain, which is a proxy for the number of individuals in the offspring that share the SNP with the parent. Genomic loci associated with the trait can thus be discovered by analyzing trends in the counts along the genome. We exploit the link between smoothing splines and generalized mixed models for estimating the underlying structure present in the SNP scatterplots.

  5. Investigating Prevalence of FOXP3 Gene Polymorphism in Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    R Rahnama

    2015-02-01

    Full Text Available Introduction: Multiple sclerosis (MS is a demyelinating disease of central nervous system. Lack of regulation in inflammatory responses is considered to be a key element in the auto reactive immune response in MS. The FOXP3 transcription factor is predominantly expressed by the Treg cell lineage and appears to act as a master regulator of effector T cell activation. Therefore, this study aimed to investigate the possible association between single nucleotide polymorphisms (SNP in the FOXP3 gene and predisposition to MS. Methods: This case-control study consisted of 115 MS patients and 115 healthy controls, which were genotyped for the SNP rs 3761549. RFLP analysis was performed using AluI restriction enzyme. Results: The frequency of A allele was 15.6% in patients and 98.3% in normal controls (p=0.33. Moreover, allele G was identified as 98.1% in MS cases and 11.3 in controls. The rs 3761549(GG was found in 84.3% of MS patients and in 88.7% of controls (p=0.33, rs 3761549 (AA was found in 0.9% of MS cases and in 1.7% of controls (p=0.5, rs 3761549 (AG was observed in 84.4% of MS cases and in 88.7% of controls (p=0.27. No significant difference was observed between patients and controls in regard with alleles and genotypes. Conclusion: The results of the present study suggest that the mentioned functional polymorphism is not likely to cause susceptibility to MS.( OR= 0.678 95% CI= 1.477-0.0319

  6. Gene, cell, and organ multiplication drives inner ear evolution.

    Science.gov (United States)

    Fritzsch, Bernd; Elliott, Karen L

    2017-11-01

    We review the development and evolution of the ear neurosensory cells, the aggregation of neurosensory cells into an otic placode, the evolution of novel neurosensory structures dedicated to hearing and the evolution of novel nuclei in the brain and their input dedicated to processing those novel auditory stimuli. The evolution of the apparently novel auditory system lies in duplication and diversification of cell fate transcription regulation that allows variation at the cellular level [transforming a single neurosensory cell into a sensory cell connected to its targets by a sensory neuron as well as diversifying hair cells], organ level [duplication of organ development followed by diversification and novel stimulus acquisition] and brain nuclear level [multiplication of transcription factors to regulate various neuron and neuron aggregate fate to transform the spinal cord into the unique hindbrain organization]. Tying cell fate changes driven by bHLH and other transcription factors into cell and organ changes is at the moment tentative as not all relevant factors are known and their gene regulatory network is only rudimentary understood. Future research can use the blueprint proposed here to provide both the deeper molecular evolutionary understanding as well as a more detailed appreciation of developmental networks. This understanding can reveal how an auditory system evolved through transformation of existing cell fate determining networks and thus how neurosensory evolution occurred through molecular changes affecting cell fate decision processes. Appreciating the evolutionary cascade of developmental program changes could allow identifying essential steps needed to restore cells and organs in the future. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. Regulation of cell-to-cell variability in divergent gene expression.

    Science.gov (United States)

    Yan, Chao; Wu, Shuyang; Pocetti, Christopher; Bai, Lu

    2016-03-24

    Cell-to-cell variability (noise) is an important feature of gene expression that impacts cell fitness and development. The regulatory mechanism of this variability is not fully understood. Here we investigate the effect on gene expression noise in divergent gene pairs (DGPs). We generated reporters driven by divergent promoters, rearranged their gene order, and probed their expressions using time-lapse fluorescence microscopy and single-molecule fluorescence in situ hybridization (smFISH). We show that two genes in a co-regulated DGP have higher expression covariance compared with the separate, tandem and convergent configurations, and this higher covariance is caused by more synchronized firing of the divergent transcriptions. For differentially regulated DGPs, the regulatory signal of one gene can stochastically 'leak' to the other, causing increased gene expression noise. We propose that the DGPs' function in limiting or promoting gene expression noise may enhance or compromise cell fitness, providing an explanation for the conservation pattern of DGPs.

  8. Prevention of Leptospirosis Infected Vector and Human Population by Multiple Control Variables

    OpenAIRE

    Muhammad Altaf Khan; Saeed Islam; Sher Afzal Khan; Ilyas Khan; Sharidan Shafie; Taza Gul

    2014-01-01

    Leptospirosis is an infectious disease that damages the liver and kidneys, found mainly in dogs and farm animals and caused by bacteria. In this paper, we present the optimal control problem applied to a dynamical leptospirosis infected vector and human population by using multiple control variables. First, we show the existence of the control problem and then use analytical and numerical techniques to investigate the existence cost effective control efforts for prevention of indirect and dir...

  9. Within-day variability on short and long walking tests in persons with multiple sclerosis

    OpenAIRE

    FEYS, Peter; Bibby, Bo; Romberg, Anders; Santoyo, Carme; Gebara, Benoit; de Noordhout, Benoit Maertens; Knuts, Kathy; Bethoux, Francois; Skjerbaek, Anders; Jensen, Ellen; BAERT, Ilse; Vaney, Claude; de Groot, Vincent; Dalgas, Ulrik

    2014-01-01

    Objective: To compare within-day variability of short (10 mwalking test at usual and fastest speed; 10MWT) and long (2 and 6-minute walking test; 2MWT/6MWT) tests in persons with multiple sclerosis. Design: Observational study. Setting: MS rehabilitation and research centers in Europe and US within RIMS (European network for best practice and research in MS rehabilitation). Subjects: Ambulatory persons with MS (Expanded Disability Status Scale 0–6.5). Intervention: Subjects of dif...

  10. Multiple antibiotic resistance genes distribution in ten large-scale membrane bioreactors for municipal wastewater treatment.

    Science.gov (United States)

    Sun, Yanmei; Shen, Yue-Xiao; Liang, Peng; Zhou, Jizhong; Yang, Yunfeng; Huang, Xia

    2016-12-01

    Wastewater treatment plants are thought to be potential reservoirs of antibiotic resistance genes. In this study, GeoChip was used for analyzing multiple antibiotic resistance genes, including four multidrug efflux system gene groups and three β-lactamase genes in ten large-scale membrane bioreactors (MBRs) for municipal wastewater treatment. Results revealed that the diversity of antibiotic genes varied a lot among MBRs, but about 40% common antibiotic resistance genes were existent. The average signal intensity of each antibiotic resistance group was similar among MBRs, nevertheless the total abundance of each group varied remarkably and the dominant resistance gene groups were different in individual MBR. The antibiotic resistance genes majorly derived from Proteobacteria and Actinobacteria. Further study indicated that TN, TP and COD of influent, temperature and conductivity of mixed liquor were significant (P<0.05) correlated to the multiple antibiotic resistance genes distribution in MBRs. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Multiple Suboptimal Solutions for Prediction Rules in Gene Expression Data

    Directory of Open Access Journals (Sweden)

    Osamu Komori

    2013-01-01

    Full Text Available This paper discusses mathematical and statistical aspects in analysis methods applied to microarray gene expressions. We focus on pattern recognition to extract informative features embedded in the data for prediction of phenotypes. It has been pointed out that there are severely difficult problems due to the unbalance in the number of observed genes compared with the number of observed subjects. We make a reanalysis of microarray gene expression published data to detect many other gene sets with almost the same performance. We conclude in the current stage that it is not possible to extract only informative genes with high performance in the all observed genes. We investigate the reason why this difficulty still exists even though there are actively proposed analysis methods and learning algorithms in statistical machine learning approaches. We focus on the mutual coherence or the absolute value of the Pearson correlations between two genes and describe the distributions of the correlation for the selected set of genes and the total set. We show that the problem of finding informative genes in high dimensional data is ill-posed and that the difficulty is closely related with the mutual coherence.

  12. Fruit specific variability in capsaicinoid accumulation and transcription of structural and regulatory genes in Capsicum fruit

    Science.gov (United States)

    Keyhaninejad, Neda; Curry, Jeanne; Romero, Joslynn; O’Connell, Mary A.

    2013-01-01

    Accumulation of capsaicinoids in the placental tissue of ripening chile (Capsicum spp.) fruit follows the coordinated expression of multiple biosynthetic enzymes producing the substrates for capsaicin synthase. Transcription factors are likely agents to regulate expression of these biosynthetic genes. Placental RNAs from habanero fruit (C. chinense) were screened for expression of candidate transcription factors; with two candidate genes identified, both in the ERF family of transcription factors. Characterization of these transcription factors, Erf and Jerf, in nine chile cultivars with distinct capsaicinoid contents demonstrated a correlation of expression with pungency. Amino acid variants were observed in both ERF and JERF from different chile cultivars; none of these changes involved the DNA binding domains. Little to no transcription of Erf was detected in non-pungent C. annuum or C. chinense mutants. This correlation was characterized at an individual fruit level in a set of jalapeño (C. annuum) lines again with distinct and variable capsaicinoid contents. Both Erf and Jerf are expressed early in fruit development, 16–20 days post-anthesis, at times prior to the accumulation of capsaicinoids in the placental tissues. These data support the hypothesis that these two members of the complex ERF family participate in regulation of the pungency phenotype in chile. PMID:24388515

  13. Upregulation of Immunoglobulin-related Genes in Cortical Sections from Multiple Sclerosis Patients

    NARCIS (Netherlands)

    Torkildsen, O.; Stansberg, C.; Angelskar, S.M.; Kooi, E.J.; Geurts, J.J.G.; van der Valk, P.; Myhr, K.M.; Steen, V.M.; Bo, L.

    2010-01-01

    Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). Microarray-based global gene expression profiling is a promising method, used to study potential genes involved in the pathogenesis of the disease. In the present study, we have examined global gene expression in

  14. Multiple independent insertions of 5S rRNA genes in the spliced-leader gene family of trypanosome species.

    Science.gov (United States)

    Beauparlant, Marc A; Drouin, Guy

    2014-02-01

    Analyses of the 5S rRNA genes found in the spliced-leader (SL) gene repeat units of numerous trypanosome species suggest that such linkages were not inherited from a common ancestor, but were the result of independent 5S rRNA gene insertions. In trypanosomes, 5S rRNA genes are found either in the tandemly repeated units coding for SL genes or in independent tandemly repeated units. Given that trypanosome species where 5S rRNA genes are within the tandemly repeated units coding for SL genes are phylogenetically related, one might hypothesize that this arrangement is the result of an ancestral insertion of 5S rRNA genes into the tandemly repeated SL gene family of trypanosomes. Here, we use the types of 5S rRNA genes found associated with SL genes, the flanking regions of the inserted 5S rRNA genes and the position of these insertions to show that most of the 5S rRNA genes found within SL gene repeat units of trypanosome species were not acquired from a common ancestor but are the results of independent insertions. These multiple 5S rRNA genes insertion events in trypanosomes are likely the result of frequent founder events in different hosts and/or geographical locations in species having short generation times.

  15. Cilia gene mutations cause atrioventricular septal defects by multiple mechanisms.

    Science.gov (United States)

    Burnicka-Turek, Ozanna; Steimle, Jeffrey D; Huang, Wenhui; Felker, Lindsay; Kamp, Anna; Kweon, Junghun; Peterson, Michael; Reeves, Roger H; Maslen, Cheryl L; Gruber, Peter J; Yang, Xinan H; Shendure, Jay; Moskowitz, Ivan P

    2016-07-15

    Atrioventricular septal defects (AVSDs) are a common severe form of congenital heart disease (CHD). In this study we identified deleterious non-synonymous mutations in two cilia genes, Dnah11 and Mks1, in independent N-ethyl-N-nitrosourea-induced mouse mutant lines with heritable recessive AVSDs by whole-exome sequencing. Cilia are required for left/right body axis determination and second heart field (SHF) Hedgehog (Hh) signaling, and we find that cilia mutations affect these requirements differentially. Dnah11avc4 did not disrupt SHF Hh signaling and caused AVSDs only concurrently with heterotaxy, a left/right axis abnormality. In contrast, Mks1avc6 disrupted SHF Hh signaling and caused AVSDs without heterotaxy. We performed unbiased whole-genome SHF transcriptional profiling and found that cilia motility genes were not expressed in the SHF whereas cilia structural and signaling genes were highly expressed. SHF cilia gene expression predicted the phenotypic concordance between AVSDs and heterotaxy in mice and humans with cilia gene mutations. A two-step model of cilia action accurately predicted the AVSD/heterotaxyu phenotypic expression pattern caused by cilia gene mutations. We speculate that cilia gene mutations contribute to both syndromic and non-syndromic AVSDs in humans and provide a model that predicts the phenotypic consequences of specific cilia gene mutations. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  16. Geoadditive latent variable modeling of count data on multiple sexual partnering in Nigeria.

    Science.gov (United States)

    Adebayo, Samson B; Fahrmeir, Ludwig; Seiler, Christian; Heumann, Christian

    2011-06-01

    The 2005 National HIV/AIDS and Reproductive Health Survey (NARHS) in Nigeria provides evidence that multiple sexual partnering increases the risk of contracting HIV and other sexually transmitted diseases. Therefore, partner reduction is one of the prevention strategies to accomplish the Millenium Development Goal of halting and reversing the spread of HIV/AIDS. We consider the numbers of girlfriends, casual, and commercial partners of heterosexual men, reported in the NARHS study, as observed indicators of their latent attitude toward multiple partnering. To explore the influence of risk factors on this latent variable, we extend semiparametric methodology for latent variable models with continuous and categorical indicators to include count indicators. This allows us to simultaneously analyze linear and nonlinear effects of covariates, such as sociodemographic factors and knowledge about HIV/AIDS, on attitude toward multiple sexual partnering, which in turn influences the observable count indicators. The results provide insights for policy makers who are aiming to reduce the spread of HIV and AIDS among the Nigerian populace through partner reduction. © 2010, The International Biometric Society.

  17. Transmission of the P250R mutation of the FGFR3 gene in four generations with highly variable phenotype

    DEFF Research Database (Denmark)

    Hove, Hanne Buciek; Dunø, Morten; Daugaard-Jensen, Jette

    Transmission of the P250R mutation of the FGFR3 gene in four generations with highly variable phenotype.......Transmission of the P250R mutation of the FGFR3 gene in four generations with highly variable phenotype....

  18. Atlantic cod (Gadus morhua) hemoglobin genes: multiplicity and polymorphism

    Science.gov (United States)

    Borza, Tudor; Stone, Cynthia; Gamperl, A Kurt; Bowman, Sharen

    2009-01-01

    Background Hemoglobin (Hb) polymorphism, assessed by protein gel electrophoresis, has been used almost exclusively to characterize the genetic structure of Atlantic cod (Gadus morhua) populations and to establish correlations with phenotypic traits such as Hb oxygen binding capacity, temperature tolerance and growth characteristics. The genetic system used to explain the results of gel electrophoresis entails the presence of one polymorphic locus with two major alleles (HbI-1; HbI-2). However, vertebrates have more than one gene encoding Hbs and recent studies have reported that more than one Hb gene is present in Atlantic cod. These observations prompted us to re-evaluate the number of Hb genes expressed in Atlantic cod, and to perform an in depth search for polymorphisms that might produce relevant phenotypes for breeding programs. Results Analysis of Expressed Sequence Tags (ESTs) led to the identification of nine distinct Hb transcripts; four corresponding to the α Hb gene family and five to the β Hb gene family. To gain insights about the Hb genes encoding these transcripts, genomic sequence data was generated from heterozygous (HbI-1/2) parents and fifteen progeny; five of each HbI type, i.e., HbI-1/1, HbI-1/2 and HbI-2/2. β Hb genes displayed more polymorphism than α Hb genes. Two major allele types (β1A and β1B) that differ by two linked non-synonymous substitutions (Met55Val and Lys62Ala) were found in the β1 Hb gene, and the distribution of these β1A and β1B alleles among individuals was congruent with that of the HbI-1 and HbI-2 alleles determined by protein gel electrophoresis. RT-PCR and Q-PCR analysis of the nine Hb genes indicates that all genes are expressed in adult fish, but their level of expression varies greatly; higher expression of almost all Hb genes was found in individuals displaying the HbI-2/2 electrophoretic type. Conclusion This study indicates that more Hb genes are present and expressed in adult Atlantic cod than previously

  19. Atlantic cod (Gadus morhua hemoglobin genes: multiplicity and polymorphism

    Directory of Open Access Journals (Sweden)

    Gamperl A Kurt

    2009-09-01

    Full Text Available Abstract Background Hemoglobin (Hb polymorphism, assessed by protein gel electrophoresis, has been used almost exclusively to characterize the genetic structure of Atlantic cod (Gadus morhua populations and to establish correlations with phenotypic traits such as Hb oxygen binding capacity, temperature tolerance and growth characteristics. The genetic system used to explain the results of gel electrophoresis entails the presence of one polymorphic locus with two major alleles (HbI-1; HbI-2. However, vertebrates have more than one gene encoding Hbs and recent studies have reported that more than one Hb gene is present in Atlantic cod. These observations prompted us to re-evaluate the number of Hb genes expressed in Atlantic cod, and to perform an in depth search for polymorphisms that might produce relevant phenotypes for breeding programs. Results Analysis of Expressed Sequence Tags (ESTs led to the identification of nine distinct Hb transcripts; four corresponding to the α Hb gene family and five to the β Hb gene family. To gain insights about the Hb genes encoding these transcripts, genomic sequence data was generated from heterozygous (HbI-1/2 parents and fifteen progeny; five of each HbI type, i.e., HbI-1/1, HbI-1/2 and HbI-2/2. β Hb genes displayed more polymorphism than α Hb genes. Two major allele types (β1A and β1B that differ by two linked non-synonymous substitutions (Met55Val and Lys62Ala were found in the β1 Hb gene, and the distribution of these β1A and β1B alleles among individuals was congruent with that of the HbI-1 and HbI-2 alleles determined by protein gel electrophoresis. RT-PCR and Q-PCR analysis of the nine Hb genes indicates that all genes are expressed in adult fish, but their level of expression varies greatly; higher expression of almost all Hb genes was found in individuals displaying the HbI-2/2 electrophoretic type. Conclusion This study indicates that more Hb genes are present and expressed in adult

  20. Transcriptional silencing of multiple genes in trophozoites of Entamoeba histolytica.

    Directory of Open Access Journals (Sweden)

    Rivka Bracha

    2006-05-01

    Full Text Available In a previous work we described the transcriptional silencing of the amoebapore A (AP-A gene (Ehap-a of Entamoeba histolytica strain HM-1:IMSS. The silencing occurred following transfection with a plasmid containing a 5' upstream region (473 bp of Ehap-a that included a truncated segment (140 bp of a short interspersed nuclear element (SINE1. Silencing remained in effect even after removal of the plasmid (clone G3. Neither short interfering RNA nor methylated DNA were detected, but the chromatin domain of Ehap-a in the gene-silenced trophozoites was modified. Two other similar genes (Ehap-b and one encoding a Saposin-like protein, SAPLIP 1 also became silenced. In the present work we demonstrate the silencing of a second gene of choice, one that encodes the light subunit of the Gal/GalNAc inhibitable lectin (Ehlgl1 and the other, the cysteine proteinase 5 (EhCP-5. This silencing occurred in G3 trophozoites transfected with a plasmid in which the 473 bp 5' upstream Ehap-a fragment was directly ligated to the second gene. Transcriptional silencing occurred in both the transgene and the chromosomal gene. SINE1 sequences were essential, as was a direct connection between the Ehap-a upstream region and the beginning of the open reading frame of the second gene. Gene silencing did not occur in strain HM-1:IMSS with any of these plasmid constructs. The trophozoites with two silenced genes were virulence-attenuated as were those of clone G3. In addition, trophozoites not expressing Lgl1 and AP-A proteins had a significantly reduced ability to cap the Gal/GalNAc-lectin to the uroid region when incubated with antibodies against the heavy (170 kDa subunit of the lectin. Lysates of trophozoites lacking cysteine proteinase 5 and AP-A proteins had 30% less cysteine proteinase activity than those of HM-1:IMSS strain or the G3 clone. Silencing of other genes in G3 amoebae could provide a model to study their various functions. In addition, double gene

  1. Multiple oscillators regulate circadian gene expression in Neurospora

    OpenAIRE

    Correa, Alejandro; Lewis, Zachary A.; Greene, Andrew V.; March, Irene J.; Gomer, Richard H.; Bell-Pedersen, Deborah

    2003-01-01

    High-density microarrays were used to profile circadian gene expression in Neurospora crassa cultures grown in constant darkness. We identified 145 clock-controlled genes (ccgs). The ccgs peaked in mRNA accumulation at all phases of the day, with the majority peaking in the late night to early morning. The predicted or known functions of the ccgs demonstrate that the clock contributes to a wide range of cellular processes, including cell signaling, development, metabolism, and stress response...

  2. A novel mutation in the tRNAIle gene (MTTI) affecting the variable loop in a patient with chronic progressive external ophthalmoplegia (CPEO)

    OpenAIRE

    Berardo, Andres; Çoku, Jorida; Kurt,Bulent; DiMauro, Salvatore; Hirano, Michio

    2010-01-01

    We describe a 62-year-old woman with chronic progressive external ophthalmoplegia (CPEO), multiple lipomas, diabetes mellitus, and a novel mitochondrial DNA (mtDNA) mutation at nucleotide 4302 (4302A>G) of the tRNAIle gene (MTTI). This is the first mutation at position 44 in the variable loop (V loop) of any mitochondrial tRNA.

  3. Adaptive control of a jet turboshaft engine driving a variable pitch propeller using multiple models

    Science.gov (United States)

    Ahmadian, Narjes; Khosravi, Alireza; Sarhadi, Pouria

    2017-08-01

    In this paper, a multiple model adaptive control (MMAC) method is proposed for a gas turbine engine. The model of a twin spool turbo-shaft engine driving a variable pitch propeller includes various operating points. Variations in fuel flow and propeller pitch inputs produce different operating conditions which force the controller to be adopted rapidly. Important operating points are three idle, cruise and full thrust cases for the entire flight envelope. A multi-input multi-output (MIMO) version of second level adaptation using multiple models is developed. Also, stability analysis using Lyapunov method is presented. The proposed method is compared with two conventional first level adaptation and model reference adaptive control techniques. Simulation results for JetCat SPT5 turbo-shaft engine demonstrate the performance and fidelity of the proposed method.

  4. Identification of multiple independent horizontal gene transfers into poxviruses using a comparative genomics approach

    Directory of Open Access Journals (Sweden)

    McLysaght Aoife

    2008-02-01

    Full Text Available Abstract Background Poxviruses are important pathogens of humans, livestock and wild animals. These large dsDNA viruses have a set of core orthologs whose gene order is extremely well conserved throughout poxvirus genera. They also contain many genes with sequence and functional similarity to host genes which were probably acquired by horizontal gene transfer. Although phylogenetic trees can indicate the occurrence of horizontal gene transfer and even uncover multiple events, their use may be hampered by uncertainties in both the topology and the rooting of the tree. We propose to use synteny conservation around the horizontally transferred gene (HTgene to distinguish between single and multiple events. Results Here we devise a method that incorporates comparative genomic information into the investigation of horizontal gene transfer, and we apply this method to poxvirus genomes. We examined the synteny conservation around twenty four pox genes that we identified, or which were reported in the literature, as candidate HTgenes. We found support for multiple independent transfers into poxviruses for five HTgenes. Three of these genes are known to be important for the survival of the virus in or out of the host cell and one of them increases susceptibility to some antiviral drugs. Conclusion In related genomes conserved synteny information can provide convincing evidence for multiple independent horizontal gene transfer events even in the absence of a robust phylogenetic tree for the HTgene.

  5. Monoamine Oxidase A (MAOA Gene and Personality Traits from Late Adolescence through Early Adulthood: A Latent Variable Investigation

    Directory of Open Access Journals (Sweden)

    Man K. Xu

    2017-10-01

    Full Text Available Very few molecular genetic studies of personality traits have used longitudinal phenotypic data, therefore molecular basis for developmental change and stability of personality remains to be explored. We examined the role of the monoamine oxidase A gene (MAOA on extraversion and neuroticism from adolescence to adulthood, using modern latent variable methods. A sample of 1,160 male and 1,180 female participants with complete genotyping data was drawn from a British national birth cohort, the MRC National Survey of Health and Development (NSHD. The predictor variable was based on a latent variable representing genetic variations of the MAOA gene measured by three SNPs (rs3788862, rs5906957, and rs979606. Latent phenotype variables were constructed using psychometric methods to represent cross-sectional and longitudinal phenotypes of extraversion and neuroticism measured at ages 16 and 26. In males, the MAOA genetic latent variable (AAG was associated with lower extraversion score at age 16 (β = −0.167; CI: −0.289, −0.045; p = 0.007, FDRp = 0.042, as well as greater increase in extraversion score from 16 to 26 years (β = 0.197; CI: 0.067, 0.328; p = 0.003, FDRp = 0.036. No genetic association was found for neuroticism after adjustment for multiple testing. Although, we did not find statistically significant associations after multiple testing correction in females, this result needs to be interpreted with caution due to issues related to x-inactivation in females. The latent variable method is an effective way of modeling phenotype- and genetic-based variances and may therefore improve the methodology of molecular genetic studies of complex psychological traits.

  6. Monoamine Oxidase A (MAOA) Gene and Personality Traits from Late Adolescence through Early Adulthood: A Latent Variable Investigation.

    Science.gov (United States)

    Xu, Man K; Gaysina, Darya; Tsonaka, Roula; Morin, Alexandre J S; Croudace, Tim J; Barnett, Jennifer H; Houwing-Duistermaat, Jeanine; Richards, Marcus; Jones, Peter B

    2017-01-01

    Very few molecular genetic studies of personality traits have used longitudinal phenotypic data, therefore molecular basis for developmental change and stability of personality remains to be explored. We examined the role of the monoamine oxidase A gene (MAOA) on extraversion and neuroticism from adolescence to adulthood, using modern latent variable methods. A sample of 1,160 male and 1,180 female participants with complete genotyping data was drawn from a British national birth cohort, the MRC National Survey of Health and Development (NSHD). The predictor variable was based on a latent variable representing genetic variations of the MAOA gene measured by three SNPs (rs3788862, rs5906957, and rs979606). Latent phenotype variables were constructed using psychometric methods to represent cross-sectional and longitudinal phenotypes of extraversion and neuroticism measured at ages 16 and 26. In males, the MAOA genetic latent variable (AAG) was associated with lower extraversion score at age 16 (β = -0.167; CI: -0.289, -0.045; p = 0.007, FDRp = 0.042), as well as greater increase in extraversion score from 16 to 26 years (β = 0.197; CI: 0.067, 0.328; p = 0.003, FDRp = 0.036). No genetic association was found for neuroticism after adjustment for multiple testing. Although, we did not find statistically significant associations after multiple testing correction in females, this result needs to be interpreted with caution due to issues related to x-inactivation in females. The latent variable method is an effective way of modeling phenotype- and genetic-based variances and may therefore improve the methodology of molecular genetic studies of complex psychological traits.

  7. Stride-Time Variability and Fall Risk in Persons with Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Yaejin Moon

    2015-01-01

    Full Text Available Gait variability is associated with falls in clinical populations. However, gait variability’s link to falls in persons with Multiple Sclerosis (PwMS is not well established. This investigation examined the relationship between stride-time variability, fall risk, and physiological fall risk factors in PwMS. 17 PwMS (62.8±7.4 years and 17 age-matched controls (62.8±5.9 years performed the 6-minute walk test. Stride-time was assessed with accelerometers attached to the participants’ shanks. Stride-time variability was measured by interstride coefficient of variation (CV of stride-time. The participant’s fall risk was measured by the short form physiological profile assessment (PPA. A Spearman correlation analysis was used to determine the relationship between variables. Increased fall risk was strongly associated with increased stride-time CV in both PwMS (ρ=0.71, p0.05. In PwMS, stride-time CV was related to postural sway (ρ=0.74, p<0.01 while in the control group, it was related to proprioception (ρ=0.61, p<0.01 and postural sway (ρ=0.78, p<0.01. Current observations suggest that gait variability is maybe more sensitive marker of fall risk than average gait parameters in PwMS. It was also noted that postural sway may be potentially targeted to modify gait variability in PwMS.

  8. Within-day variability on short and long walking tests in persons with multiple sclerosis.

    Science.gov (United States)

    Feys, Peter; Bibby, Bo; Romberg, Anders; Santoyo, Carme; Gebara, Benoit; de Noordhout, Benoit Maertens; Knuts, Kathy; Bethoux, Francois; Skjerbæk, Anders; Jensen, Ellen; Baert, Ilse; Vaney, Claude; de Groot, Vincent; Dalgas, Ulrik

    2014-03-15

    To compare within-day variability of short (10 m walking test at usual and fastest speed; 10MWT) and long (2 and 6-minute walking test; 2MWT/6MWT) tests in persons with multiple sclerosis. Observational study. MS rehabilitation and research centers in Europe and US within RIMS (European network for best practice and research in MS rehabilitation). Ambulatory persons with MS (Expanded Disability Status Scale 0-6.5). Subjects of different centers performed walking tests at 3 time points during a single day. 10MWT, 2MWT and 6MWT at fastest speed and 10MWT at usual speed. Ninety-five percent limits of agreement were computed using a random effects model with individual pwMS as random effect. Following this model, retest scores are with 95% certainty within these limits of baseline scores. In 102 subjects, within-day variability was constant in absolute units for the 10MWT, 2MWT and 6MWT at fastest speed (+/-0.26, 0.16 and 0.15m/s respectively, corresponding to +/-19.2m and +/-54 m for the 2MWT and 6MWT) independent on the severity of ambulatory dysfunction. This implies a greater relative variability with increasing disability level, often above 20% depending on the applied test. The relative within-day variability of the 10MWT at usual speed was +/-31% independent of ambulatory function. Absolute values of within-day variability on walking tests at fastest speed were independent of disability level and greater with short compared to long walking tests. Relative within-day variability remained overall constant when measured at usual speed. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

  9. Evaluation of dominance-based ordinal multiple regression for variables with few categories.

    Science.gov (United States)

    Woods, Carol M

    2013-02-01

    Dominance-based ordinal multiple regression (DOR) is designed to answer ordinal questions about relationships among ordinal variables. Only one parameter per predictor is estimated, and the number of parameters is constant for any number of outcome levels. The majority of existing simulation evaluations of DOR use predictors that are continuous or ordinal with many categories, so the performance of the method is not well understood for ordinal variables with few categories. This research evaluates DOR in simulations using three-category ordinal variables for the outcome and predictors, with a comparison to the cumulative logits proportional odds model (POC). Although ordinary least squares (OLS) regression is inapplicable for theoretical reasons, it was also included in the simulations because of its popularity in the social sciences. Most simulation outcomes indicated that DOR performs well for variables with few categories, and is preferable to the POC for smaller samples and when the proportional odds assumption is violated. Nevertheless, confidence interval coverage for DOR was not flawless and possibilities for improvement are suggested. © 2012 The British Psychological Society.

  10. Phylogeny of the caniform carnivora: evidence from multiple genes.

    Science.gov (United States)

    Yu, Li; Zhang, Ya-ping

    2006-05-01

    The monophyletic group Caniformia in the order Carnivora currently comprises seven families whose relationships remain contentious. The phylogenetic positions of the two panda species within the Caniformia have also been evolutionary puzzles over the past decades, especially for Ailurus fulgens (the red panda). Here, new nuclear sequences from two introns of the beta-fibrinogen gene (beta-fibrinogen introns 4 and 7) and a complete mitochondrial (mt) gene (ND2) from 17 caniform representatives were explored for their utilities in resolving higher-level relationships in the Caniformia. In addition, two previously available nuclear (IRBP exon 1 and TTR intron 1) data sets were also combined and analyzed simultaneously with the newly obtained sequence data in this study. Combined analyses of four nuclear and one mt genes (4417 bp) recover a branching order in which almost all nodes were strongly supported. The present analyses provide evidence in favor of Ailurus fulgens as the closest taxon to the procyonid-mustelid (i.e., Musteloidea sensu stricto) clade, followed by pinnipeds (i.e., Otariidae and Phocidae), Ursidae (including Ailuropoda melanoleuca), and Canidae, the most basal lineage in the Caniformia. The potential utilities of different genes in the context of caniform phylogeny were also evaluated, with special attention to the previously unexplored beta-fibrinogen intron 4 and 7 genes.

  11. progressiveMauve: multiple genome alignment with gene gain, loss and rearrangement.

    Directory of Open Access Journals (Sweden)

    Aaron E Darling

    2010-06-01

    Full Text Available Multiple genome alignment remains a challenging problem. Effects of recombination including rearrangement, segmental duplication, gain, and loss can create a mosaic pattern of homology even among closely related organisms.We describe a new method to align two or more genomes that have undergone rearrangements due to recombination and substantial amounts of segmental gain and loss (flux. We demonstrate that the new method can accurately align regions conserved in some, but not all, of the genomes, an important case not handled by our previous work. The method uses a novel alignment objective score called a sum-of-pairs breakpoint score, which facilitates accurate detection of rearrangement breakpoints when genomes have unequal gene content. We also apply a probabilistic alignment filtering method to remove erroneous alignments of unrelated sequences, which are commonly observed in other genome alignment methods. We describe new metrics for quantifying genome alignment accuracy which measure the quality of rearrangement breakpoint predictions and indel predictions. The new genome alignment algorithm demonstrates high accuracy in situations where genomes have undergone biologically feasible amounts of genome rearrangement, segmental gain and loss. We apply the new algorithm to a set of 23 genomes from the genera Escherichia, Shigella, and Salmonella. Analysis of whole-genome multiple alignments allows us to extend the previously defined concepts of core- and pan-genomes to include not only annotated genes, but also non-coding regions with potential regulatory roles. The 23 enterobacteria have an estimated core-genome of 2.46Mbp conserved among all taxa and a pan-genome of 15.2Mbp. We document substantial population-level variability among these organisms driven by segmental gain and loss. Interestingly, much variability lies in intergenic regions, suggesting that the Enterobacteriacae may exhibit regulatory divergence.The multiple genome alignments

  12. Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene.

    Science.gov (United States)

    Annunziata, Ida; Bouchè, Valentina; Lombardi, Alessia; Settembre, Carmine; Ballabio, Andrea

    2007-09-01

    Sulfatases catalyze the hydrolysis of sulfate ester bonds from a wide variety of substrates and are implicated in several human inherited diseases. Multiple sulfatase deficiency (MSD) is a rare autosomal recessive disorder characterized by the simultaneous deficiency of all known sulfatases. MSD is caused by mutations in the Sulfatase Modifying Factor 1 (SUMF1) gene encoding the alpha-formylglycine generating enzyme (FGE), which is responsible for the post-translational modification of sulfatases. In all MSD patients, residual sulfatase activities are detectable, at variable levels. To correlate the nature of the residual sulfatase activities detected in MSD patients with residual FGE activity, four FGE mutants (i.e. p.S155P, p.R224W, p.R345C, p.R349W) found in homozygosis in MSD patients were analyzed. Using viral-mediated gene delivery, these mutants were over-expressed in mouse embryonic fibroblasts (MEFs) from a recently developed Sumf1 KO mouse line which is completely devoid of all sulfatase activities. The results obtained indicate that mutant SUMF1 cDNAs encode stable SUMF1 proteins which are of the appropriate molecular weight and are properly localized in the endoplasmic reticulum. Expression of these cDNAs in Sumf1-/- MEFs results in partial rescue of sulfatase activities. These data indicate that MSD is due to hypomorphic SUMF1 mutations and suggest that complete loss of SUMF1 function is likely to be lethal in humans. (c) 2007 Wiley-Liss, Inc.

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

    Directory of Open Access Journals (Sweden)

    Zambon Alexander C

    2007-05-01

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

  14. Comparison of multiple gene assembly methods for metabolic engineering

    Science.gov (United States)

    Chenfeng Lu; Karen Mansoorabadi; Thomas Jeffries

    2007-01-01

    A universal, rapid DNA assembly method for efficient multigene plasmid construction is important for biological research and for optimizing gene expression in industrial microbes. Three different approaches to achieve this goal were evaluated. These included creating long complementary extensions using a uracil-DNA glycosylase technique, overlap extension polymerase...

  15. Recognizable cerebellar dysplasia associated with mutations in multiple tubulin genes

    NARCIS (Netherlands)

    R. Oegema (Renske); T.D. Cushion (Thomas); I.G. Phelps (Ian G.); S.-K. Chung (Seo-Kyung); J.C. Dempsey (Jennifer C.); S. Collins (Sarah); J.G.L. Mullins (Jonathan G.L.); T. Dudding (Tracy); H. Gill (Harinder); A.J. Green (Andrew J.); W.B. Dobyns (William); G.E. Ishak (Gisele E.); M.I. Rees (Mark); D. Doherty (Dan)

    2015-01-01

    textabstractMutations in alpha- and beta-tubulins are increasingly recognized as a major cause of malformations of cortical development (MCD), typically lissencephaly, pachygyria and polymicrogyria; however, sequencing tubulin genes in large cohorts of MCD patients has detected tubulin mutations in

  16. Identification of multiple FXYD genes in a teleost fish

    DEFF Research Database (Denmark)

    Tipsmark, Christian Kølbæk; Madsen, Steffen

    2007-01-01

    and gill differed between fresh water and seawater salmon. The present study identified novel FXYD isoforms and demonstrated the tissue dependence in their expression. Modulation of FXYD proteins in osmoregulatory organs in response to salinity substantiate the importance of these genes in ion transport...

  17. Multiple CMS-restorer gene polymorphism in gynodioecious Plantago coronopus

    NARCIS (Netherlands)

    Damme, van J.M.M.; Hundscheid, M.P.J.; Ivanovic, S.; Koelewijn, H.P.

    2004-01-01

    The mode of inheritance of the male sterility trait is crucial for understanding the evolutionary dynamics of the sexual system gynodioecy, which is the co-occurrence of female and hermaphrodite plants in natural populations. Both cytoplasmic (CMS) and nuclear (restorer) genes are known to be

  18. Glutamate gene polymorphisms predict brain volumes in multiple sclerosis

    NARCIS (Netherlands)

    Strijbis, E.M.M.; Inkster, B.; Vounou, M.; Naegelin, Y.; Kappos, L.; Radue, E.W.; Matthews, P.M.; Uitdehaag, B.M.J.; Barkhof, F.; Polman, C.H.; Montana, G.; Geurts, J.J.G.

    2013-01-01

    Background: Several genetic markers have been associated with multiple sclerosis (MS) susceptibility; however, uncovering the genetic aetiology of the complex phenotypic expression of MS has been more difficult so far. The most common approach in imaging genetics is based on mass-univariate linear

  19. Multiple controls affect arsenite oxidase gene expression in Herminiimonas arsenicoxydans

    Directory of Open Access Journals (Sweden)

    Coppée Jean-Yves

    2010-02-01

    Full Text Available Abstract Background Both the speciation and toxicity of arsenic are affected by bacterial transformations, i.e. oxidation, reduction or methylation. These transformations have a major impact on environmental contamination and more particularly on arsenic contamination of drinking water. Herminiimonas arsenicoxydans has been isolated from an arsenic- contaminated environment and has developed various mechanisms for coping with arsenic, including the oxidation of As(III to As(V as a detoxification mechanism. Results In the present study, a differential transcriptome analysis was used to identify genes, including arsenite oxidase encoding genes, involved in the response of H. arsenicoxydans to As(III. To get insight into the molecular mechanisms of this enzyme activity, a Tn5 transposon mutagenesis was performed. Transposon insertions resulting in a lack of arsenite oxidase activity disrupted aoxR and aoxS genes, showing that the aox operon transcription is regulated by the AoxRS two-component system. Remarkably, transposon insertions were also identified in rpoN coding for the alternative N sigma factor (σ54 of RNA polymerase and in dnaJ coding for the Hsp70 co-chaperone. Western blotting with anti-AoxB antibodies and quantitative RT-PCR experiments allowed us to demonstrate that the rpoN and dnaJ gene products are involved in the control of arsenite oxidase gene expression. Finally, the transcriptional start site of the aoxAB operon was determined using rapid amplification of cDNA ends (RACE and a putative -12/-24 σ54-dependent promoter motif was identified upstream of aoxAB coding sequences. Conclusion These results reveal the existence of novel molecular regulatory processes governing arsenite oxidase expression in H. arsenicoxydans. These data are summarized in a model that functionally integrates arsenite oxidation in the adaptive response to As(III in this microorganism.

  20. Conditional Inference Tree for Multiple Gene-Environment Interactions on Myocardial Infarction Among Chinese Men.

    Science.gov (United States)

    Wu, Zhijun; Su, Xiuxiu; Sheng, Haihui; Chen, Yanjia; Gao, Xiang; Bao, Le; Jin, Wei

    2017-12-16

    Identifying gene-environment interaction in the context of multiple environmental factors has been a challenging task. We aimed to use conditional inference tree (CTREE) to strata myocardial infarction (MI) risk synthesizing information from both genetic and environmental factors. We conducted a case-control study including 1440 Chinese men (730 MI patients and 710 controls). We first calculated a weighted genetic risk score (GRS) by combining 25 single nucleotide polymorphisms (SNPs) that had been identified to be associated with coronary artery diseases in previous genome wide association studies. We then developed a CTREE model to interpret the gene-environment interaction network in predicting MI. We detected high-order interactions between dyslipidemia, GRS, smoking status, age and diabetes. Of all the variables examined, high density lipoprotein cholesterol (HDL-C) of 1.25 mmlo/L was identified as the key discriminator. The subsequent splits of MI were low density lipoprotein cholesterol (LDL-C) of 4.01 mmol/L and GRS of 20.9. We found that individuals with HDL-C ≤1.25 mmol/L, GRS >20.9 and lipoprotein (a) > 0.09 g/L had a higher risk of MI than those who at the lowest risk group (OR: 5.89, 95% CI: 3.99-8.69). This magnitude of MI risk was similar to the combination of HDL-C ≤1.25 mmol/L, GRS ≤20.9, smoking and lipoprotein (a) > 0.15 g/L (OR: 5.49, 95% CI: 3.51-8.58). The multiple interactions between genetic and environmental factors can be visually present via the CTREE approach. The tree diagram also simplifies the decision making procedure by answering a sequence of questions along the branches. Copyright © 2017. Published by Elsevier Inc.

  1. Bayesian Joint Modeling of Multiple Gene Networks and Diverse Genomic Data to Identify Target Genes of a Transcription Factor.

    Science.gov (United States)

    Wei, Peng; Pan, Wei

    2012-01-01

    We consider integrative modeling of multiple gene networks and diverse genomic data, including protein-DNA binding, gene expression and DNA sequence data, to accurately identify the regulatory target genes of a transcription factor (TF). Rather than treating all the genes equally and independently a priori in existing joint modeling approaches, we incorporate the biological prior knowledge that neighboring genes on a gene network tend to be (or not to be) regulated together by a TF. A key contribution of our work is that, to maximize the use of all existing biological knowledge, we allow incorporation of multiple gene networks into joint modeling of genomic data by introducing a mixture model based on the use of multiple Markov random fields (MRFs). Another important contribution of our work is to allow different genomic data to be correlated and to examine the validity and effect of the independence assumption as adopted in existing methods. Due to a fully Bayesian approach, inference about model parameters can be carried out based on MCMC samples. Application to an E. coli data set, together with simulation studies, demonstrates the utility and statistical efficiency gains with the proposed joint model.

  2. The Effects of Multiple Sets of Squats and Jump Squats on Mechanical Variables.

    Science.gov (United States)

    Rossetti, Michael L; Munford, Shawn N; Snyder, Brandon W; Davis, Shala E; Moir, Gavin L

    2017-07-28

    The mechanical responses to two non-ballistic squat and two ballistic jump squat protocols performed over multiple sets were investigated. One protocol from each of the two non-ballistic and ballistic conditions incorporated a pause between the eccentric and concentric phases of the movements in order to determine the influence of the coupling time on the mechanical variables and post-activation potentiation (PAP). Eleven men (age: 21.9 ± 1.8 years; height: 1.79 ± 0.05 m; mass: 87.0 ± 7.4 kg) attended four sessions where they performed multiple sets of squats and jump squats with a load equivalent to 30% 1-repeititon maximum under one of the following conditions: 1) 3 × 4 repetitions of non-ballistic squats (30N-B); 2) 3 × 4 repetitions of non-ballistic squats with a 3-second pause between the eccentric and concentric phases of each repetition (30PN-B); 3) 3 × 4 repetitions of ballistic jump squats (30B); 4) 3 × 4 repetitions of ballistic jump squats with a 3-second pause between the eccentric and concentric phases of each repetition (30PB). Force plates were used to calculate variables including average vertical velocity, average vertical force (GRF), and average power output (PO). Vertical velocities during the ballistic conditions were significantly greater than those attained during the non-ballistic conditions (mean differences: 0.21 - 0.25 m/s, p0.05). Ballistic jump squats may be an effective exercise for developing PO given the high velocities and forces generated in these exercises. Furthermore, the completion of multiple sets of jump squats may induce PAP to enhance PO. The coupling times between the eccentric and concentric phases of the jump squats should be short in order to maximize the GRF and PO across the sets.

  3. Consanguineous mating, specialization, and the environment: how multiple variable interactions affect the evolution of dioecy.

    Science.gov (United States)

    Sinclair, Jordan P; Maxwell, Glenn D; Freeman, D Carl

    2013-06-01

    The evolution of dioecy in plants is usually modeled as a consequence of self-fertilization. While increased seed and pollen production and dispersal patterns of specialized unisexuals have been examined, mating among relatives and interaction effects have been largely ignored. Here, we examine multiple variables simultaneously providing a more ecologically realistic set of conditions favoring the evolution of dioecy. • We developed two complementary models to explore the evolution of dioecious plants. In both models, we examined the effects of inbreeding, compensation, and specialization on unisexual invasibility and were able to directly measure the influence of related matings on such a system. • Our results support previous studies indicating dispersal specialization, consanguineous mating, and inbreeding depression facilitate the evolution of dioecy. However, our results suggest that it is the interaction effect of multiple forces acting simultaneously that allows for unisexual invasion at thresholds and frequencies witnessed in nature. Additionally, our results suggest that subdioecious populations often result, and depending on population conditions, dioecy evolves at different rates, lending importance to the ecological and life history conditions of the species. • Mating among relatives significantly enhances the invasibility of a unisexual mutant into a hermaphroditic population and lowers the levels of inbreeding depression required for invasion than previously reported conditions for unisexual invasion especially, if we consider multiple pressures simultaneously.

  4. A plant virus evolved by acquiring multiple nonconserved genes to extend its host range.

    Science.gov (United States)

    Tatineni, Satyanarayana; Robertson, Cecile J; Garnsey, Stephen M; Dawson, William O

    2011-10-18

    Viruses have evolved as combinations of genes whose products interact with cellular components to produce progeny virus throughout the plants. Some viral genes, particularly those that are involved in replication and assembly, tend to be relatively conserved, whereas other genes that have evolved for interactions with the specific host for movement and to counter host-defense systems tend to be less conserved. Closteroviridae encode 1-5 nonconserved ORFs. Citrus tristeza virus (CTV), a Closterovirus, possesses nonconserved p33, p18, and p13 genes that are expendable for systemic infection of the two laboratory hosts, Citrus macrophylla and Mexican lime. In this study, we show that the extended host range of CTV requires these nonconserved genes. The p33 gene was required to systemically infect sour orange and lemon trees, whereas either the p33 or the p18 gene was sufficient for systemic infection of grapefruit trees and the p33 or the p13 gene was sufficient for systemic infection of calamondin plants. Thus, these three genes are required for systemic infection of the full host range of CTV, but different genes were specific for different hosts. Remarkably, either of two genes was sufficient for infection of some citrus hybrids. These findings suggest that CTV acquired multiple nonconserved genes (p33, p18, and p13) and, as a result, gained the ability to interact with multiple hosts, thus extending its host range during the course of evolution. These results greatly extend the complexity of known virus-plant interactions.

  5. A plant virus evolved by acquiring multiple nonconserved genes to extend its host range

    Science.gov (United States)

    Tatineni, Satyanarayana; Robertson, Cecile J.; Garnsey, Stephen M.; Dawson, William O.

    2011-01-01

    Viruses have evolved as combinations of genes whose products interact with cellular components to produce progeny virus throughout the plants. Some viral genes, particularly those that are involved in replication and assembly, tend to be relatively conserved, whereas other genes that have evolved for interactions with the specific host for movement and to counter host–defense systems tend to be less conserved. Closteroviridae encode 1–5 nonconserved ORFs. Citrus tristeza virus (CTV), a Closterovirus, possesses nonconserved p33, p18, and p13 genes that are expendable for systemic infection of the two laboratory hosts, Citrus macrophylla and Mexican lime. In this study, we show that the extended host range of CTV requires these nonconserved genes. The p33 gene was required to systemically infect sour orange and lemon trees, whereas either the p33 or the p18 gene was sufficient for systemic infection of grapefruit trees and the p33 or the p13 gene was sufficient for systemic infection of calamondin plants. Thus, these three genes are required for systemic infection of the full host range of CTV, but different genes were specific for different hosts. Remarkably, either of two genes was sufficient for infection of some citrus hybrids. These findings suggest that CTV acquired multiple nonconserved genes (p33, p18, and p13) and, as a result, gained the ability to interact with multiple hosts, thus extending its host range during the course of evolution. These results greatly extend the complexity of known virus–plant interactions. PMID:21987809

  6. Multiple oscillators regulate circadian gene expression in Neurospora

    Science.gov (United States)

    Correa, Alejandro; Lewis, Zachary A.; Greene, Andrew V.; March, Irene J.; Gomer, Richard H.; Bell-Pedersen, Deborah

    2003-01-01

    High-density microarrays were used to profile circadian gene expression in Neurospora crassa cultures grown in constant darkness. We identified 145 clock-controlled genes (ccgs). The ccgs peaked in mRNA accumulation at all phases of the day, with the majority peaking in the late night to early morning. The predicted or known functions of the ccgs demonstrate that the clock contributes to a wide range of cellular processes, including cell signaling, development, metabolism, and stress responses. Although the period of rhythm of most of the ccgs was found to depend on the well characterized frequency (FRQ)-based oscillator, three ccgs appeared to have a rhythm that was significantly short in the long period (29-h) frq7 mutant strain. These ccgs accumulate mRNA rhythmically with a circadian period in a frq-null strain, confirming the existence of a second oscillator in N. crassa. PMID:14597725

  7. Impacts of Variability and Uncertainty in Solar Photovoltaic Generation at Multiple Timescales

    Energy Technology Data Exchange (ETDEWEB)

    Ela, E.; Diakov, V.; Ibanez, E.; Heaney, M.

    2013-05-01

    The characteristics of variability and uncertainty of PV solar power have been studied extensively. These characteristics can create challenges for system operators who must ensure a balance between generation and demand while obeying power system constraints at the lowest possible cost. A number of studies have looked at the impact of wind power plants, and some recent studies have also included solar PV. The simulations that are used in these studies, however, are typically fixed to one time resolution. This makes it difficult to analyze the variability across several timescales. In this study, we use a simulation tool that has the ability to evaluate both the economic and reliability impacts of PV variability and uncertainty at multiple timescales. This information should help system operators better prepare for increases of PV on their systems and develop improved mitigation strategies to better integrate PV with enhanced reliability. Another goal of this study is to understand how different mitigation strategies and methods can improve the integration of solar power more reliably and efficiently.

  8. Multiple Neuropeptide-Coding Genes Involved in Planarian Pharynx Extension.

    Science.gov (United States)

    Shimoyama, Seira; Inoue, Takeshi; Kashima, Makoto; Agata, Kiyokazu

    2016-06-01

    Planarian feeding behavior involves three steps: moving toward food, extending the pharynx from their planarian's ventral side after arriving at the food, and ingesting the food through the pharynx. Although pharynx extension is a remarkable behavior, it remains unknown what neuronal cell types are involved in its regulation. To identify neurons involved in regulating pharynx extension, we quantitatively analyzed pharynx extension and sought to identify these neurons by RNA interference (RNAi) and in situ hybridization. This assay, when performed using planarians with amputation of various body parts, clearly showed that the head portion is indispensable for inducing pharynx extension. We thus tested the effects of knockdown of brain neurons such as serotonergic, GABAergic, and dopaminergic neurons by RNAi, but did not observe any effects on pharynx extension behavior. However, animals with RNAi of the Prohormone Convertase 2 (PC2, a neuropeptide processing enzyme) gene did not perform the pharynx extension behavior, suggesting the possible involvement of neuropeptide(s in the regulation of pharynx extension. We screened 24 neuropeptide-coding genes, analyzed their functions by RNAi using the pharynx extension assay system, and identified at least five neuropeptide genes involved in pharynx extension. These was expressed in different cells or neurons, and some of them were expressed in the brain, suggesting complex regulation of planarian feeding behavior by the nervous system.

  9. Associations between period 3 gene polymorphisms and sleep- /chronotype-related variables in patients with late-life insomnia.

    Science.gov (United States)

    Mansour, Hader A; Wood, Joel; Chowdari, Kodavali V; Tumuluru, Divya; Bamne, Mikhil; Monk, Timothy H; Hall, Martica H; Buysse, Daniel J; Nimgaonkar, Vishwajit L

    2017-01-01

    for multiple comparisons). In conclusion, alleles of the VNTR are expressed at the transcript level and may have a functional effect in cells expressing the PER3 gene. PER3 polymorphisms had a modest impact on selected sleep/circadian variables in our sample, suggesting that PER3 is associated with sleep and circadian function beyond VNTR polymorphisms. Further replicate analyses in larger, independent samples are recommended.

  10. A light-switchable bidirectional expression module allowing simultaneous regulation of multiple genes.

    Science.gov (United States)

    Chen, Xianjun; Li, Ting; Wang, Xue; Yang, Yi

    2015-10-02

    Several light-regulated genetic circuits have been applied to spatiotemporally control transgene expression in mammalian cells. However, simultaneous regulation of multiple genes using one genetic device by light has not yet been reported. In this study, we engineered a bidirectional expression module based on LightOn system. Our data showed that both reporter genes could be regulated at defined and quantitative levels. Simultaneous regulation of four genes was further achieved in cultured cells and mice. Additionally, we successfully utilized the bidirectional expression module to monitor the expression of a suicide gene, showing potential for photodynamic gene therapy. Collectively, we provide a robust and useful tool to simultaneously control multiple genes expression by light, which will be widely used in biomedical research and biotechnology. Copyright © 2015 Elsevier Inc. All rights reserved.

  11. Analysis of mouse embryonic gene library for the frequency of single and multiple copy genes.

    Science.gov (United States)

    Mory, Y Y; Keshet, E; Ram, D; Kaminchik, Y

    1980-12-31

    A gene library was constructed from embryonic mouse DNA by ligating DNA fragments generated by partial Eco RI digestion with Charon 4A vector and in vitro packaging. A special consideration was given to randomization of target DNA. The general applicability of a gene library prepared in this manner was assessed through cloning a variety of genes of known reiteration frequency in the mouse genome. The survey included a single copy gene--C region of the immunoglobulin heavy chain, and genes that appear in more than one copy--V region of the immunoglobulin light chain genes and the endogenous retrovirus related genes. In all cases tested the frequency of clone isolation was in good agreement with the expected incidence based on the number of genome equivalents screened and the reiteration frequency of that particular gene. Moreover, we found no preference with regard to the clonability of genes contained in fragments of a wide-size range.

  12. Predictive performance of microarray gene signatures: impact of tumor heterogeneity and multiple mechanisms of drug resistance

    OpenAIRE

    Ng, Charlotte K. Y.; Weigelt, Britta; A’Hern, Roger; Bidard, Francois-Clement; Lemetre, Christophe; Swanton, Charles; Shen, Ronglai; Reis-Filho, Jorge S.

    2014-01-01

    Gene signatures have failed to predict responses to breast cancer therapy in patients to date. In this study, we used bioinformatic methods to explore the hypothesis that the existence of multiple drug resistance mechanisms in different patients may limit the power of gene signatures to predict responses to therapy. Additionally, we explored whether sub-stratification of resistant cases could improve performance. Gene expression profiles from 1,550 breast cancers analyzed with the same microa...

  13. Multiple common variants for celiac disease influencing immune gene expression

    OpenAIRE

    MCMANUS, ROSS; KELLEHER, DERMOT

    2010-01-01

    PUBLISHED We performed a second-generation genome-wide association study of 4,533 individuals with celiac disease (cases) and 10,750 control subjects. We genotyped 113 selected SNPs with P(GWAS) < 10(-4) and 18 SNPs from 14 known loci in a further 4,918 cases and 5,684 controls. Variants from 13 new regions reached genome-wide significance (P(combined) < 5 x 10(-8)); most contain genes with immune functions (BACH2, CCR4, CD80, CIITA-SOCS1-CLEC16A, ICOSLG and ZMIZ1), with ETS1, RUNX3, THEMI...

  14. A fast gene selection method for multi-cancer classification using multiple support vector data description.

    Science.gov (United States)

    Cao, Jin; Zhang, Li; Wang, Bangjun; Li, Fanzhang; Yang, Jiwen

    2015-02-01

    For cancer classification problems based on gene expression, the data usually has only a few dozen sizes but has thousands to tens of thousands of genes which could contain a large number of irrelevant genes. A robust feature selection algorithm is required to remove irrelevant genes and choose the informative ones. Support vector data description (SVDD) has been applied to gene selection for many years. However, SVDD cannot address the problems with multiple classes since it only considers the target class. In addition, it is time-consuming when applying SVDD to gene selection. This paper proposes a novel fast feature selection method based on multiple SVDD and applies it to multi-class microarray data. A recursive feature elimination (RFE) scheme is introduced to iteratively remove irrelevant features, so the proposed method is called multiple SVDD-RFE (MSVDD-RFE). To make full use of all classes for a given task, MSVDD-RFE independently selects a relevant gene subset for each class. The final selected gene subset is the union of these relevant gene subsets. The effectiveness and accuracy of MSVDD-RFE are validated by experiments on five publicly available microarray datasets. Our proposed method is faster and more effective than other methods. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. A non-inheritable maternal Cas9-based multiple-gene editing system in mice

    OpenAIRE

    Sakurai, Takayuki; Kamiyoshi, Akiko; Kawate, Hisaka; Mori, Chie; Watanabe, Satoshi; Tanaka, Megumu; Uetake, Ryuichi; Sato, Masahiro; Shindo, Takayuki

    2016-01-01

    The CRISPR/Cas9 system is capable of editing multiple genes through one-step zygote injection. The preexisting method is largely based on the co-injection of Cas9 DNA (or mRNA) and guide RNAs (gRNAs); however, it is unclear how many genes can be simultaneously edited by this method, and a reliable means to generate transgenic (Tg) animals with multiple gene editing has yet to be developed. Here, we employed non-inheritable maternal Cas9 (maCas9) protein derived from Tg mice with systemic Cas9...

  16. Multiple-locus variable-number tandem-repeat analysis of pathogenic Yersinia enterocolitica in China.

    Directory of Open Access Journals (Sweden)

    Xin Wang

    Full Text Available The predominant bioserotypes of pathogenic Yersinia enterocolitica in China are 2/O: 9 and 3/O: 3; no pathogenic O: 8 strains have been found to date. Multiple-Locus Variable-Number Tandem-Repeat Analysis (MLVA based on seven loci was able to distinguish 104 genotypes among 218 pathogenic Y. enterocolitica isolates in China and from abroad, showing a high resolution. The major pathogenic serogroups in China, O: 3 and O: 9, were divided into two clusters based on MLVA genotyping. The different distribution of Y. enterocolitica MLVA genotypes maybe due to the recent dissemination of specific clones of 2/O: 9 and 3/O: 3 strains in China. MLVA was a helpful tool for bacterial pathogen surveillance and investigation of pathogenic Y. enterocolitica outbreaks.

  17. Auxiliary variables in multiple imputation in regression with missing X: a warning against including too many in small sample research

    Science.gov (United States)

    2012-01-01

    Background Multiple imputation is becoming increasingly popular. Theoretical considerations as well as simulation studies have shown that the inclusion of auxiliary variables is generally of benefit. Methods A simulation study of a linear regression with a response Y and two predictors X1 and X2 was performed on data with n = 50, 100 and 200 using complete cases or multiple imputation with 0, 10, 20, 40 and 80 auxiliary variables. Mechanisms of missingness were either 100% MCAR or 50% MAR + 50% MCAR. Auxiliary variables had low (r=.10) vs. moderate correlations (r=.50) with X’s and Y. Results The inclusion of auxiliary variables can improve a multiple imputation model. However, inclusion of too many variables leads to downward bias of regression coefficients and decreases precision. When the correlations are low, inclusion of auxiliary variables is not useful. Conclusion More research on auxiliary variables in multiple imputation should be performed. A preliminary rule of thumb could be that the ratio of variables to cases with complete data should not go below 1 : 3. PMID:23216665

  18. Auxiliary variables in multiple imputation in regression with missing X: a warning against including too many in small sample research.

    Science.gov (United States)

    Hardt, Jochen; Herke, Max; Leonhart, Rainer

    2012-12-05

    Multiple imputation is becoming increasingly popular. Theoretical considerations as well as simulation studies have shown that the inclusion of auxiliary variables is generally of benefit. A simulation study of a linear regression with a response Y and two predictors X1 and X2 was performed on data with n = 50, 100 and 200 using complete cases or multiple imputation with 0, 10, 20, 40 and 80 auxiliary variables. Mechanisms of missingness were either 100% MCAR or 50% MAR + 50% MCAR. Auxiliary variables had low (r=.10) vs. moderate correlations (r=.50) with X's and Y. The inclusion of auxiliary variables can improve a multiple imputation model. However, inclusion of too many variables leads to downward bias of regression coefficients and decreases precision. When the correlations are low, inclusion of auxiliary variables is not useful. More research on auxiliary variables in multiple imputation should be performed. A preliminary rule of thumb could be that the ratio of variables to cases with complete data should not go below 1 : 3.

  19. Surface epitope localization and gene structure of a Babesia bovis 44-kilodalton variable merozoite surface antigen.

    Science.gov (United States)

    Jasmer, D P; Reduker, D W; Hines, S A; Perryman, L E; McGuire, T C

    1992-10-01

    Variation of Babesia bovis merozoite surface antigens occurs among geographic strains of the parasite. In this and a concurrent report, we investigate this variation at the gene and protein level. Using a monoclonal antibody (mAb 23/70.174), B. bovis gene sequences were identified that encoded a surface epitope of a 44-kDa merozoite surface antigen (MSA-2). This epitope is variably expressed among geographic isolates of B. bovis. Here, we describe the MSA-2 protein gene sequence, localize this surface epitope to a repeated amino acid sequence, and investigate the genomic organization of the gene in B. bovis strains from Mexico and Australia. The predicted protein sequence had hydrophobic regions at its amino and carboxy termini consistent with a signal peptide and a membrane anchor via glycosylphosphatidyl inositol, respectively. The surface epitope recognized by mAb 23/70.174 was localized within a 24-amino acid sequence which is repeated twice in tandem. Six different EcoRI bands hybridized to the MSA-2 gene sequence with varying intensities in genomic Southern blots of the homologous strain. Two of these appear to be alleles of the MSA-2 gene. Whereas 5' and 3' sequences of the MSA-2 gene sequence were detected in an Australia strain of B. bovis, internal gene sequences encoding the surface epitope were not. The 3' sequences of the MSA-2 gene also had significant sequence similarity with the MSA-1 gene of the Mexico strain B. bovis and a gene from the previously described BabR locus. These data indicate that the MSA-2 protein gene belongs to the BabR locus which encodes variable merozoite surface antigens.

  20. Depressive symptomology in multiple sclerosis: Disability, cardiorespiratory fitness and heart rate variability.

    Science.gov (United States)

    Ensari, I; Pilutti, L A; Motl, R W

    2017-11-01

    This study aimed to investigate whether neurological disability status, heart rate variability (HRV), cardiorespiratory fitness (CRF) explained the variance in depressive symptoms in multiple sclerosis (MS). Associations between CRF (via maximal oxygen uptake; VO 2peak ), HRV indices of normalized ultra-low (nULF) and very low frequency domains (nVLF), neurological disability status and depressive symptoms (using the Depression subscale of the Hospital Anxiety Depression Scale; HADS-D) were assessed in 53 participants with MS and 17 matched controls. Hierarchical linear regression analysis was conducted within the MS subsample to examine the variance explained by neurological disability alone and CRF. The groups were similar in mean age (MS=52.0 years, Control=51.1 years) and sex (MS=72% female, Control=77% female). Among individuals with MS, HADS-D scores significantly correlated with disability status (sample mean score=4) and VO 2peak (r=-.62, Plinear regression indicated that VO 2peak (P.05). Heart rate variability does not seem to significantly differ between individuals with MS and healthy controls. When accounting for CRF, disability status no longer explains significant variance in depressive symptoms in MS. Accordingly, targeting CRF might be an effective approach for effectively managing depressive symptoms in individuals with MS. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Beyond fatigue: Assessing variables associated with sleep problems and use of sleep medications in multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Alyssa M Bamer

    2010-05-01

    Full Text Available Alyssa M Bamer, Kurt L Johnson, Dagmar A Amtmann, George H KraftDepartment of Rehabilitation Medicine, University of Washington, Seattle, WA, USABackground: Recent research indicates that sleep disturbances are common in persons with multiple sclerosis (MS, though research to date has primarily focused on the relationship between fatigue and sleep. In order to improve treatment of sleep disorders in MS, a better understanding of other factors that contribute to MS sleep disturbance and use of sleep medications in this population is needed.Methods: Individuals with MS (N = 473 involved in an ongoing self-report survey study were asked to report on use of over-the-counter and prescription sleep medications. Participants completed the Medical Outcomes Study Sleep (MOSS scale and other common self-report symptom measures. Multiple regression was used to evaluate factors associated with sleep problems and descriptive statistics were generated to examine use of sleep medications.Results: The mean score on the MOSS scale was 35.9 (standard deviation, 20.2 and 46.8% of the sample had moderate or severe sleep problems. The majority of participants did not use over-the-counter (78% or prescription (70% sleep medications. In a regression model variables statistically significantly associated with sleep problems included depression, nighttime leg cramps, younger age, pain, female sex, fatigue, shorter duration of MS, and nocturia. The model explained 45% of the variance in sleep problems. Of the variance explained, depression accounted for the majority of variance in sleep problems (33%, with other variables explaining significantly less variance.Conclusions: Regression results indicate that fatigue may play a minor role in sleep disturbance in MS and that clinicians should consider the interrelationship between depression and sleep problems when treating either symptom in this population. More research is needed to explore the possibility of under

  2. Variability in Metagenomic Count Data and Its Influence on the Identification of Differentially Abundant Genes.

    Science.gov (United States)

    Jonsson, Viktor; Österlund, Tobias; Nerman, Olle; Kristiansson, Erik

    2017-04-01

    Metagenomics is the study of microorganisms in environmental and clinical samples using high-throughput sequencing of random fragments of their DNA. Since metagenomics does not require any prior culturing of isolates, entire microbial communities can be studied directly in their natural state. In metagenomics, the abundance of genes is quantified by sorting and counting the DNA fragments. The resulting count data are high-dimensional and affected by high levels of technical and biological noise that make the statistical analysis challenging. In this article, we introduce an hierarchical overdispersed Poisson model to explore the variability in metagenomic data. By analyzing three comprehensive data sets, we show that the gene-specific variability varies substantially between genes and is dependent on biological function. We also assess the power of identifying differentially abundant genes and show that incorrect assumptions about the gene-specific variability can lead to unacceptable high rates of false positives. Finally, we evaluate shrinkage approaches to improve the variance estimation and show that the prior choice significantly affects the statistical power. The results presented in this study further elucidate the complex variance structure of metagenomic data and provide suggestions for accurate and reliable identification of differentially abundant genes.

  3. A Hox Gene, Antennapedia, Regulates Expression of Multiple Major Silk Protein Genes in the Silkworm Bombyx mori*

    Science.gov (United States)

    Tsubota, Takuya; Tomita, Shuichiro; Uchino, Keiro; Kimoto, Mai; Takiya, Shigeharu; Kajiwara, Hideyuki; Yamazaki, Toshimasa; Sezutsu, Hideki

    2016-01-01

    Hox genes play a pivotal role in the determination of anteroposterior axis specificity during bilaterian animal development. They do so by acting as a master control and regulating the expression of genes important for development. Recently, however, we showed that Hox genes can also function in terminally differentiated tissue of the lepidopteran Bombyx mori. In this species, Antennapedia (Antp) regulates expression of sericin-1, a major silk protein gene, in the silk gland. Here, we investigated whether Antp can regulate expression of multiple genes in this tissue. By means of proteomic, RT-PCR, and in situ hybridization analyses, we demonstrate that misexpression of Antp in the posterior silk gland induced ectopic expression of major silk protein genes such as sericin-3, fhxh4, and fhxh5. These genes are normally expressed specifically in the middle silk gland as is Antp. Therefore, the evidence strongly suggests that Antp activates these silk protein genes in the middle silk gland. The putative sericin-1 activator complex (middle silk gland-intermolt-specific complex) can bind to the upstream regions of these genes, suggesting that Antp directly activates their expression. We also found that the pattern of gene expression was well conserved between B. mori and the wild species Bombyx mandarina, indicating that the gene regulation mechanism identified here is an evolutionarily conserved mechanism and not an artifact of the domestication of B. mori. We suggest that Hox genes have a role as a master control in terminally differentiated tissues, possibly acting as a primary regulator for a range of physiological processes. PMID:26814126

  4. Anthropological features of the CFTR gene: Its variability in an African population.

    Science.gov (United States)

    Maria Ciminelli, Bianca; Bombieri, Cristina; Ciccacci, Cinzia; Belpinati, Francesca; Pompei, Fiorenza; Maselli, Roberta; Simporé, Jacques; Pignatti, Pier Franco; Modiano, Guido

    2011-03-01

    The CFTR gene (Cystic Fibrosis conductance Transmembrane Regulator) is the gene responsible for Cystic Fibrosis, the most common severe autosomal recessive disease in Europeans. It has been extensively explored in several European and European-derived populations, but poorly studied in the other major human groups. To characterize the variability of the CFTR gene in an African population. Using DGGE, all 27 exons (4443 bp) and 2184 bp of the flanking intronic regions of the CFTR gene were studied in a random sample of 45 Mossì from Burkina Faso (Western sub-Saharan Africa). Sixteen variable sites were found: 13 SNPs (one in the promoter region, four non-synonymous and five synonymous in the exons and three in the introns) and three intronic STRs. Only the promoter site ( - 94 G/T), slightly polymorphic in the present survey, was not variable in different European populations. Comparison between Western Africans, Eastern Africans, Europeans and Eastern Asians showed that alleles at two intronic STRs (T(n) and (TG)(m) in intron 8), four exonic (M470V, 2694 T/G, 4002 A/G and 4521 G/A) and one intronic (875+40 A/G) SNPs have very different frequencies among at least two major human groups. Moreover, the overall degree of non-synonymous variability in Mossì is much lower than that in Europeans. A possible interpretation of this finding is proposed. The CFTR gene has been since long hypothesized to have undergone selection in Europeans. The present study by comparing Africans and Europeans for the overall variability of the gene supports this hypothesis.

  5. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study.

    Directory of Open Access Journals (Sweden)

    Alexandra C Nica

    2011-02-01

    Full Text Available While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL, skin, and fat. The samples (156 LCL, 160 skin, 166 fat were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes. In addition, we apply factor analysis (FA to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes. The unique study design (Matched Co-Twin Analysis--MCTA permits immediate replication of eQTLs using co-twins (93%-98% and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20% have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.

  6. Multiple Gene Variants in Hypertrophic Cardiomyopathy in the Era of Next-Generation Sequencing.

    Science.gov (United States)

    Burns, Charlotte; Bagnall, Richard D; Lam, Lien; Semsarian, Christopher; Ingles, Jodie

    2017-08-01

    Multiple likely pathogenic/pathogenic (LP/P; ≥2) variants in patients with hypertrophic cardiomyopathy were described 10 years ago with a prevalence of 5%. We sought to re-examine the significance of multiple rare variants in patients with hypertrophic cardiomyopathy in the setting of comprehensive and targeted panels. Of 758 hypertrophic cardiomyopathy probands, we included 382 with ≥45 cardiomyopathy genes screened. There were 224 (59%) with ≥1 rare variant (allele frequency ≤0.02%). Variants were analyzed using varying sized gene panels to represent comprehensive or targeted testing. Based on a 45-gene panel, 127 (33%) had a LP/P variant, 139 (36%) had variants of uncertain significance, and 66 (17%) had multiple rare variants. A targeted 8-gene panel yielded 125 (32%) LP/P variants, 52 (14%) variants of uncertain significance, and 14 (4%) had multiple rare variants. No proband had 2 LP/P variants. Including affected family members (total n=412), cluster-adjusted analyses identified a phenotype effect, with younger age (odds ratio, 0.95; 95% confidence interval, 0.92-0.98; P =0.004) and family history of sudden cardiac death (odds ratio, 3.5; 95% confidence interval, 1.3-9.9; P =0.02) significantly more likely in multiple versus single variant patients when considering an 8-gene panel but not larger panels. Those with multiple variants had worse event-free survival from all-cause death, cardiac transplantation, and cardiac arrest (log-rank P =0.008). No proband had multiple LP/P variants in contrast to previous reports. However, multiple rare variants regardless of classification were seen in 4% and contributed to earlier disease onset and cardiac events. Our findings support a cumulative variant hypothesis in hypertrophic cardiomyopathy. © 2017 American Heart Association, Inc.

  7. Multiple crown size variables of the upper incisors in patients with supernumerary teeth compared with controls.

    Science.gov (United States)

    Khalaf, K; Smith, R N; Elcock, C; Brook, A H

    2009-12-01

    As part of ongoing studies of the aetiology of dental anomalies the aims of this study were to identify multiple components of tooth size of the upper permanent incisors in 34 patients with supernumerary teeth and to compare them with those in a control group to determine whether the presence of a supernumerary tooth has a local effect on the size of the surrounding dentition. The labial and occlusal aspects of the clinical crowns of the upper permanent central and lateral incisors on the study models of 74 subjects were digitally imaged and measured using an image analysis system and automated macro (34 patients with supernumerary in the upper incisor region: 17 males and 17 females and 40 controls: 20 males and 20 females). The macro-defined 17 variables from each view. From the labial view these were: the mesio-distal and occluso-gingival length and additional measurements along 25 and 75% of the mesio-distal line and at 25, 50 and 75% along the occluso-gingival line such that all these sub-divisions extended to the periphery of the tooth. From the occlusal view these were: the mesio-distal and labio-lingual lengths, and additional variables that sub-divided the mesio-distal again at 25 and 75% along the length and at 25, 50 and 75% along the labio-lingual dimension. Principal component analysis (PCA) was used to identify the key factors with the most random variability. Comparisons were then carried out between the supernumerary cases and control group using 2-way ANOVA. Seven factors of tooth size for the upper central incisors and eight factors for the upper lateral incisors were extracted. Most of these variables were found to be larger in the supernumerary group than in the control. Statistically significant differences were found for 5 out of 7 and 4 out of 8 for the upper central and lateral incisors respectively. A number of factors of tooth size were identified and found to be larger in the supernumerary group compared to the control (7 for upper

  8. Comparative genomics of four closely related Clostridium perfringens bacteriophages reveals variable evolution among core genes with therapeutic potential

    Directory of Open Access Journals (Sweden)

    Siragusa Gregory R

    2011-06-01

    Full Text Available Abstract Background Because biotechnological uses of bacteriophage gene products as alternatives to conventional antibiotics will require a thorough understanding of their genomic context, we sequenced and analyzed the genomes of four closely related phages isolated from Clostridium perfringens, an important agricultural and human pathogen. Results Phage whole-genome tetra-nucleotide signatures and proteomic tree topologies correlated closely with host phylogeny. Comparisons of our phage genomes to 26 others revealed three shared COGs; of particular interest within this core genome was an endolysin (PF01520, an N-acetylmuramoyl-L-alanine amidase and a holin (PF04531. Comparative analyses of the evolutionary history and genomic context of these common phage proteins revealed two important results: 1 strongly significant host-specific sequence variation within the endolysin, and 2 a protein domain architecture apparently unique to our phage genomes in which the endolysin is located upstream of its associated holin. Endolysin sequences from our phages were one of two very distinct genotypes distinguished by variability within the putative enzymatically-active domain. The shared or core genome was comprised of genes with multiple sequence types belonging to five pfam families, and genes belonging to 12 pfam families, including the holin genes, which were nearly identical. Conclusions Significant genomic diversity exists even among closely-related bacteriophages. Holins and endolysins represent conserved functions across divergent phage genomes and, as we demonstrate here, endolysins can have significant variability and host-specificity even among closely-related genomes. Endolysins in our phage genomes may be subject to different selective pressures than the rest of the genome. These findings may have important implications for potential biotechnological applications of phage gene products.

  9. Transcriptional Response of Multiple ESBL Genes Within Escherichia coli Under Oxyimino-Cephalosporin Stress.

    Science.gov (United States)

    Maurya, Anand Prakash; Chanda, Debadatta Dhar; Bora, Debajyoti; Das Talukdar, Anupam; Chakravarty, Atanu; Bhattacharjee, Amitabha

    2017-03-01

    The expression of extended-spectrum beta-lactamases directly interferes with the treatment options in a clinical setting. It is not clearly defined why bacteria acquire multiple beta-lactamases and how they are being expressed in antibiotic stress. With this key question, the study was designed to understand the transcriptional response in Escherichia coli harboring multiple bla ESBLs against different oxyimino-cephalosporin stress. A total of 169 consecutive, nonduplicate oxyimino-cephalosporin-resistant isolates of E. coli were screened and were ESBL positive. Among them six isolates were found to harbor multiple beta-lactamase genes and we, as per our objective, selected them for this study. Molecular characterization was done by multiplex polymerase chain reaction (PCR) assay. Minimum inhibitory concentration, transcriptional expression, transferability, and plasmid incompatibility typing of multiple bla ESBLs were carried out. Plasmid stability and antibiotic susceptibility of donor and transconjugants were performed. A total of six isolates were found to be harboring multiple ESBL genes and MIC above the breakpoint level against all the tested antibiotics. Quantitative real-time PCR showed that in basal level without antibiotic stress, SHV-148 expressed more, but with ceftriaxone stressed, expression of CTX-M-15 and SHV-148 was high. In case of PER-1, expression was high with ceftazidime stress. bla ESBLs were horizontally transferable and originated through multiple inc types. Plasmids were stable till 115 serial passages. Pulsed-field gel electrophoresis results showed that multiple ESBL genes were spread through six pulsotypes. Our study concludes that acquisition of multiple ESBL genes in E. coli was a specific adaptation for survival against multiple oxyimino-cephalosporin stress in this clinical setting.

  10. Genetic variability of bovine GHR, IGF-1 and IGFBP-3 genes in ...

    African Journals Online (AJOL)

    The identification of genetic polymorphisms in the genes that play a crucial role in regulatiing growth and development of livestock enables us to evaluate the biological similarities and to acquire a better perspective of quantitative traits. The present study was undertaken to characterize genetic variability in the bovine ...

  11. How changes in extracellular matrix mechanics and gene expression variability might combine to drive cancer progression.

    Directory of Open Access Journals (Sweden)

    Justin Werfel

    Full Text Available Changes in extracellular matrix (ECM structure or mechanics can actively drive cancer progression; however, the underlying mechanism remains unknown. Here we explore whether this process could be mediated by changes in cell shape that lead to increases in genetic noise, given that both factors have been independently shown to alter gene expression and induce cell fate switching. We do this using a computer simulation model that explores the impact of physical changes in the tissue microenvironment under conditions in which physical deformation of cells increases gene expression variability among genetically identical cells. The model reveals that cancerous tissue growth can be driven by physical changes in the microenvironment: when increases in cell shape variability due to growth-dependent increases in cell packing density enhance gene expression variation, heterogeneous autonomous growth and further structural disorganization can result, thereby driving cancer progression via positive feedback. The model parameters that led to this prediction are consistent with experimental measurements of mammary tissues that spontaneously undergo cancer progression in transgenic C3(1-SV40Tag female mice, which exhibit enhanced stiffness of mammary ducts, as well as progressive increases in variability of cell-cell relations and associated cell shape changes. These results demonstrate the potential for physical changes in the tissue microenvironment (e.g., altered ECM mechanics to induce a cancerous phenotype or accelerate cancer progression in a clonal population through local changes in cell geometry and increased phenotypic variability, even in the absence of gene mutation.

  12. [Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses].

    Science.gov (United States)

    Cammarata-Scalisi, Francisco; Cozar, Mónica; Grinberg, Daniel; Balcells, Susana; Asteggiano, Carla G; Martínez-Domenech, Gustavo; Bracho, Ana; Sánchez, Yanira; Stock, Frances; Delgado-Luengo, Wilmer; Zara-Chirinos, Carmen; Chacín, José Antonio

    2015-04-01

    Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

  13. A Precisely Regulated Gene Expression Cassette Potently Modulates Metastasis and Survival in Multiple Solid Cancers

    Science.gov (United States)

    Yu, Kun; Ganesan, Kumaresan; Tan, Lay Keng; Laban, Mirtha; Wu, Jeanie; Zhao, Xiao Dong; Li, Hongmin; Leung, Carol Ho Wing; Zhu, Yansong; Wei, Chia Lin; Hooi, Shing Chuan; Miller, Lance; Tan, Patrick

    2008-01-01

    Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this “Poised Gene Cassette” (PGC) was robustly validated across 11 independent cohorts of ∼1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies. PMID:18636107

  14. A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.

    Directory of Open Access Journals (Sweden)

    Kun Yu

    2008-07-01

    Full Text Available Successful tumor development and progression involves the complex interplay of both pro- and anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270 compared to nonmalignant tissues (n = 71. Comprising genes linked to multiple cancer-related pathways, the restricted expression of this "Poised Gene Cassette" (PGC was robustly validated across 11 independent cohorts of approximately 1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP, which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies.

  15. Multiple sclerosis genetics: Results from meta-analyses of candidate-gene association studies.

    Science.gov (United States)

    Tizaoui, Kalthoum

    2017-11-02

    As a complex disease, multiple sclerosis (MS) susceptibility implicates many genetic and environmental factors. Usually, individual genetic association studies have several limitations, and results are specific to the population of study. The Meta-analysis approach has been proposed to resolve these limitations and to increase the power of statistical analyses. In this review, we summarize results from meta-analyses of candidate genes of MS. Using the keywords: multiple sclerosis, genetic polymorphism and meta-analysis, we searched electronic databases (PubMed, Embase and Web of Sciences) for published meta-analyses until May 2017. Meta-analyses confirmed the association of polymorphisms in fifteen candidate genes with MS disease. However, polymorphisms in fourteen genes showed none significant association. Results outlined the importance of confirmed genes to understand signaling pathways in MS disease and shed light on their utility to develop new drugs targets. Copyright © 2017. Published by Elsevier Ltd.

  16. Variability of Creatine Metabolism Genes in Children with Autism Spectrum Disorder

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    Jessie M. Cameron

    2017-07-01

    Full Text Available Creatine deficiency syndrome (CDS comprises three separate enzyme deficiencies with overlapping clinical presentations: arginine:glycine amidinotransferase (GATM gene, glycine amidinotransferase, guanidinoacetate methyltransferase (GAMT gene, and creatine transporter deficiency (SLC6A8 gene, solute carrier family 6 member 8. CDS presents with developmental delays/regression, intellectual disability, speech and language impairment, autistic behaviour, epileptic seizures, treatment-refractory epilepsy, and extrapyramidal movement disorders; symptoms that are also evident in children with autism. The objective of the study was to test the hypothesis that genetic variability in creatine metabolism genes is associated with autism. We sequenced GATM, GAMT and SLC6A8 genes in 166 patients with autism (coding sequence, introns and adjacent untranslated regions. A total of 29, 16 and 25 variants were identified in each gene, respectively. Four variants were novel in GATM, and 5 in SLC6A8 (not present in the 1000 Genomes, Exome Sequencing Project (ESP or Exome Aggregation Consortium (ExAC databases. A single variant in each gene was identified as non-synonymous, and computationally predicted to be potentially damaging. Nine variants in GATM were shown to have a lower minor allele frequency (MAF in the autism population than in the 1000 Genomes database, specifically in the East Asian population (Fisher’s exact test. Two variants also had lower MAFs in the European population. In summary, there were no apparent associations of variants in GAMT and SLC6A8 genes with autism. The data implying there could be a lower association of some specific GATM gene variants with autism is an observation that would need to be corroborated in a larger group of autism patients, and with sub-populations of Asian ethnicities. Overall, our findings suggest that the genetic variability of creatine synthesis/transport is unlikely to play a part in the pathogenesis of autism

  17. Flux variability scanning based on enforced objective flux for identifying gene amplification targets

    Science.gov (United States)

    2012-01-01

    Background In order to reduce time and efforts to develop microbial strains with better capability of producing desired bioproducts, genome-scale metabolic simulations have proven useful in identifying gene knockout and amplification targets. Constraints-based flux analysis has successfully been employed for such simulation, but is limited in its ability to properly describe the complex nature of biological systems. Gene knockout simulations are relatively straightforward to implement, simply by constraining the flux values of the target reaction to zero, but the identification of reliable gene amplification targets is rather difficult. Here, we report a new algorithm which incorporates physiological data into a model to improve the model’s prediction capabilities and to capitalize on the relationships between genes and metabolic fluxes. Results We developed an algorithm, flux variability scanning based on enforced objective flux (FVSEOF) with grouping reaction (GR) constraints, in an effort to identify gene amplification targets by considering reactions that co-carry flux values based on physiological omics data via “GR constraints”. This method scans changes in the variabilities of metabolic fluxes in response to an artificially enforced objective flux of product formation. The gene amplification targets predicted using this method were validated by comparing the predicted effects with the previous experimental results obtained for the production of shikimic acid and putrescine in Escherichia coli. Moreover, new gene amplification targets for further enhancing putrescine production were validated through experiments involving the overexpression of each identified targeted gene under condition-controlled batch cultivation. Conclusions FVSEOF with GR constraints allows identification of gene amplification targets for metabolic engineering of microbial strains in order to enhance the production of desired bioproducts. The algorithm was validated through the

  18. Gene expression analysis of interferon-beta treatment in multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, F.; Datta, P.; Larsen, J.

    2008-01-01

    by treatment with IFN-beta. We use DNA microarrays to study gene expression in 10 multiple sclerosis (MS) patients who began de novo treatment with IFN-beta. After the first injection of IFN-beta, the expression of 74 out of 3428 genes changed at least two-fold and statistically significantly (after Bonferroni...... type I immunity and T-cell activation, as novel effects of IFN-beta therapy in MS Udgivelsesdato: 2008/6...

  19. Characterisation of silent and active genes for a variable large protein of Borrelia recurrentis

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    Scragg Ian G

    2002-10-01

    Full Text Available Abstract Background We report the characterisation of the variable large protein (vlp gene expressed by clinical isolate A1 of Borrelia recurrentis; the agent of the life-threatening disease louse-borne relapsing fever. Methods The major vlp protein of this isolate was characterised and a DNA probe created. Use of this together with standard molecular methods was used to determine the location of the vlp1B. recurrentis A1 gene in both this and other isolates. Results This isolate was found to carry silent and expressed copies of the vlp1B. recurrentis A1 gene on plasmids of 54 kbp and 24 kbp respectively, whereas a different isolate, A17, had only the silent vlp1B. recurrentis A17 on a 54 kbp plasmid. Silent and expressed vlp1 have identical mature protein coding regions but have different 5' regions, both containing different potential lipoprotein leader sequences. Only one form of vlp1 is transcribed in the A1 isolate of B. recurrentis, yet both 5' upstream sequences of this vlp1 gene possess features of bacterial promoters. Conclusion Taken together these results suggest that antigenic variation in B. recurrentis may result from recombination of variable large and small protein genes at the junction between lipoprotein leader sequence and mature protein coding region. However, this hypothetical model needs to be validated by further identification of expressed and silent variant protein genes in other B. recurrentis isolates.

  20. Prognostic modeling of oral cancer by gene profiles and clinicopathological co-variables.

    Science.gov (United States)

    Mes, Steven W; Te Beest, Dennis; Poli, Tito; Rossi, Silvia; Scheckenbach, Kathrin; van Wieringen, Wessel N; Brink, Arjen; Bertani, Nicoletta; Lanfranco, Davide; Silini, Enrico M; van Diest, Paul J; Bloemena, Elisabeth; Leemans, C René; van de Wiel, Mark A; Brakenhoff, Ruud H

    2017-08-29

    Accurate staging and outcome prediction is a major problem in clinical management of oral cancer patients, hampering high precision treatment and adjuvant therapy planning. Here, we have built and validated multivariable models that integrate gene signatures with clinical and pathological variables to improve staging and survival prediction of patients with oral squamous cell carcinoma (OSCC). Gene expression profiles from 249 human papillomavirus (HPV)-negative OSCCs were explored to identify a 22-gene lymph node metastasis signature (LNMsig) and a 40-gene overall survival signature (OSsig). To facilitate future clinical implementation and increase performance, these signatures were transferred to quantitative polymerase chain reaction (qPCR) assays and validated in an independent cohort of 125 HPV-negative tumors. When applied in the clinically relevant subgroup of early-stage (cT1-2N0) OSCC, the LNMsig could prevent overtreatment in two-third of the patients. Additionally, the integration of RT-qPCR gene signatures with clinical and pathological variables provided accurate prognostic models for oral cancer, strongly outperforming TNM. Finally, the OSsig gene signature identified a subpopulation of patients, currently considered at low-risk for disease-related survival, who showed an unexpected poor prognosis. These well-validated models will assist in personalizing primary treatment with respect to neck dissection and adjuvant therapies.

  1. Expression Profiles of the Individual Genes Corresponding to the Genes Generated by Cytotoxicity Experiments with Bortezomib in Multiple Myeloma

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    Mehdi Ghasemi

    2016-12-01

    Full Text Available Objective: Multiple myeloma (MM is currently incurable due to refractory disease relapse even under novel anti-myeloma treatment. In silico studies are effective for key decision making during clinicopathological battles against the chronic course of MM. The aim of this present in silico study was to identify individual genes whose expression profiles match that of the one generated by cytotoxicity experiments for bortezomib. Materials and Methods: We used an in silico literature mining approach to identify potential biomarkers by creating a summarized set of metadata derived from relevant information. The E-MTAB-783 dataset containing expression data from 789 cancer cell lines including 8 myeloma cell lines with drug screening data from the Wellcome Trust Sanger Institute database obtained from ArrayExpress was “Robust Multi-array analysis” normalized using GeneSpring v.12.5. Drug toxicity data were obtained from the Genomics of Drug Sensitivity in Cancer project. In order to identify individual genes whose expression profiles matched that of the one generated by cytotoxicity experiments for bortezomib, we used a linear regressionbased approach, where we searched for statistically significant correlations between gene expression values and IC50 data. The intersections of the genes were identified in 8 cell lines and used for further analysis. Results: Our linear regression model identified 73 genes and some genes expression levels were found to very closely correlated with bortezomib IC50 values. When all 73 genes were used in a hierarchical cluster analysis, two major clusters of cells representing relatively sensitive and resistant cells could be identified. Pathway and molecular function analysis of all the significant genes was also investigated, as well as the genes involved in pathways. Conclusion: The findings of our present in silico study could be important not only for the understanding of the genomics of MM but also for the

  2. 10 km running performance predicted by a multiple linear regression model with allometrically adjusted variables.

    Science.gov (United States)

    Abad, Cesar C C; Barros, Ronaldo V; Bertuzzi, Romulo; Gagliardi, João F L; Lima-Silva, Adriano E; Lambert, Mike I; Pires, Flavio O

    2016-06-01

    The aim of this study was to verify the power of VO 2max , peak treadmill running velocity (PTV), and running economy (RE), unadjusted or allometrically adjusted, in predicting 10 km running performance. Eighteen male endurance runners performed: 1) an incremental test to exhaustion to determine VO 2max and PTV; 2) a constant submaximal run at 12 km·h -1 on an outdoor track for RE determination; and 3) a 10 km running race. Unadjusted (VO 2max , PTV and RE) and adjusted variables (VO 2max 0.72 , PTV 0.72 and RE 0.60 ) were investigated through independent multiple regression models to predict 10 km running race time. There were no significant correlations between 10 km running time and either the adjusted or unadjusted VO 2max . Significant correlations (p 0.84 and power > 0.88. The allometrically adjusted predictive model was composed of PTV 0.72 and RE 0.60 and explained 83% of the variance in 10 km running time with a standard error of the estimate (SEE) of 1.5 min. The unadjusted model composed of a single PVT accounted for 72% of the variance in 10 km running time (SEE of 1.9 min). Both regression models provided powerful estimates of 10 km running time; however, the unadjusted PTV may provide an uncomplicated estimation.

  3. Breathing variability and brainstem serotonergic loss in a genetic model of multiple system atrophy.

    Science.gov (United States)

    Flabeau, Olivier; Meissner, Wassilios G; Ozier, Annaig; Berger, Patrick; Tison, François; Fernagut, Pierre-Olivier

    2014-03-01

    Breathing disorders like sleep apnea, stridor, and dysrythmic breathing are frequent in patients with multiple system atrophy (MSA). These observations have been related to neurodegeneration in several pontomedullary respiratory nuclei and may explain the occurrence of sudden death. In this study, we sought to determine whether these functional and neuropathological characteristics could be replicated in a transgenic model of MSA. Mice expressing human wild-type α-synuclein under the control of the proteolipid promoter (PLP-αSYN) were compared with age-matched controls. Using whole-body, unrestrained plethysmography, the following breathing parameters were measured: inspiratory and expiratory times, tidal volume, expiratory volume, peak inspiratory and expiratory flows, and respiratory frequency. For each category, the mean, coefficient of variation, and irregularity score were analyzed. Brains were then processed for stereological cell counts of pontomedullary respiratory nuclei. A significant increase in the coefficient of variation and irregularity score was observed for inspiratory time, tidal volume, and expiratory volume in PLP-αSYN mice (P cell counts (P breathing variability and part of the neuronal depletion in pontomedullary respiratory nuclei observed in patients with MSA. Our findings support the use of this model for future candidate drugs in the breathing disorders observed in MSA. © 2014 International Parkinson and Movement Disorder Society.

  4. CRITICAL RADAR: TOOL AND METHODOLOGY FOR EVALUATING CURRENT PROJECTS USING MULTIPLE VARIABLES

    Directory of Open Access Journals (Sweden)

    André M. Ferrari

    2017-06-01

    Full Text Available Many resources are invested in measurement processes of projects indicators without, however, give a clear view of which projects deserves the right attention at the right time. This paper proposes the use of statistics, through the analysis of multiple variables and their interrelationships, to give better basis to a critical assessment methodology of current projects used in a multinational mining company. The contribution of the research is to report the methodology called Critical Radar which is based on a graphical tool with simple operationalization that can support the decision making in complex environments, and has great flexibility across the different market scenarios and possible changes in companies guidelines. The tool has great potential to help evaluate current projects due to their characteristics of flexible use in different business areas; high degree of freedom for improvement; use of known market tool in its development; ease of viewing the results through charts and notes and user freedom to use any existing indicators in the company if complied with some statistical data quality characteristics.

  5. On Thermally Interacting Multiple Boreholes with Variable Heating Strength: Comparison between Analytical and Numerical Approaches

    Directory of Open Access Journals (Sweden)

    Marc A. Rosen

    2012-08-01

    Full Text Available The temperature response in the soil surrounding multiple boreholes is evaluated analytically and numerically. The assumption of constant heat flux along the borehole wall is examined by coupling the problem to the heat transfer problem inside the borehole and presenting a model with variable heat flux along the borehole length. In the analytical approach, a line source of heat with a finite length is used to model the conduction of heat in the soil surrounding the boreholes. In the numerical method, a finite volume method in a three dimensional meshed domain is used. In order to determine the heat flux boundary condition, the analytical quasi-three-dimensional solution to the heat transfer problem of the U-tube configuration inside the borehole is used. This solution takes into account the variation in heating strength along the borehole length due to the temperature variation of the fluid running in the U-tube. Thus, critical depths at which thermal interaction occurs can be determined. Finally, in order to examine the validity of the numerical method, a comparison is made with the results of line source method.

  6. Novel method to load multiple genes onto a mammalian artificial chromosome.

    Science.gov (United States)

    Tóth, Anna; Fodor, Katalin; Praznovszky, Tünde; Tubak, Vilmos; Udvardy, Andor; Hadlaczky, Gyula; Katona, Robert L

    2014-01-01

    Mammalian artificial chromosomes are natural chromosome-based vectors that may carry a vast amount of genetic material in terms of both size and number. They are reasonably stable and segregate well in both mitosis and meiosis. A platform artificial chromosome expression system (ACEs) was earlier described with multiple loading sites for a modified lambda-integrase enzyme. It has been shown that this ACEs is suitable for high-level industrial protein production and the treatment of a mouse model for a devastating human disorder, Krabbe's disease. ACEs-treated mutant mice carrying a therapeutic gene lived more than four times longer than untreated counterparts. This novel gene therapy method is called combined mammalian artificial chromosome-stem cell therapy. At present, this method suffers from the limitation that a new selection marker gene should be present for each therapeutic gene loaded onto the ACEs. Complex diseases require the cooperative action of several genes for treatment, but only a limited number of selection marker genes are available and there is also a risk of serious side-effects caused by the unwanted expression of these marker genes in mammalian cells, organs and organisms. We describe here a novel method to load multiple genes onto the ACEs by using only two selectable marker genes. These markers may be removed from the ACEs before therapeutic application. This novel technology could revolutionize gene therapeutic applications targeting the treatment of complex disorders and cancers. It could also speed up cell therapy by allowing researchers to engineer a chromosome with a predetermined set of genetic factors to differentiate adult stem cells, embryonic stem cells and induced pluripotent stem (iPS) cells into cell types of therapeutic value. It is also a suitable tool for the investigation of complex biochemical pathways in basic science by producing an ACEs with several genes from a signal transduction pathway of interest.

  7. Variable coordination of cotranscribed genes in Escherichia coli following antisense repression

    Directory of Open Access Journals (Sweden)

    Kulyté Agne

    2006-11-01

    Full Text Available Abstract Background A majority of bacterial genes belong to tight clusters and operons, which complicates gene functional studies using conventional knock-out methods. Antisense agents can down-regulate the expression of genes without disrupting the genome because they bind mRNA and block its expression. However, it is unclear how antisense inhibition affects expression from genes that are cotranscribed with the target. Results To examine the effects of antisense inhibition on cotranscribed genes, we constructed a plasmid expressing the two reporter genes gfp and DsRed as one transcriptional unit. Incubation with antisense peptide nucleic acid (PNA targeted to the mRNA start codon region of either the upstream gfp or the downstream DsRed gene resulted in a complete expression discoordination from this artificial construct. The same approach was applied to the three cotranscribed genes in the endogenously expressed lac-operon (lacZ, Y and A and partial downstream expression coordination was seen when the lacZ start codon was targeted with antisense PNA. Targeting the lacY mRNA start codon region showed no effect on the upstream lacZ gene expression whereas expression from the downstream lacA gene was affected as strongly as the lacY gene. Determination of lacZ and lacY mRNA levels revealed a pattern of reduction that was similar to the Lac-proteins, indicating a relation between translation inhibition and mRNA degradation as a response to antisense PNA treatment. Conclusion The results show that antisense mediated repression of genes within operons affect cotranscribed genes to a variable degree. Target transcript stability appears to be closely related to inhibition of translation and presumably depends on translating ribosomes protecting the mRNA from intrinsic decay mechanisms. Therefore, for genes within operons and clusters it is likely that the nature of the target transcript will determine the inhibitory effects on cotranscribed genes

  8. A cfr-Like Gene from Clostridium difficile Confers Multiple Antibiotic Resistance by the Same Mechanism as the cfr Gene

    DEFF Research Database (Denmark)

    Hansen, Lykke H; Vester, Birte

    2015-01-01

    The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA. Many cfr-like gene sequences in the databases code for unknown functions. This study confirms that a Cfr-like protein from a Peptoclostridium difficile (formerly Clostrid...... Clostridium difficile) strain does function as a Cfr protein. The enzyme is expressed in Escherichia coli and shows elevated MICs for five classes of antibiotics. A primer extension stop indicates a modification at A2503 in 23S rRNA.......The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA. Many cfr-like gene sequences in the databases code for unknown functions. This study confirms that a Cfr-like protein from a Peptoclostridium difficile (formerly...

  9. A cfr-Like Gene from Clostridium difficile Confers Multiple Antibiotic Resistance by the Same Mechanism as the cfr Gene

    DEFF Research Database (Denmark)

    Hansen, Lykke H; Vester, Birte

    2015-01-01

    The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA. Many cfr-like gene sequences in the databases code for unknown functions. This study confirms that a Cfr-like protein from a Peptoclostridium difficile (formerly Clostrid......The Cfr RNA methyltransferase causes multiple resistances to peptidyl transferase inhibitors by methylation of A2503 23S rRNA. Many cfr-like gene sequences in the databases code for unknown functions. This study confirms that a Cfr-like protein from a Peptoclostridium difficile (formerly...... Clostridium difficile) strain does function as a Cfr protein. The enzyme is expressed in Escherichia coli and shows elevated MICs for five classes of antibiotics. A primer extension stop indicates a modification at A2503 in 23S rRNA....

  10. Multiple Divergent Haplotypes Express Completely Distinct Sets of Class I MHC Genes in Zebrafish

    Science.gov (United States)

    McConnell, Sean C.; Restaino, Anthony C.; de Jong, Jill L.O.

    2014-01-01

    The zebrafish is an important animal model for stem cell biology, cancer, and immunology research. Histocompatibility represents a key intersection of these disciplines, however histocompatibility in zebrafish remains poorly understood. We examined a set of diverse zebrafish Class I major histocompatibility complex (MHC) genes that segregate with specific haplotypes at chromosome 19, and for which donor-recipient matching has been shown to improve engraftment after hematopoietic transplantation. Using flanking gene polymorphisms we identified six distinct chromosome 19 haplotypes. We describe several novel Class I U lineage genes and characterize their sequence properties, expression, and haplotype distribution. Altogether ten full-length zebrafish Class I genes were analyzed, mhc1uba through mhc1uka. Expression data and sequence properties indicate that most are candidate classical genes. Several substitutions in putative peptide anchor residues, often shared with deduced MHC molecules from additional teleost species, suggest flexibility in antigen binding. All ten zebrafish Class I genes were uniquely assigned among the six haplotypes, with dominant or co-dominant expression of one to three genes per haplotype. Interestingly, while the divergent MHC haplotypes display variable gene copy number and content, the different genes appear to have ancient origin, with extremely high levels of sequence diversity. Furthermore, haplotype variability extends beyond the MHC genes to include divergent forms of psmb8. The many disparate haplotypes at this locus therefore represent a remarkable form of genomic region configuration polymorphism. Defining the functional MHC genes within these divergent Class I haplotypes in zebrafish will provide an important foundation for future studies in immunology and transplantation. PMID:24291825

  11. A Hox Gene, Antennapedia, Regulates Expression of Multiple Major Silk Protein Genes in the Silkworm Bombyx mori.

    Science.gov (United States)

    Tsubota, Takuya; Tomita, Shuichiro; Uchino, Keiro; Kimoto, Mai; Takiya, Shigeharu; Kajiwara, Hideyuki; Yamazaki, Toshimasa; Sezutsu, Hideki

    2016-03-25

    Hoxgenes play a pivotal role in the determination of anteroposterior axis specificity during bilaterian animal development. They do so by acting as a master control and regulating the expression of genes important for development. Recently, however, we showed that Hoxgenes can also function in terminally differentiated tissue of the lepidopteranBombyx mori In this species,Antennapedia(Antp) regulates expression of sericin-1, a major silk protein gene, in the silk gland. Here, we investigated whether Antpcan regulate expression of multiple genes in this tissue. By means of proteomic, RT-PCR, and in situ hybridization analyses, we demonstrate that misexpression of Antpin the posterior silk gland induced ectopic expression of major silk protein genes such assericin-3,fhxh4, and fhxh5 These genes are normally expressed specifically in the middle silk gland as is Antp Therefore, the evidence strongly suggests that Antpactivates these silk protein genes in the middle silk gland. The putativesericin-1 activator complex (middle silk gland-intermolt-specific complex) can bind to the upstream regions of these genes, suggesting that Antpdirectly activates their expression. We also found that the pattern of gene expression was well conserved between B. moriand the wild species Bombyx mandarina, indicating that the gene regulation mechanism identified here is an evolutionarily conserved mechanism and not an artifact of the domestication of B. mori We suggest that Hoxgenes have a role as a master control in terminally differentiated tissues, possibly acting as a primary regulator for a range of physiological processes. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Transcriptional network of multiple capsule and melanin genes governed by the Cryptococcus neoformans cyclic AMP cascade.

    Science.gov (United States)

    Pukkila-Worley, Read; Gerrald, Quincy D; Kraus, Peter R; Boily, Marie-Josée; Davis, Matthew J; Giles, Steven S; Cox, Gary M; Heitman, Joseph; Alspaugh, J Andrew

    2005-01-01

    Cryptococcus neoformans is an opportunistic human fungal pathogen that elaborates several virulence attributes, including a polysaccharide capsule and melanin pigments. A conserved Galpha protein/cyclic AMP (cAMP) pathway controls melanin and capsule production. To identify targets of this pathway, we used an expression profiling approach to define genes that are transcriptionally regulated by the Galpha protein Gpa1. This approach revealed that Gpa1 transcriptionally regulates multiple genes involved in capsule assembly and identified two additional genes with a marked dependence on Gpa1 for transcription. The first is the LAC1 gene, encoding the laccase enzyme that catalyzes a rate-limiting step in diphenol oxidation and melanin production. The second gene identified (LAC2) is adjacent to the LAC1 gene and encodes a second laccase that shares 75% nucleotide identity with LAC1. Similar to the LAC1 gene, LAC2 is induced in response to glucose deprivation. However, LAC2 basal transcript levels are much lower than those for LAC1. Accordingly, a lac2 mutation results in only a modest delay in melanin formation. LAC2 overexpression suppresses the melanin defects of gpa1 and lac1 mutants and partially restores virulence of these strains. These studies provide mechanistic insights into the regulation of capsule and melanin production by the C. neoformans cAMP pathway and demonstrate that multiple laccases contribute to C. neoformans melanin production and pathogenesis.

  13. Disulfide bond-conjugated dual PEGylated siRNAs for prolonged multiple gene silencing.

    Science.gov (United States)

    Liao, Zi-Xian; Hsiao, Chun-Wen; Ho, Yi-Cheng; Chen, Hsin-Lung; Sung, Hsing-Wen

    2013-09-01

    Many human diseases carry at least two independent gene mutations, further exacerbating clinical disorders. In this work, disulfide bond-conjugated dual PEGylated siRNAs were synthesized, capable of specifically targeting and silencing two genes simultaneously. To achieve efficient delivery, the conjugated siRNAs were formulated with the cationic chitosan together with an anionic polymer, poly(γ-glutamic acid) (γPGA), to form a ternary complex. Experimental results indicate that the incorporated γPGA could significantly enhance their intracellular delivery efficiency, allowing for reduction of the disulfide bond-conjugated PEGylated siRNAs delivered to the PEGylated siRNAs in the reductive cytoplasmic environment. The PEGylated siRNAs could more significantly increase their enzymatic tolerability, effectively silence multiple genes, and prolong the duration of their gene silencing capability than the unmodified siRNAs could. Silencing of different genes simultaneously significantly contributes to the efforts to treat multiple gene disorders, and prolonged duration of gene silencing can reduce the need for frequent administrations. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. A synthetic small molecule for rapid induction of multiple pluripotency genes in mouse embryonic fibroblasts

    Science.gov (United States)

    Pandian, Ganesh N.; Nakano, Yusuke; Sato, Shinsuke; Morinaga, Hironobu; Bando, Toshikazu; Nagase, Hiroki; Sugiyama, Hiroshi

    2012-07-01

    Cellular reprogramming involves profound alterations in genome-wide gene expression that is precisely controlled by a hypothetical epigenetic code. Small molecules have been shown to artificially induce epigenetic modifications in a sequence independent manner. Recently, we showed that specific DNA binding hairpin pyrrole-imidazole polyamides (PIPs) could be conjugated with chromatin modifying histone deacetylase inhibitors like SAHA to epigenetically activate certain pluripotent genes in mouse fibroblasts. In our steadfast progress to improve the efficiency of SAHA-PIPs, we identified a novel compound termed, δ that could dramatically induce the endogenous expression of Oct-3/4 and Nanog. Genome-wide gene analysis suggests that in just 24 h and at nM concentration, δ induced multiple pluripotency-associated genes including Rex1 and Cdh1 by more than ten-fold. δ treated MEFs also rapidly overcame the rate-limiting step of epithelial transition in cellular reprogramming by switching ``'' the complex transcriptional gene network.

  15. Multi-modal multi-task learning for joint prediction of multiple regression and classification variables in Alzheimer's disease.

    Science.gov (United States)

    Zhang, Daoqiang; Shen, Dinggang

    2012-01-16

    Many machine learning and pattern classification methods have been applied to the diagnosis of Alzheimer's disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). Recently, rather than predicting categorical variables as in classification, several pattern regression methods have also been used to estimate continuous clinical variables from brain images. However, most existing regression methods focus on estimating multiple clinical variables separately and thus cannot utilize the intrinsic useful correlation information among different clinical variables. On the other hand, in those regression methods, only a single modality of data (usually only the structural MRI) is often used, without considering the complementary information that can be provided by different modalities. In this paper, we propose a general methodology, namely multi-modal multi-task (M3T) learning, to jointly predict multiple variables from multi-modal data. Here, the variables include not only the clinical variables used for regression but also the categorical variable used for classification, with different tasks corresponding to prediction of different variables. Specifically, our method contains two key components, i.e., (1) a multi-task feature selection which selects the common subset of relevant features for multiple variables from each modality, and (2) a multi-modal support vector machine which fuses the above-selected features from all modalities to predict multiple (regression and classification) variables. To validate our method, we perform two sets of experiments on ADNI baseline MRI, FDG-PET, and cerebrospinal fluid (CSF) data from 45 AD patients, 91 MCI patients, and 50 healthy controls (HC). In the first set of experiments, we estimate two clinical variables such as Mini Mental State Examination (MMSE) and Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), as well as one categorical variable (with value of 'AD', 'MCI' or 'HC'), from the

  16. Functional interconnections of Arabidopsis exon junction complex proteins and genes at multiple steps of gene expression.

    Science.gov (United States)

    Mufarrege, Eduardo F; Gonzalez, Daniel H; Curi, Graciela C

    2011-10-01

    The exon junction complex (EJC) is deposited on mRNA after splicing and participates in several aspects of RNA metabolism, from intracellular transport to translation. In this work, the functional and molecular interactions of Arabidopsis homologues of Mago, Y14, and PYM, three EJC components that participate in intron-mediated enhancement of gene expression in animals, have been analysed. AtMago, AtY14, and AtPYM are encoded by single genes that show similar expression patterns and contain common regulatory elements, known as site II, that are required for expression. AtPYM and AtY14 are phosphorylated by plant extracts and this modification regulates complex formation between both proteins. In addition, overexpression of AtMago and AtY14 in plants produces an increase in AtPYM protein levels, while overexpression of AtPYM results in increased formation of a complex that contains the three proteins. The effect of AtMago and AtY14 on AtPYM expression is most likely to be due to intron-mediated enhacement of AtPYM expression, since the AtPYM gene contains a leader intron that is required for expression. Indeed, transient transformation asssays indicated that the three proteins are able to increase expression from reporter constructs that contain leader introns required for the expression of different genes. The results indicate that the plant homologues of Mago, Y14, and PYM are closely interconnected, not only through their function as EJC components but also at different steps of their own gene expression mechanisms, probably reflecting the importance of their interaction for the correct expression of plant genes.

  17. Gene expression profiling for molecular classification of multiple myeloma in newly diagnosed patients

    NARCIS (Netherlands)

    Broyl, Annemiek; Hose, Dirk; Lokhorst, Henk; de Knegt, Yvonne; Peeters, Justine; Jauch, Anna; Bertsch, Uta; Buijs, Arjan; Stevens-Kroef, Marian; Beverloo, H. Berna; Vellenga, Edo; Zweegman, Sonja; Kersten, Marie-Josee; van der Holt, Bronno; el Jarari, Laila; Mulligan, George; Goldschmidt, Hartmut; van Duin, Mark; Sonneveld, Pieter

    2010-01-01

    To identify molecularly defined subgroups in multiple myeloma, gene expression profiling was performed on purified CD138(+) plasma cells of 320 newly diagnosed myeloma patients included in the Dutch-Belgian/German HOVON-65/GMMG-HD4 trial. Hierarchical clustering identified 10 subgroups; 6

  18. Tumor suppressor miR-1 inhibits tumor growth and metastasis by simultaneously targeting multiple genes

    Science.gov (United States)

    Liu, Cuilian; Zhang, Song; Wang, Qizhi; Zhang, Xiaobo

    2017-01-01

    Cancer progression depends on tumor growth and metastasis, which are activated or suppressed by multiple genes. An individual microRNA may target multiple genes, suggesting that a miRNA may suppress tumor growth and metastasis via simultaneously targeting different genes. However, thus far, this issue has not been explored. In the present study, the findings showed that miR-1 could simultaneously inhibit tumor growth and metastasis of gastric and breast cancers by targeting multiple genes. The results indicated that miR-1 was significantly downregulated in cancer tissues compared with normal tissues. The miR-1 overexpression led to cell cycle arrest in the G1 phase in gastric and breast cancer cells but not in normal cells. Furthermore, the miR-1 overexpression significantly inhibited the metastasis of gastric and breast cancer cells. An analysis of the underlying mechanism revealed that the simultaneous inhibition of tumor growth and metastasis mediated by miR-1 was due to the synchronous targeting of 6 miR-1 target genes encoding cyclin dependent kinase 4, twinfilin actin binding protein 1, calponin 3, coronin 1C, WAS protein family member 2 and thymosin beta 4, X-linked. In vivo assays demonstrated that miR-1 efficiently inhibited tumor growth and metastasis of gastric and breast cancers in nude mice. Therefore, our study contributed novel insights into the miR-1′s roles in tumorigenesis of gastric and breast cancers. PMID:28159933

  19. Immuno-Oncology-The Translational Runway for Gene Therapy: Gene Therapeutics to Address Multiple Immune Targets.

    Science.gov (United States)

    Weß, Ludger; Schnieders, Frank

    2017-12-01

    Cancer therapy is once again experiencing a paradigm shift. This shift is based on extensive clinical experience demonstrating that cancer cannot be successfully fought by addressing only single targets or pathways. Even the combination of several neo-antigens in cancer vaccines is not sufficient for successful, lasting tumor eradication. The focus has therefore shifted to the immune system's role in cancer and the striking abilities of cancer cells to manipulate and/or deactivate the immune system. Researchers and pharma companies have started to target the processes and cells known to support immune surveillance and the elimination of tumor cells. Immune processes, however, require novel concepts beyond the traditional "single-target-single drug" paradigm and need parallel targeting of diverse cells and mechanisms. This review gives a perspective on the role of gene therapy technologies in the evolving immuno-oncology space and identifies gene therapy as a major driver in the development and regulation of effective cancer immunotherapy. Present challenges and breakthroughs ranging from chimeric antigen receptor T-cell therapy, gene-modified oncolytic viruses, combination cancer vaccines, to RNA therapeutics are spotlighted. Gene therapy is recognized as the most prominent technology enabling effective immuno-oncology strategies.

  20. Multiple-locus variable-number tandem repeat analysis for molecular typing of Aspergillus fumigatus

    Directory of Open Access Journals (Sweden)

    Chermette René

    2010-12-01

    Full Text Available Abstract Background Multiple-locus variable-number tandem repeat (VNTR analysis (MLVA is a prominent subtyping method to resolve closely related microbial isolates to provide information for establishing genetic patterns among isolates and to investigate disease outbreaks. The usefulness of MLVA was recently demonstrated for the avian major pathogen Chlamydophila psittaci. In the present study, we developed a similar method for another pathogen of birds: the filamentous fungus Aspergillus fumigatus. Results We selected 10 VNTR markers located on 4 different chromosomes (1, 5, 6 and 8 of A. fumigatus. These markers were tested with 57 unrelated isolates from different hosts or their environment (53 isolates from avian species in France, China or Morocco, 3 isolates from humans collected at CHU Henri Mondor hospital in France and the reference strain CBS 144.89. The Simpson index for individual markers ranged from 0.5771 to 0.8530. A combined loci index calculated with all the markers yielded an index of 0.9994. In a second step, the panel of 10 markers was used in different epidemiological situations and tested on 277 isolates, including 62 isolates from birds in Guangxi province in China, 95 isolates collected in two duck farms in France and 120 environmental isolates from a turkey hatchery in France. A database was created with the results of the present study http://minisatellites.u-psud.fr/MLVAnet/. Three major clusters of isolates were defined by using the graphing algorithm termed Minimum Spanning Tree (MST. The first cluster comprised most of the avian isolates collected in the two duck farms in France, the second cluster comprised most of the avian isolates collected in poultry farms in China and the third one comprised most of the isolates collected in the turkey hatchery in France. Conclusions MLVA displayed excellent discriminatory power. The method showed a good reproducibility. MST analysis revealed an interesting clustering with a

  1. Molecular and evolutionary analyses of a variable series of genes in Borrelia burgdorferi that are related to ospE and ospF, constitute a gene family, and share a common upstream homology box.

    Science.gov (United States)

    Marconi, R T; Sung, S Y; Hughes, C A; Carlyon, J A

    1996-10-01

    In this study we report on the molecular characterization of a series of genes that constitute a gene family related to ospE and ospF. Some members of this family appear to represent recombined or variant forms of ospE and ospF. Variant ospE and ospF genes were found in several Borrelia burgdorferi isolates, demonstrating that their occurrence is not a phenomenon relevant to only a single isolate. Hybridization analyses revealed that the upstream sequence originally identified 5' of the full-length ospEF operon exists in multiple copies ranging in number from two to six depending on the isolate. This repeated sequence, which we refer to as the upstream homology box (UHB), carries a putative promoter element. In some isolates, UHB elements were found to flank copies of ospE and ospF that exist independently of each other. We refer to this group of UHB-flanked genes collectively as the UHB gene family. The evolutionary relationships among UHB gene family members were assessed through DNA sequence analysis and gene tree construction. These analyses suggest that some UHB-flanked genes might actually represent divergent forms of other previously described genes. Analysis of the restriction fragment length polymorphism patterns of the UHB-flanked genes among B. burgdorferi isolates demonstrated that these patterns are highly variable among isolates, suggesting that these genes are not phylogenetically conserved. The variable restriction fragment length polymorphism patterns could indicate recombinational activity in these sequences. The presence of numerous copies of the UHB elements and the high degree of homology among UHB-flanked genes could provide the necessary elements to allow for homologous recombination, leading to the generation of recombination variants of UHB gene family members.

  2. Imported brucellosis in Denmark: Molecular identification and multiple-locus variable number tandem repeat analysis (MLVA) genotyping of the bacteria

    DEFF Research Database (Denmark)

    Aftab, H.; Dargis, R.; Christensen, J. J.

    2011-01-01

    A polymerase chain reaction was used to identify Brucella species isolated from humans in Denmark. Consecutive analysis of referred bacteria and re-examination of historical isolates identified all as Brucella melitensis. Multiple-locus variable number tandem repeat analysis (MLVA) placed...

  3. Validity and variability of the 5-repetition sit-to-stand test in patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Møller, Andreas Buch; Bibby, Bo Martin; Guldhammer, Anders

    2012-01-01

    Purpose: To investigate; (i) the relationship between the 5STS-test and lower extremity muscle strength and balance, and (ii) the variability of the 5STS-test in multiple sclerosis (MS) patients. Method: 22 MS patients were divided into two groups (Group A and Group B) who completed one 5STS...

  4. Lack of Association of Estrogen Receptor Alpha Gene Polymorphisms with Cardiorespiratory and Metabolic Variables in Young Women

    Directory of Open Access Journals (Sweden)

    Mario Hirata

    2012-10-01

    Full Text Available This study examined the association of estrogen receptor alpha gene (ESR1 polymorphisms with cardiorespiratory and metabolic parameters in young women. In total, 354 healthy women were selected for cardiopulmonary exercise testing and short-term heart rate (HR variability (HRV evaluation. The HRV analysis was determined by the temporal indices rMSSD (square root of the mean squared differences of successive R–R intervals (RRi divided by the number of RRi minus one, SDNN (root mean square of differences from mean RRi, divided by the number of RRi and power spectrum components by low frequency (LF, high frequency (HF and LF/HF ratio. Blood samples were obtained for serum lipids, estradiol and DNA extraction. ESR1 rs2234693 and rs9340799 polymorphisms were analyzed by PCR and fragment restriction analysis. HR and oxygen uptake (VO2 values did not differ between the ESR1 polymorphisms with respect to autonomic modulation. We not find a relationship between ESR1 T–A, T–G, C–A and C–G haplotypes and cardiorespiratory and metabolic variables. Multiple linear regression analysis demonstrated that VO2, total cholesterol and triglycerides influence HRV (p < 0.05. The results suggest that ESR1 variants have no effect on cardiorespiratory and metabolic variables, while HRV indices are influenced by aerobic capacity and lipids in healthy women.

  5. Variations in the multiple tbp genes in different Halobacterium salinarum strains and their expression during growth.

    Science.gov (United States)

    Teufel, Katharina; Bleiholder, Anne; Griesbach, Tim; Pfeifer, Felicitas

    2008-09-01

    The presence and expression of the multiple tbp genes encoding TATA-box binding proteins (TBPs) was investigated in various strains and mutants of the archaeon Halobacterium salinarum. Six genes, tbpA through tbpF, are present in the genome of Hbt. salinarum NRC-1 and also in the gas vesicle negative mutant strain R1. The only tbp gene located in the chromosome is tbpE, whereas all others are found in the plasmid DNA. Due to the dynamic nature of the plasmids in the Halobacterium strains, the copy numbers of the alternative tbp genes vary significantly. Five tbp genes (tbpA through tbpE) were present in the wild-type strain Hbt. salinarum PHH1. The tbpC gene of Hbt. salinarum PHH1 carried an ISH27-2 insertion element at the start of the reading frame that prevented the expression. All other tbp genes of PHH1 were expressed under aerobic and anaerobic growth conditions and quantitative RT-PCR yielded tbpE as dominant tbp transcript during the exponential growth phase. The plasmid deletion variant Hbt. salinarum PHH4 lacked all of the tbp genes except for tbpE and showed an altered growth behaviour compared to PHH1 wild-type in the stationary growth phase under anaerobic growth conditions.

  6. Reference gene selection for quantitative gene expression studies during biological invasions: A test on multiple genes and tissues in a model ascidian Ciona savignyi.

    Science.gov (United States)

    Huang, Xuena; Gao, Yangchun; Jiang, Bei; Zhou, Zunchun; Zhan, Aibin

    2016-01-15

    As invasive species have successfully colonized a wide range of dramatically different local environments, they offer a good opportunity to study interactions between species and rapidly changing environments. Gene expression represents one of the primary and crucial mechanisms for rapid adaptation to local environments. Here, we aim to select reference genes for quantitative gene expression analysis based on quantitative Real-Time PCR (qRT-PCR) for a model invasive ascidian, Ciona savignyi. We analyzed the stability of ten candidate reference genes in three tissues (siphon, pharynx and intestine) under two key environmental stresses (temperature and salinity) in the marine realm based on three programs (geNorm, NormFinder and delta Ct method). Our results demonstrated only minor difference for stability rankings among the three methods. The use of different single reference gene might influence the data interpretation, while multiple reference genes could minimize possible errors. Therefore, reference gene combinations were recommended for different tissues - the optimal reference gene combination for siphon was RPS15 and RPL17 under temperature stress, and RPL17, UBQ and TubA under salinity treatment; for pharynx, TubB, TubA and RPL17 were the most stable genes under temperature stress, while TubB, TubA and UBQ were the best under salinity stress; for intestine, UBQ, RPS15 and RPL17 were the most reliable reference genes under both treatments. Our results suggest that the necessity of selection and test of reference genes for different tissues under varying environmental stresses. The results obtained here are expected to reveal mechanisms of gene expression-mediated invasion success using C. savignyi as a model species. Copyright © 2015 Elsevier B.V. All rights reserved.

  7. Feature selection and classification of MAQC-II breast cancer and multiple myeloma microarray gene expression data.

    Directory of Open Access Journals (Sweden)

    Qingzhong Liu

    Full Text Available Microarray data has a high dimension of variables but available datasets usually have only a small number of samples, thereby making the study of such datasets interesting and challenging. In the task of analyzing microarray data for the purpose of, e.g., predicting gene-disease association, feature selection is very important because it provides a way to handle the high dimensionality by exploiting information redundancy induced by associations among genetic markers. Judicious feature selection in microarray data analysis can result in significant reduction of cost while maintaining or improving the classification or prediction accuracy of learning machines that are employed to sort out the datasets. In this paper, we propose a gene selection method called Recursive Feature Addition (RFA, which combines supervised learning and statistical similarity measures. We compare our method with the following gene selection methods: Support Vector Machine Recursive Feature Elimination (SVMRFE, Leave-One-Out Calculation Sequential Forward Selection (LOOCSFS, Gradient based Leave-one-out Gene Selection (GLGS. To evaluate the performance of these gene selection methods, we employ several popular learning classifiers on the MicroArray Quality Control phase II on predictive modeling (MAQC-II breast cancer dataset and the MAQC-II multiple myeloma dataset. Experimental results show that gene selection is strictly paired with learning classifier. Overall, our approach outperforms other compared methods. The biological functional analysis based on the MAQC-II breast cancer dataset convinced us to apply our method for phenotype prediction. Additionally, learning classifiers also play important roles in the classification of microarray data and our experimental results indicate that the Nearest Mean Scale Classifier (NMSC is a good choice due to its prediction reliability and its stability across the three performance measurements: Testing accuracy, MCC values, and

  8. Single and Multiple Gene Manipulations in Mouse Models of Human Cancer

    Directory of Open Access Journals (Sweden)

    Heather L. Lehman

    2015-01-01

    Full Text Available Mouse models of human cancer play a critical role in understanding the molecular and cellular mechanisms of tumorigenesis. Advances continue to be made in modeling human disease in a mouse, though the relevance of a mouse model often relies on how closely it is able to mimic the histologic, molecular, and physiologic characteristics of the respective human cancer. A classic use of a genetically engineered mouse in studying cancer is through the overexpression or deletion of a gene. However, the manipulation of a single gene often falls short of mimicking all the characteristics of the carcinoma in humans; thus a multiple gene approach is needed. Here we review genetic mouse models of cancers and their abilities to recapitulate human carcinoma with single versus combinatorial approaches with genes commonly involved in cancer.

  9. Physiological, Diurnal and Stress-Related Variability of Cadmium-Metallothionein Gene Expression in Land Snails.

    Directory of Open Access Journals (Sweden)

    Veronika Pedrini-Martha

    Full Text Available The terrestrial Roman snail Helix pomatia has successfully adapted to strongly fluctuating conditions in its natural soil habitat. Part of the snail's stress defense strategy is its ability to express Metallothioneins (MTs. These are multifunctional, cysteine-rich proteins that bind and inactivate transition metal ions (Cd(2+, Zn(2+, Cu(+ with high affinity. In Helix pomatia a Cadmium (Cd-selective, inducible Metallothionein Isoform (CdMT is mainly involved in detoxification of this harmful metal. In addition, the snail CdMT has been shown to also respond to certain physiological stressors. The aim of the present study was to investigate the physiological and diurnal variability of CdMT gene expression in snails exposed to Cd and non-metallic stressors such as desiccation and oxygen depletion. CdMT gene expression was upregulated by Cd exposure and desiccation, whereas no significant impact on the expression of CdMT was measured due to oxygen depletion. Overall, Cd was clearly more effective as an inducer of the CdMT gene expression compared to the applied non-metallic stressors. In unexposed snails, diurnal rhythmicity of CdMT gene expression was observed with higher mRNA concentrations at night compared to daytime. This rhythmicity was severely disrupted in Cd-exposed snails which exhibited highest CdMT gene transcription rates in the morning. Apart from diurnal rhythmicity, feeding activity also had a strong impact on CdMT gene expression. Although underlying mechanisms are not completely understood, it is clear that factors increasing MT expression variability have to be considered when using MT mRNA quantification as a biomarker for environmental stressors.

  10. Physiological, Diurnal and Stress-Related Variability of Cadmium-Metallothionein Gene Expression in Land Snails.

    Science.gov (United States)

    Pedrini-Martha, Veronika; Niederwanger, Michael; Kopp, Renate; Schnegg, Raimund; Dallinger, Reinhard

    2016-01-01

    The terrestrial Roman snail Helix pomatia has successfully adapted to strongly fluctuating conditions in its natural soil habitat. Part of the snail's stress defense strategy is its ability to express Metallothioneins (MTs). These are multifunctional, cysteine-rich proteins that bind and inactivate transition metal ions (Cd(2+), Zn(2+), Cu(+)) with high affinity. In Helix pomatia a Cadmium (Cd)-selective, inducible Metallothionein Isoform (CdMT) is mainly involved in detoxification of this harmful metal. In addition, the snail CdMT has been shown to also respond to certain physiological stressors. The aim of the present study was to investigate the physiological and diurnal variability of CdMT gene expression in snails exposed to Cd and non-metallic stressors such as desiccation and oxygen depletion. CdMT gene expression was upregulated by Cd exposure and desiccation, whereas no significant impact on the expression of CdMT was measured due to oxygen depletion. Overall, Cd was clearly more effective as an inducer of the CdMT gene expression compared to the applied non-metallic stressors. In unexposed snails, diurnal rhythmicity of CdMT gene expression was observed with higher mRNA concentrations at night compared to daytime. This rhythmicity was severely disrupted in Cd-exposed snails which exhibited highest CdMT gene transcription rates in the morning. Apart from diurnal rhythmicity, feeding activity also had a strong impact on CdMT gene expression. Although underlying mechanisms are not completely understood, it is clear that factors increasing MT expression variability have to be considered when using MT mRNA quantification as a biomarker for environmental stressors.

  11. Dramatic variability of the carbonate system of the coastal ocean is regulated by physical and biogeochemical processes on multiple timescales

    Science.gov (United States)

    Johnson, Z. I.; Hunt, D.

    2013-12-01

    Increased atmospheric carbon dioxide (CO2) from anthropogenic sources is acidifying marine environments with potentially dramatic implications for the physical, chemical and biological functioning of these ecosystems. If current trends continue, mean ocean pH is expected to decrease by ~0.2 units over the next ~50 years. Yet, at the same time there is substantial spatial and temporal variability in pH and other carbon system parameters in the ocean resulting in regions that already exceed long term projected pH changes, suggesting that short-term variability is an important layer of complexity on top of long term acidification. Thus, in order to develop predictions of future climate change impacts including ocean acidification, there is a critical need to characterize the natural range and variability of the marine CO2 system and the mechanisms responsible for this variability. Here we examine pH and dissolved inorganic carbon (DIC) variability at time intervals spanning 1 hour to >1 year in a dynamic coastal marine system to quantify variability of the carbon system at multiple time scales. Daily and seasonal variability of the carbon system is largely driven by temperature, alkalinity and the balance between primary production and respiration, but high frequency variability (hours to days) is further influenced by water mass movement (e.g. tides) and stochastic events (e.g. storms). Both annual variability (~0.3 units) and diurnal variability (~0.1 units) in coastal ocean acidity are similar in magnitude to long term projections associated with increasing atmospheric CO2 and their drivers highlight the importance of characterizing the complete carbonate system (and not just pH). Short term variability of ocean carbon parameters may already exert significant pressure on some coastal marine ecosystems with implications for ecology, biogeochemistry and evolution and this shorter term variability layers additive effects and complexity, including extreme values, on

  12. Meta-analysis of gene-environment interaction exploiting gene-environment independence across multiple case-control studies.

    Science.gov (United States)

    Estes, Jason P; Rice, John D; Li, Shi; Stringham, Heather M; Boehnke, Michael; Mukherjee, Bhramar

    2017-10-30

    Multiple papers have studied the use of gene-environment (G-E) independence to enhance power for testing gene-environment interaction in case-control studies. However, studies that evaluate the role of G-E independence in a meta-analysis framework are limited. In this paper, we extend the single-study empirical Bayes type shrinkage estimators proposed by Mukherjee and Chatterjee (2008) to a meta-analysis setting that adjusts for uncertainty regarding the assumption of G-E independence across studies. We use the retrospective likelihood framework to derive an adaptive combination of estimators obtained under the constrained model (assuming G-E independence) and unconstrained model (without assumptions of G-E independence) with weights determined by measures of G-E association derived from multiple studies. Our simulation studies indicate that this newly proposed estimator has improved average performance across different simulation scenarios than the standard alternative of using inverse variance (covariance) weighted estimators that combines study-specific constrained, unconstrained, or empirical Bayes estimators. The results are illustrated by meta-analyzing 6 different studies of type 2 diabetes investigating interactions between genetic markers on the obesity related FTO gene and environmental factors body mass index and age. Copyright © 2017 John Wiley & Sons, Ltd.

  13. NIMEFI: gene regulatory network inference using multiple ensemble feature importance algorithms.

    Directory of Open Access Journals (Sweden)

    Joeri Ruyssinck

    Full Text Available One of the long-standing open challenges in computational systems biology is the topology inference of gene regulatory networks from high-throughput omics data. Recently, two community-wide efforts, DREAM4 and DREAM5, have been established to benchmark network inference techniques using gene expression measurements. In these challenges the overall top performer was the GENIE3 algorithm. This method decomposes the network inference task into separate regression problems for each gene in the network in which the expression values of a particular target gene are predicted using all other genes as possible predictors. Next, using tree-based ensemble methods, an importance measure for each predictor gene is calculated with respect to the target gene and a high feature importance is considered as putative evidence of a regulatory link existing between both genes. The contribution of this work is twofold. First, we generalize the regression decomposition strategy of GENIE3 to other feature importance methods. We compare the performance of support vector regression, the elastic net, random forest regression, symbolic regression and their ensemble variants in this setting to the original GENIE3 algorithm. To create the ensemble variants, we propose a subsampling approach which allows us to cast any feature selection algorithm that produces a feature ranking into an ensemble feature importance algorithm. We demonstrate that the ensemble setting is key to the network inference task, as only ensemble variants achieve top performance. As second contribution, we explore the effect of using rankwise averaged predictions of multiple ensemble algorithms as opposed to only one. We name this approach NIMEFI (Network Inference using Multiple Ensemble Feature Importance algorithms and show that this approach outperforms all individual methods in general, although on a specific network a single method can perform better. An implementation of NIMEFI has been made

  14. Biallelic germline mutations of mismatch-repair genes: a possible cause for multiple pediatric malignancies.

    Science.gov (United States)

    Poley, Jan-Werner; Wagner, Anja; Hoogmans, Monique M C P; Menko, Fred H; Tops, Carli; Kros, Johan M; Reddingius, Roel E; Meijers-Heijboer, Hanne; Kuipers, Ernst J; Dinjens, Winand N M

    2007-06-01

    Heterozygous defects in mismatch-repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC). In this syndrome, tumors typically arise from age 25 years onward. Case reports have shown that homozygosity or compound heterozygosity for MMR gene mutations can cause multiple tumors in childhood, sometimes combined with neurofibromatosis type I (NF1)-like features. Therefore, the authors studied the role of homozygosity or compound heterozygosity (CZ) for MMR gene defects in children with multiple primary tumors. A database that contained all pediatric oncology patients who were seen between 1982 and 2003 at the author's institution was queried to identify patients aged Saccharomyces cerevisiae 2 [PMS2] expression) and a Wilms tumor (high MSI; no MLH1 or PMS2 expression). Apart from >6 cafe-au-lait spots, he had no other signs of NF1. The patient had CZ identified for a pathogenic MLH1 mutation (593delAG frameshift) and an unclassified MLH1 variant (Met35Asn). There was strong evidence that this unclassified variant was a pathogenic mutation. The second patient was diagnosed with a non-Hodgkin lymphoma (no tissue available) and an anaplastic oligodendroglioma (low MSI; no MSH6 expression) at age 4 years and 6 years, respectively. His brother had died of a medulloblastoma at age 6 years (low MSI, no MSH6 expression). Both boys had cafe-au-lait spots. Further genetic testing was not possible. Carriage of biallelic MMR gene defects can be associated with multiple malignancies in childhood that may differ from the standard spectrum of HNPCC tumor types. In 15 pediatric patients with multiple malignancies, the authors identified 1 clear case and 1 possible case of biallelic MMR gene defect. Recognition of the inherited nature of the tumors in these patients is important for counseling these patients and their families. (c) 2007 American Cancer Society.

  15. Transcriptome analysis reveals crosstalk of responsive genes to multiple abiotic stresses in cotton (Gossypium hirsutum L.).

    Science.gov (United States)

    Zhu, Ya-Na; Shi, Dong-Qiao; Ruan, Meng-Bin; Zhang, Li-Li; Meng, Zhao-Hong; Liu, Jie; Yang, Wei-Cai

    2013-01-01

    Abiotic stress is a major environmental factor that limits cotton growth and yield, moreover, this problem has become more and more serious recently, as multiple stresses often occur simultaneously due to the global climate change and environmental pollution. In this study, we sought to identify genes involved in diverse stresses including abscisic acid (ABA), cold, drought, salinity and alkalinity by comparative microarray analysis. Our result showed that 5790, 3067, 5608, 778 and 6148 transcripts, were differentially expressed in cotton seedlings under treatment of ABA (1 μM ABA), cold (4°C), drought (200 mM mannitol), salinity (200 mM NaCl) and alkalinity (pH=11) respectively. Among the induced or suppressed genes, 126 transcripts were shared by all of the five kinds of abiotic stresses, with 64 up-regulated and 62 down-regulated. These common members are grouped as stress signal transduction, transcription factors (TFs), stress response/defense proteins, metabolism, transport facilitation, as well as cell wall/structure, according to the function annotation. We also noticed that large proportion of significant differentially expressed genes specifically regulated in response to different stress. Nine of the common transcripts of multiple stresses were selected for further validation with quantitative real time RT-PCR (qRT-PCR). Furthermore, several well characterized TF families, for example, WRKY, MYB, NAC, AP2/ERF and zinc finger were shown to be involved in different stresses. As an original report using comparative microarray to analyze transcriptome of cotton under five abiotic stresses, valuable information about functional genes and related pathways of anti-stress, and/or stress tolerance in cotton seedlings was unveiled in our result. Besides this, some important common factors were focused for detailed identification and characterization. According to our analysis, it suggested that there was crosstalk of responsive genes or pathways to multiple

  16. A magnetic nanoparticle-based multiple-gene delivery system for transfection of porcine kidney cells.

    Directory of Open Access Journals (Sweden)

    Yan Wang

    Full Text Available Superparamagnetic nanoparticles are promising candidates for gene delivery into mammalian somatic cells and may be useful for reproductive cloning using the somatic cell nuclear transfer technique. However, limited investigations of their potential applications in animal genetics and breeding, particularly multiple-gene delivery by magnetofection, have been performed. Here, we developed a stable, targetable and convenient system for delivering multiple genes into the nuclei of porcine somatic cells using magnetic Fe3O4 nanoparticles as gene carriers. After surface modification by polyethylenimine, the spherical magnetic Fe3O4 nanoparticles showed strong binding affinity for DNA plasmids expressing the genes encoding a green (DNAGFP or red (DNADsRed fluorescent protein. At weight ratios of DNAGFP or DNADsRed to magnetic nanoparticles lower than or equal to 10∶1 or 5∶1, respectively, the DNA molecules were completely bound by the magnetic nanoparticles. Atomic force microscopy analyses confirmed binding of the spherical magnetic nanoparticles to stretched DNA strands up to several hundred nanometers in length. As a result, stable and efficient co-expression of GFP and DsRed in porcine kidney PK-15 cells was achieved by magnetofection. The results presented here demonstrate the potential application of magnetic nanoparticles as an attractive delivery system for animal genetics and breeding studies.

  17. High-risk oral leukoplakia is associated with aberrant promoter methylation of multiple genes.

    Science.gov (United States)

    Abe, Masanobu; Yamashita, Satoshi; Mori, Yoshiyuki; Abe, Takahiro; Saijo, Hideto; Hoshi, Kazuto; Ushijima, Toshikazu; Takato, Tsuyoshi

    2016-06-03

    Early detection of oral squamous cell carcinomas (OSCCs) is urgently needed to improve the prognosis and quality of life (QOL) of patients. Oral leukoplakias (OLs), known as the most common premalignant lesions in the oral cavity, often precede OSCCs. Especially, OLs with dysplasia are known to have a high risk of malignant transformation. Here, we searched for the promoter methylation characteristic of high-risk OLs. To identify methylation-silenced genes, a combined analysis of methylated DNA immunoprecipitation (MeDIP) - CpG island (CGI) microarray analysis and expression microarray analysis after treatment with a demethylating agent was performed in two OSCC cell lines (Ca9-22 and HSC-2). The methylation statuses of each gene were examined by methylation-specific PCR. A total of 52 genes were identified as candidates for methylation-silenced genes in Ca9-22 or HSC-2. The promoter regions of 13 genes among the 15 genes randomly selected for further analysis were confirmed to be methylated in one or more of five cell lines. In OSCC tissues (n = 26), 8 of the 13 genes, TSPYL5, EGFLAM, CLDN11, NKX2-3, RBP4, CMTM3, TRPC4, and MAP6, were methylated. In OL tissues (n = 24), seven of the eight genes, except for EGFLAM, were found to be methylated in their promoter regions. There were significantly greater numbers of methylated genes in OLs with dysplasia than in those without dysplasia (p < 0.0001). OLs at high risk for malignant transformation were associated with aberrant promoter methylation of multiple genes.

  18. False Positives in Multiple Regression: Unanticipated Consequences of Measurement Error in the Predictor Variables

    Science.gov (United States)

    Shear, Benjamin R.; Zumbo, Bruno D.

    2013-01-01

    Type I error rates in multiple regression, and hence the chance for false positive research findings, can be drastically inflated when multiple regression models are used to analyze data that contain random measurement error. This article shows the potential for inflated Type I error rates in commonly encountered scenarios and provides new…

  19. Transcriptome analysis of recurrently deregulated genes across multiple cancers identifies new pan-cancer biomarkers

    DEFF Research Database (Denmark)

    Kaczkowski, Bogumil; Tanaka, Yuji; Kawaji, Hideya

    2016-01-01

    Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression (CAGE) profiles from 225 different cancer cell lines and 339 corresponding primary cell...... RNAs which are upregulated in cancer, defining promoters which overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall...

  20. CSI: a nonparametric Bayesian approach to network inference from multiple perturbed time series gene expression data.

    Science.gov (United States)

    Penfold, Christopher A; Shifaz, Ahmed; Brown, Paul E; Nicholson, Ann; Wild, David L

    2015-06-01

    Here we introduce the causal structure identification (CSI) package, a Gaussian process based approach to inferring gene regulatory networks (GRNs) from multiple time series data. The standard CSI approach infers a single GRN via joint learning from multiple time series datasets; the hierarchical approach (HCSI) infers a separate GRN for each dataset, albeit with the networks constrained to favor similar structures, allowing for the identification of context specific networks. The software is implemented in MATLAB and includes a graphical user interface (GUI) for user friendly inference. Finally the GUI can be connected to high performance computer clusters to facilitate analysis of large genomic datasets.

  1. Dosage changes of a segment at 17p13.1 lead to intellectual disability and microcephaly as a result of complex genetic interaction of multiple genes

    DEFF Research Database (Denmark)

    Carvalho, Claudia M B; Vasanth, Shivakumar; Shinawi, Marwan

    2014-01-01

    The 17p13.1 microdeletion syndrome is a recently described genomic disorder with a core clinical phenotype of intellectual disability, poor to absent speech, dysmorphic features, and a constellation of more variable clinical features, most prominently microcephaly. We identified five subjects...... of discrete gene pairings induce microcephaly. Taken together, these studies support a model in which concomitant dosage perturbation of multiple genes within the CNV drive the microcephaly and possibly other neurodevelopmental phenotypes associated with rearrangements in the 17p13.1 SRO....

  2. svapls: an R package to correct for hidden factors of variability in gene expression studies.

    Science.gov (United States)

    Chakraborty, Sutirtha; Datta, Somnath; Datta, Susmita

    2013-07-24

    Hidden variability is a fundamentally important issue in the context of gene expression studies. Collected tissue samples may have a wide variety of hidden effects that may alter their transcriptional landscape significantly. As a result their actual differential expression pattern can be potentially distorted, leading to inaccurate results from a genome-wide testing for the important transcripts. We present an R package svapls that can be used to identify several types of unknown sample-specific sources of heterogeneity in a gene expression study and adjust for them in order to provide a more accurate inference on the original expression pattern of the genes over different varieties of samples. The proposed method implements Partial Least Squares regression to extract the hidden signals of sample-specific heterogeneity in the data and uses them to find the genes that are actually correlated with the phenotype of interest. We also compare our package with three other popular softwares for testing differential gene expression along with a detailed illustration on the widely popular Golub dataset. Results from the sensitivity analyes on simulated data with widely different hidden variation patterns reveal the improved detection power of our R package compared to the other softwares along with reasonably smaller error rates. Application on the real-life dataset exhibits the efficacy of the R package in detecting potential batch effects from the dataset. Overall, Our R package provides the user with a simplified framework for analyzing gene expression data with a wide range of hidden variation patterns and delivering a differential gene expression analysis with substantially improved power and accuracy.The R package svapls is freely available at http://cran.r-project.org/web/packages/svapls/index.html.

  3. Genetic variability in mitochondrial and nuclear genes of Larus dominicanus (Charadriiformes, Laridae) from the Brazilian coast

    Science.gov (United States)

    de Mendonça Dantas, Gisele Pires; Meyer, Diogo; Godinho, Raquel; Ferrand, Nuno; Morgante, João Stenghel

    2012-01-01

    Several phylogeographic studies of seabirds have documented low genetic diversity that has been attributed to bottleneck events or individual capacity for dispersal. Few studies have been done in seabirds on the Brazilian coast and all have shown low genetic differentiation on a wide geographic scale. The Kelp Gull is a common species with a wide distribution in the Southern Hemisphere. In this study, we used mitochondrial and nuclear markers to examine the genetic variability of Kelp Gull populations on the Brazilian coast and compared this variability with that of sub-Antarctic island populations of this species. Kelp Gulls showed extremely low genetic variability for mitochondrial markers (cytb and ATPase) and high diversity for a nuclear locus (intron 7 of the β-fibrinogen). The intraspecific evolutionary history of Kelp Gulls showed that the variability found in intron 7 of the β-fibrinogen gene was compatible with the variability expected under neutral evolution but suggested an increase in population size during the last 10,000 years. However, none of the markers revealed evidence of a bottleneck population. These findings indicate that the recent origin of Kelp Gulls is the main explanation for their nuclear diversity, although selective pressure on the mtDNA of this species cannot be discarded. PMID:23271950

  4. Genetic variability in mitochondrial and nuclear genes of Larus dominicanus (Charadriiformes, Laridae) from the Brazilian coast.

    Science.gov (United States)

    de Mendonça Dantas, Gisele Pires; Meyer, Diogo; Godinho, Raquel; Ferrand, Nuno; Morgante, João Stenghel

    2012-12-01

    Several phylogeographic studies of seabirds have documented low genetic diversity that has been attributed to bottleneck events or individual capacity for dispersal. Few studies have been done in seabirds on the Brazilian coast and all have shown low genetic differentiation on a wide geographic scale. The Kelp Gull is a common species with a wide distribution in the Southern Hemisphere. In this study, we used mitochondrial and nuclear markers to examine the genetic variability of Kelp Gull populations on the Brazilian coast and compared this variability with that of sub-Antarctic island populations of this species. Kelp Gulls showed extremely low genetic variability for mitochondrial markers (cytb and ATPase) and high diversity for a nuclear locus (intron 7 of the β-fibrinogen). The intraspecific evolutionary history of Kelp Gulls showed that the variability found in intron 7 of the β-fibrinogen gene was compatible with the variability expected under neutral evolution but suggested an increase in population size during the last 10,000 years. However, none of the markers revealed evidence of a bottleneck population. These findings indicate that the recent origin of Kelp Gulls is the main explanation for their nuclear diversity, although selective pressure on the mtDNA of this species cannot be discarded.

  5. Genetic variability in mitochondrial and nuclear genes of Larus dominicanus (Charadriiformes, Laridae from the Brazilian coast

    Directory of Open Access Journals (Sweden)

    Gisele Pires de Mendonça Dantas

    2012-01-01

    Full Text Available Several phylogeographic studies of seabirds have documented low genetic diversity that has been attributed to bottleneck events or individual capacity for dispersal. Few studies have been done in seabirds on the Brazilian coast and all have shown low genetic differentiation on a wide geographic scale. The Kelp Gull is a common species with a wide distribution in the Southern Hemisphere. In this study, we used mitochondrial and nuclear markers to examine the genetic variability of Kelp Gull populations on the Brazilian coast and compared this variability with that of sub-Antarctic island populations of this species. Kelp Gulls showed extremely low genetic variability for mitochondrial markers (cytb and ATPase and high diversity for a nuclear locus (intron 7 of the β-fibrinogen. The intraspecific evolutionary history of Kelp Gulls showed that the variability found in intron 7 of the β-fibrinogen gene was compatible with the variability expected under neutral evolution but suggested an increase in population size during the last 10,000 years. However, none of the markers revealed evidence of a bottleneck population. These findings indicate that the recent origin of Kelp Gulls is the main explanation for their nuclear diversity, although selective pressure on the mtDNA of this species cannot be discarded.

  6. Gene encoding erythrocyte binding ligand linked to blood stage multiplication rate phenotype in Plasmodium yoelii yoelii.

    Science.gov (United States)

    Pattaradilokrat, Sittiporn; Culleton, Richard L; Cheesman, Sandra J; Carter, Richard

    2009-04-28

    Variation in the multiplication rate of blood stage malaria parasites is often positively correlated with the severity of the disease they cause. The rodent malaria parasite Plasmodium yoelii yoelii has strains with marked differences in multiplication rate and pathogenicity in the blood. We have used genetic analysis by linkage group selection (LGS) to identify genes that determine differences in multiplication rate. Genetic crosses were generated between genetically unrelated, fast- (17XYM) and slowly multiplying (33XC) clones of P. y. yoelii. The uncloned progenies of these crosses were placed under multiplication rate selection in blood infections in mice. The selected progenies were screened for reduction in intensity of quantitative genetic markers of the slowly multiplying parent. A small number of strongly selected markers formed a linkage group on P. y. yoelii chromosome 13. Of these, that most strongly selected marked the gene encoding the P. yoelii erythrocyte binding ligand (pyebl), which has been independently identified by Otsuki and colleagues [Otsuki H, et al. (2009) Proc Natl Acad Sci USA 106:10.1073/pnas.0811313106] as a major determinant of virulence in these parasites. In an analysis of a previous genetic cross in P. y. yoelii, pyebl alleles of fast- and slowly multiplying parents segregated with the fast and slow multiplication rate phenotype in the cloned recombinant progeny, implying the involvement of the pyebl locus in determining the multiplication rate. Our genome-wide LGS analysis also indicated effects of at least 1 other locus on multiplication rate, as did the findings of Otsuki and colleagues on virulence in P. y. yoelii.

  7. Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival.

    Science.gov (United States)

    Sharafeldin, Noha; Slattery, Martha L; Liu, Qi; Franco-Villalobos, Conrado; Caan, Bette J; Potter, John D; Yasui, Yutaka

    2017-09-28

    Characterization of gene-environment interactions (GEIs) in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11), TLR4 (OR = 2.34, 95% CI: 1.38, 3.98), and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78) with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72), TLR4 (OR = 2.10, 95% CI: 1.22, 3.60) and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46) with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92) and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81) with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75) with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73), TLR2 (HR = 9.06, 95% CI: 1.14, 72.11), EGR2 (HR = 2.45, 95% CI: 1.42, 4.22), and EGFR (HR = 6.33, 95% CI: 1.95, 20.54) with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes.

  8. Multiple Gene-Environment Interactions on the Angiogenesis Gene-Pathway Impact Rectal Cancer Risk and Survival

    Directory of Open Access Journals (Sweden)

    Noha Sharafeldin

    2017-09-01

    Full Text Available Characterization of gene-environment interactions (GEIs in cancer is limited. We aimed at identifying GEIs in rectal cancer focusing on a relevant biologic process involving the angiogenesis pathway and relevant environmental exposures: cigarette smoking, alcohol consumption, and animal protein intake. We analyzed data from 747 rectal cancer cases and 956 controls from the Diet, Activity and Lifestyle as a Risk Factor for Rectal Cancer study. We applied a 3-step analysis approach: first, we searched for interactions among single nucleotide polymorphisms on the pathway genes; second, we searched for interactions among the genes, both steps using Logic regression; third, we examined the GEIs significant at the 5% level using logistic regression for cancer risk and Cox proportional hazards models for survival. Permutation-based test was used for multiple testing adjustment. We identified 8 significant GEIs associated with risk among 6 genes adjusting for multiple testing: TNF (OR = 1.85, 95% CI: 1.10, 3.11, TLR4 (OR = 2.34, 95% CI: 1.38, 3.98, and EGR2 (OR = 2.23, 95% CI: 1.04, 4.78 with smoking; IGF1R (OR = 1.69, 95% CI: 1.04, 2.72, TLR4 (OR = 2.10, 95% CI: 1.22, 3.60 and EGR2 (OR = 2.12, 95% CI: 1.01, 4.46 with alcohol; and PDGFB (OR = 1.75, 95% CI: 1.04, 2.92 and MMP1 (OR = 2.44, 95% CI: 1.24, 4.81 with protein. Five GEIs were associated with survival at the 5% significance level but not after multiple testing adjustment: CXCR1 (HR = 2.06, 95% CI: 1.13, 3.75 with smoking; and KDR (HR = 4.36, 95% CI: 1.62, 11.73, TLR2 (HR = 9.06, 95% CI: 1.14, 72.11, EGR2 (HR = 2.45, 95% CI: 1.42, 4.22, and EGFR (HR = 6.33, 95% CI: 1.95, 20.54 with protein. GEIs between angiogenesis genes and smoking, alcohol, and animal protein impact rectal cancer risk. Our results support the importance of considering the biologic hypothesis to characterize GEIs associated with cancer outcomes.

  9. Locating disease genes using Bayesian variable selection with the Haseman-Elston method

    Directory of Open Access Journals (Sweden)

    He Qimei

    2003-12-01

    Full Text Available Abstract Background We applied stochastic search variable selection (SSVS, a Bayesian model selection method, to the simulated data of Genetic Analysis Workshop 13. We used SSVS with the revisited Haseman-Elston method to find the markers linked to the loci determining change in cholesterol over time. To study gene-gene interaction (epistasis and gene-environment interaction, we adopted prior structures, which incorporate the relationship among the predictors. This allows SSVS to search in the model space more efficiently and avoid the less likely models. Results In applying SSVS, instead of looking at the posterior distribution of each of the candidate models, which is sensitive to the setting of the prior, we ranked the candidate variables (markers according to their marginal posterior probability, which was shown to be more robust to the prior. Compared with traditional methods that consider one marker at a time, our method considers all markers simultaneously and obtains more favorable results. Conclusions We showed that SSVS is a powerful method for identifying linked markers using the Haseman-Elston method, even for weak effects. SSVS is very effective because it does a smart search over the entire model space.

  10. Hierarchical probabilistic models for multiple gene/variant associations based on next-generation sequencing data

    OpenAIRE

    Vavoulis, Dimitrios V.; Taylor, Jenny C.; Schuh, Anna

    2017-01-01

    Abstract Motivation The identification of genetic variants influencing gene expression (known as expression quantitative trait loci or eQTLs) is important in unravelling the genetic basis of complex traits. Detecting multiple eQTLs simultaneously in a population based on paired DNA-seq and RNA-seq assays employs two competing types of models: models which rely on appropriate transformations of RNA-seq data (and are powered by a mature mathematical theory), or count-based models, which represe...

  11. Using multiple biomarkers and determinants to obtain a better measurement of oxidative stress: a latent variable structural equation model approach.

    Science.gov (United States)

    Eldridge, Ronald C; Flanders, W Dana; Bostick, Roberd M; Fedirko, Veronika; Gross, Myron; Thyagarajan, Bharat; Goodman, Michael

    2017-09-01

    Since oxidative stress involves a variety of cellular changes, no single biomarker can serve as a complete measure of this complex biological process. The analytic technique of structural equation modeling (SEM) provides a possible solution to this problem by modelling a latent (unobserved) variable constructed from the covariance of multiple biomarkers. Using three pooled datasets, we modelled a latent oxidative stress variable from five biomarkers related to oxidative stress: F 2 -isoprostanes (FIP), fluorescent oxidation products, mitochondrial DNA copy number, γ-tocopherol (Gtoc) and C-reactive protein (CRP, an inflammation marker closely linked to oxidative stress). We validated the latent variable by assessing its relation to pro- and anti-oxidant exposures. FIP, Gtoc and CRP characterized the latent oxidative stress variable. Obesity, smoking, aspirin use and β-carotene were statistically significantly associated with oxidative stress in the theorized directions; the same exposures were weakly and inconsistently associated with the individual biomarkers. Our results suggest that using SEM with latent variables decreases the biomarker-specific variability, and may produce a better measure of oxidative stress than do single variables. This methodology can be applied to similar areas of research in which a single biomarker is not sufficient to fully describe a complex biological phenomenon.

  12. An evolvable oestrogen receptor activity sensor: development of a modular system for integrating multiple genes into the yeast genome

    NARCIS (Netherlands)

    Fox, J.E.; Bridgham, J.T.; Bovee, T.F.H.; Thornton, J.W.

    2007-01-01

    To study a gene interaction network, we developed a gene-targeting strategy that allows efficient and stable genomic integration of multiple genetic constructs at distinct target loci in the yeast genome. This gene-targeting strategy uses a modular plasmid with a recyclable selectable marker and a

  13. SATB1 tethers multiple gene loci to reprogram expression profiledriving breast cancer metastasis

    Energy Technology Data Exchange (ETDEWEB)

    Han, Hye-Jung; Kohwi, Yoshinori; Kohwi-Shigematsu, Terumi

    2006-07-13

    Global changes in gene expression occur during tumor progression, as indicated by expression profiling of metastatic tumors. How this occurs is poorly understood. SATB1 functions as a genome organizer by folding chromatin via tethering multiple genomic loci and recruiting chromatin remodeling enzymes to regulate chromatin structure and expression of a large number of genes. Here we show that SATB1 is expressed at high levels in aggressive breast cancer cells, and is undetectable in non-malignant breast epithelial cells. Importantly, RNAi-mediated removal of SATB1 from highly-aggressive MDA-MB-231 cells altered the expression levels of over 1200 genes, restored breast-like acinar polarity in three-dimensional cultures, and prevented the metastastic phenotype in vivo. Conversely, overexpression of SATB1 in the less-aggressive breast cancer cell line Hs578T altered the gene expression profile and increased metastasis dramatically in vivo. Thus, SATB1 is a global regulator of gene expression in breast cancer cells, directly regulating crucial metastasis-associated genes, including ERRB2 (HER2/NEU), TGF-{beta}1, matrix metalloproteinase 3, and metastasin. The identification of SATB1 as a protein that re-programs chromatin organization and transcription profiles to promote breast cancer metastasis suggests a new model for metastasis and may provide means of therapeutic intervention.

  14. Multiple sclerosis is accompanied by lack of KIR2DS1 gene: A meta-analysis

    Directory of Open Access Journals (Sweden)

    Farhad Shahsavar

    2016-12-01

    Full Text Available Multiple sclerosis (MS is a disease in which we can recognize destruction of the myelin that is around nerve cells of brain and spinal cord called as oligodendrocytes. Both genetic and environmental factors play roles in MS. One of these genes is the killer-cell immunoglobulin-like receptor (KIR which expressed on surface of natural killer cells (NKs. These genes have loci (not locus in human genome, so they inherit as haplotypes. The results of previous studies show that different genes of KIR may affect both susceptibility and resistance to such autoimmune disorders that their pathogenesis in MS is still unclear. Since NKs play key roles in immune tolerance, we intend to perform a meta-analysis for the correlation of KIR genes and MS. We used the software comprehensive meta-analysis for data of totally 568 MS patients and 280 controls. Among the 14 genes of KIR in the human genome, lack of KIR2DS1 is accompanied by MS. No KIR gene found to be a risk factor for MS. Further studies on other molecules of NKs like CD94 and NKG2a is suggested.

  15. Permethrin induction of multiple cytochrome P450 genes in insecticide resistant mosquitoes, Culex quinquefasciatus.

    Science.gov (United States)

    Gong, Youhui; Li, Ting; Zhang, Lee; Gao, Xiwu; Liu, Nannan

    2013-01-01

    The expression of some insect P450 genes can be induced by both exogenous and endogenous compounds and there is evidence to suggest that multiple constitutively overexpressed P450 genes are co-responsible for the development of resistance to permethrin in resistant mosquitoes. This study characterized the permethrin induction profiles of P450 genes known to be constitutively overexpressed in resistant mosquitoes, Culex quinquefasciatus. The gene expression in 7 of the 19 P450 genes CYP325K3v1, CYP4D42v2, CYP9J45, (CYP) CPIJ000926, CYP325G4, CYP4C38, CYP4H40 in the HAmCqG8 strain, increased more than 2-fold after exposure to permethrin at an LC50 concentration (10 ppm) compared to their acetone treated counterpart; no significant differences in the expression of these P450 genes in susceptible S-Lab mosquitoes were observed after permethrin treatment. Eleven of the fourteen P450 genes overexpressed in the MAmCqG6 strain, CYP9M10, CYP6Z12, CYP9J33, CYP9J43, CYP9J34, CYP306A1, CYP6Z15, CYP9J45, CYPPAL1, CYP4C52v1, CYP9J39, were also induced more than doubled after exposure to an LC50 (0.7 ppm) dose of permethrin. No significant induction in P450 gene expression was observed in the susceptible S-Lab mosquitoes after permethrin treatment except for CYP6Z15 and CYP9J39, suggesting that permethrin induction of these two P450 genes are common to both susceptible and resistant mosquitoes while the induction of the others are specific to insecticide resistant mosquitoes. These results demonstrate that multiple P450 genes are co-up-regulated in insecticide resistant mosquitoes through both constitutive overexpression and induction mechanisms, providing additional support for their involvement in the detoxification of insecticides and the development of insecticide resistance.

  16. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes...... regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster...... of chemokine genes. Further, we show differential expression of Ccl2, Ccl11 and Ccl11 during EAE in rat strains with opposite susceptibility to EAE, regulated by genotype in Eae18b. The human homologous genes were tested for association to MS in 3841 cases and 4046 controls from four Nordic countries...

  17. A non-inheritable maternal Cas9-based multiple-gene editing system in mice.

    Science.gov (United States)

    Sakurai, Takayuki; Kamiyoshi, Akiko; Kawate, Hisaka; Mori, Chie; Watanabe, Satoshi; Tanaka, Megumu; Uetake, Ryuichi; Sato, Masahiro; Shindo, Takayuki

    2016-01-28

    The CRISPR/Cas9 system is capable of editing multiple genes through one-step zygote injection. The preexisting method is largely based on the co-injection of Cas9 DNA (or mRNA) and guide RNAs (gRNAs); however, it is unclear how many genes can be simultaneously edited by this method, and a reliable means to generate transgenic (Tg) animals with multiple gene editing has yet to be developed. Here, we employed non-inheritable maternal Cas9 (maCas9) protein derived from Tg mice with systemic Cas9 overexpression (Cas9 mice). The maCas9 protein in zygotes derived from mating or in vitro fertilization of Tg/+ oocytes and +/+ sperm could successfully edit the target genome. The efficiency of such maCas9-based genome editing was comparable to that of zygote microinjection-based genome editing widely used at present. Furthermore, we demonstrated a novel approach to create "Cas9 transgene-free" gene-modified mice using non-Tg (+/+) zygotes carrying maCas9. The maCas9 protein in mouse zygotes edited nine target loci simultaneously after injection with nine different gRNAs alone. Cas9 mouse-derived zygotes have the potential to facilitate the creation of genetically modified animals carrying the Cas9 transgene, enabling repeatable genome engineering and the production of Cas9 transgene-free mice.

  18. CD1 gene polymorphisms and phenotypic variability in X-linked adrenoleukodystrophy.

    Directory of Open Access Journals (Sweden)

    Mathieu Barbier

    Full Text Available X-linked adrenoleukodystrophy (X-ALD is characterized by marked phenotypic variation ranging from adrenomyeloneuropathy (AMN to childhood cerebral ALD (CCALD. X-ALD is caused by mutations in the ABCD1 gene, but no genotype-phenotype correlation has been established so far and modifier gene variants are suspected to modulate phenotypes. Specific classes of lipids, enriched in very long-chain fatty acids that accumulate in plasma and tissues from X-ALD patients are suspected to be involved in the neuroinflammatory process of CCALD. CD1 proteins are lipid- antigen presenting molecules encoded by five CD1 genes in human (CD1A-E. Association studies with 23 tag SNPs covering the CD1 locus was performed in 52 patients with AMN and 87 patients with CCALD. The minor allele of rs973742 located 4-kb downstream from CD1D was significantly more frequent in AMN patients (χ² = 7.6; P = 0.006. However, this association was no longer significant after Bonferroni correction for multiple testing. The other polymorphisms of the CD1 locus did not reveal significant association. Further analysis of other CD1D polymorphisms did not detect stronger association with X-ALD phenotypes. Although the association with rs973742 warrants further investigations, these results indicate that the genetic variants of CD1 genes do not contribute markedly to the phenotypic variance of X-ALD.

  19. Re-expression of an inactivated variable surface glycoprotein gene in Trypanosoma equiperdum.

    Science.gov (United States)

    Buck, G A; Jacquemot, C; Baltz, T; Eisen, H

    1984-12-01

    Variable surface glycoprotein (VSG) genes in African trypanosomes are often activated by the duplicative transposition of a silent basic copy (BC) gene into an unlinked telomerically located expression site, producing an active expression-linked copy (ELC) of that gene. However, some BC genes that are already linked to a telomere are activated without apparent duplication or transposition. We have recently shown that an active VSG ELC can be inactivated in situ, apparently without rearrangement. To explain these observations it has been suggested that VSG genes that are associated with chromosome telomeres are activated by chromosome end exchanges that occur at a considerable distance upstream from the genes themselves and place them cis to a unique VSG expression element. In an attempt to test this model we derived five VSG-1 expressing variants from BoTat-2, a VSG-2 expressing variant of Trypanosoma equiperdum which carries an inactive residual VSG-1 ELC (R-ELC) as well as the active VSG-2 ELC near unlinked chromosome telomeres. We examined the fates of the VSG-2 ELC and the VSG-1 R-ELC in these variants. All five had maintained the VSG-1 R-ELC; three in a reactivated form and two in an inactive state. The latter two variants carried new, active VSG-1 ELCs: one in the site that had previously contained the VSG-2 ELC and one in a previously unidentified site. The VSG-2 ELC was lost in all five of the variants. The results are not consistent with the simple chromosome end exchange model, which predicts that the VSG-2 ELC would be inactivated but not deleted when the VSG-1 R-ELC was reactivated.

  20. C/EBPβ Mediates Growth Hormone-Regulated Expression of Multiple Target Genes

    Science.gov (United States)

    Cui, Tracy X.; Lin, Grace; LaPensee, Christopher R.; Calinescu, Anda-Alexandra; Rathore, Maanjot; Streeter, Cale; Piwien-Pilipuk, Graciela; Lanning, Nathan; Jin, Hui; Carter-Su, Christin; Qin, Zhaohui S.

    2011-01-01

    Regulation of c-Fos transcription by GH is mediated by CCAAT/enhancer binding protein β (C/EBPβ). This study examines the role of C/EBPβ in mediating GH activation of other early response genes, including Cyr61, Btg2, Socs3, Zfp36, and Socs1. C/EBPβ depletion using short hairpin RNA impaired responsiveness of these genes to GH, as seen for c-Fos. Rescue with wild-type C/EBPβ led to GH-dependent recruitment of the coactivator p300 to the c-Fos promoter. In contrast, rescue with C/EBPβ mutated at the ERK phosphorylation site at T188 failed to induce GH-dependent recruitment of p300, indicating that ERK-mediated phosphorylation of C/EBPβ at T188 is required for GH-induced recruitment of p300 to c-Fos. GH also induced the occupancy of phosphorylated C/EBPβ and p300 on Cyr61, Btg2, and Socs3 at predicted C/EBP-cAMP response element-binding protein motifs in their promoters. Consistent with a role for ERKs in GH-induced expression of these genes, treatment with U0126 to block ERK phosphorylation inhibited their GH-induced expression. In contrast, GH-dependent expression of Zfp36 and Socs1 was not inhibited by U0126. Thus, induction of multiple early response genes by GH in 3T3-F442A cells is mediated by C/EBPβ. A subset of these genes is regulated similarly to c-Fos, through a mechanism involving GH-stimulated ERK 1/2 activation, phosphorylation of C/EBPβ, and recruitment of p300. Overall, these studies suggest that C/EBPβ, like the signal transducer and activator of transcription proteins, regulates multiple genes in response to GH. PMID:21292824

  1. Complex regulation and multiple developmental functions of misfire, the Drosophila melanogaster ferlin gene

    Directory of Open Access Journals (Sweden)

    Wakimoto Barbara T

    2007-03-01

    Full Text Available Abstract Background Ferlins are membrane proteins with multiple C2 domains and proposed functions in Ca2+ mediated membrane-membrane interactions in animals. Caenorhabditis elegans has two ferlin genes, one of which is required for sperm function. Mammals have several ferlin genes and mutations in the human dysferlin (DYSF and otoferlin (OTOF genes result in muscular dystrophy and hearing loss, respectively. Drosophila melanogaster has a single ferlin gene called misfire (mfr. A previous study showed that a mfr mutation caused male sterility because of defects in fertilization. Here we analyze the expression and structure of the mfr gene and the consequences of multiple mutations to better understand the developmental function of ferlins. Results We show that mfr is expressed in the testis and ovaries of adult flies, has tissue-specific promoters, and expresses alternatively spliced transcripts that are predicted to encode distinct protein isoforms. Studies of 11 male sterile mutations indicate that a predicted Mfr testis isoform with five C2 domains and a transmembrane (TM domain is required for sperm plasma membrane breakdown (PMBD and completion of sperm activation during fertilization. We demonstrate that Mfr is not required for localization of Sneaky, another membrane protein necessary for PMBD. The mfr mutations vary in their effects in females, with a subset disrupting egg patterning and causing a maternal effect delay in early embryonic development. Locations of these mutations indicate that a short Mfr protein isoform carries out ferlin activities during oogenesis. Conclusion The mfr gene exhibits complex transcriptional and post-transcriptional regulation and functions in three developmental processes: sperm activation, egg patterning, and early embryogenesis. These functions are in part due to the production of protein isoforms that vary in the number of C2 domains. These findings help establish D. melanogaster as model system for

  2. CRISPR/Cas9 gene drives in genetically variable and nonrandomly mating wild populations.

    Science.gov (United States)

    Drury, Douglas W; Dapper, Amy L; Siniard, Dylan J; Zentner, Gabriel E; Wade, Michael J

    2017-05-01

    Synthetic gene drives based on CRISPR/Cas9 have the potential to control, alter, or suppress populations of crop pests and disease vectors, but it is unclear how they will function in wild populations. Using genetic data from four populations of the flour beetle Tribolium castaneum, we show that most populations harbor genetic variants in Cas9 target sites, some of which would render them immune to drive (ITD). We show that even a rare ITD allele can reduce or eliminate the efficacy of a CRISPR/Cas9-based synthetic gene drive. This effect is equivalent to and accentuated by mild inbreeding, which is a characteristic of many disease-vectoring arthropods. We conclude that designing such drives will require characterization of genetic variability and the mating system within and among targeted populations.

  3. Modeling suggests that gene circuit architecture controls phenotypic variability in a bacterial persistence network.

    Science.gov (United States)

    Koh, Rachel S; Dunlop, Mary J

    2012-05-20

    Bacterial persistence is a non-inherited bet-hedging mechanism where a subpopulation of cells enters a dormant state, allowing those cells to survive environmental stress such as treatment with antibiotics. Persister cells are not mutants; they are formed by natural stochastic variation in gene expression. Understanding how regulatory architecture influences the level of phenotypic variability can help us explain how the frequency of persistence events can be tuned. We present a model of the regulatory network controlling the HipBA toxin-antitoxin system from Escherichia coli. Using a biologically realistic model we first determine that the persistence phenotype is not the result of bistability within the network. Next, we develop a stochastic model and show that cells can enter persistence due to random fluctuations in transcription, translation, degradation, and complex formation. We then examine alternative gene circuit architectures for controlling hipBA expression and show that networks with more noise (more persisters) and less noise (fewer persisters) are straightforward to achieve. Thus, we propose that the gene circuit architecture can be used to tune the frequency of persistence, a trait that can be selected for by evolution. We develop deterministic and stochastic models describing how the regulation of toxin and antitoxin expression influences phenotypic variation within a population. Persistence events are the result of stochastic fluctuations in toxin levels that cross a threshold, and their frequency is controlled by the regulatory topology governing gene expression.

  4. Modeling suggests that gene circuit architecture controls phenotypic variability in a bacterial persistence network

    Directory of Open Access Journals (Sweden)

    Koh Rachel S

    2012-05-01

    Full Text Available Abstract Background Bacterial persistence is a non-inherited bet-hedging mechanism where a subpopulation of cells enters a dormant state, allowing those cells to survive environmental stress such as treatment with antibiotics. Persister cells are not mutants; they are formed by natural stochastic variation in gene expression. Understanding how regulatory architecture influences the level of phenotypic variability can help us explain how the frequency of persistence events can be tuned. Results We present a model of the regulatory network controlling the HipBA toxin-antitoxin system from Escherichia coli. Using a biologically realistic model we first determine that the persistence phenotype is not the result of bistability within the network. Next, we develop a stochastic model and show that cells can enter persistence due to random fluctuations in transcription, translation, degradation, and complex formation. We then examine alternative gene circuit architectures for controlling hipBA expression and show that networks with more noise (more persisters and less noise (fewer persisters are straightforward to achieve. Thus, we propose that the gene circuit architecture can be used to tune the frequency of persistence, a trait that can be selected for by evolution. Conclusions We develop deterministic and stochastic models describing how the regulation of toxin and antitoxin expression influences phenotypic variation within a population. Persistence events are the result of stochastic fluctuations in toxin levels that cross a threshold, and their frequency is controlled by the regulatory topology governing gene expression.

  5. The variability of bx1 DIMBOA biosynthesis gene in maize inbred lines

    Directory of Open Access Journals (Sweden)

    Mikić Sanja

    2016-01-01

    Full Text Available 2,4-dihydroxy-7-methoxy-1,4-benzoxazin-3-one (DIMBOA is a secondary metabolite in plants that renders defense against phytopatogenic bacteria, fungi, insects and other pest organisms. The biosynthesis of DIMBOA is controlled by nine genes, the first bx1 gene governs the transcription of a key enzyme in DIMBOA biosynthesis. The aim of this study was to genotype maize inbred lines used in breeding programmes for the presence of resistant allele in order to identify the source of biotic stress resistance. The variability of bx1 gene was assessed in a set of 96 diverse inbred lines with a functional microsatellite marker umc1022 located in bx1 gene. Two marker alleles, the length of 91 and 97 bp, were found in the majority of inbred lines, the former being predominant among Lancaster inbred lines and the latter in the BSSS heterotic group. By comparing previous findings on the inbred lines with high level of DIMBOA and resistance with the pedigree information of the maize inbred lines analyzed in this study, we postulated that the allele 91 bp could be associate with DIMBOA accumulation and pest resistance. The DIMBOA quantification and evaluation of pest infestations in field trials are needed to verify our results.

  6. Common variable immune deficiency with mutated TNFSRF13B gene presenting with autoimmune hematologic manifestations

    Directory of Open Access Journals (Sweden)

    Elpis Mantadakis

    2016-10-01

    Full Text Available Patients with common variable immunodeficiency (CVID develop autoimmune hematologic manifestations. We report a 14-year-old boy with Evans syndrome, who presented at the age of 11.5 years with autoimmune hemolysis and was successfully managed with corticosteroids. Initially, the serum immunoglobulins were within the low-normal range for age, but two years after presentation he definitely fulfilled the diagnostic criteria for CVID, despite a negative history for serious infections. DNA sequencing by PCR of the TNFSRF13B gene that encodes the TACI receptor disclosed the heterozygous mutation C104R that is found in approximately 10–15% of patients with CVID. Common variable immunodeficiency should be considered in the differential diagnosis of autoimmune hematologic manifestations, since its timely diagnosis may considerably affect clinical management and patient outcome.

  7. Autologous haematopoietic stem cell transplantation reduces abnormalities in the expression of immune genes in multiple sclerosis.

    Science.gov (United States)

    de Paula A Sousa, Alessandra; Malmegrim, Kelen C R; Panepucci, Rodrigo A; Brum, Doralina S; Barreira, Amilton A; Carlos Dos Santos, Antonio; Araújo, Amélia G; Covas, Dimas Tadeu; Oliveira, Maria C; Moraes, Daniela A; Pieroni, Fabiano; Barros, George M; Simões, Belinda P; Nicholas, Richard; Burt, Richard K; Voltarelli, Júlio C; Muraro, Paolo A

    2015-01-01

    Autologous haematopoietic stem-cell transplantation (AHSCT) has been experimented as a treatment in patients affected by severe forms of multiple sclerosis (MS) who failed to respond to standard immunotherapy. The rationale of AHSCT is to 'reboot' the immune system and reconstitute a new adaptive immunity. The aim of our study was to identify, through a robust and unbiased transcriptomic analysis, any changes of gene expression in T-cells potentially underlying the treatment effect in patients who underwent non-myeloablative AHSCT for treatment of MS. We evaluated by microarray DNA-chip technology the gene expression of peripheral CD4+ and CD8+ T-cell subsets sorted from patients with MS patients before AHSCT, at 6 months, 1 year and 2 years after AHSCT and from healthy control subjects. Hierarchical clustering analysis revealed that reconstituted CD8+ T-cells of MS patients at 2 years post-transplantation, aggregated together with healthy controls, suggesting a normalization of gene expression in CD8+ cells post-therapy. When we compared the gene expression in MS patients before and after therapy, we detected a large number of differentially expressed genes (DEG) in both CD8+ and CD4+ T-cell subsets at all time points after transplantation. We catalogued the biological function of DEG and we selected 27 genes known to be involved in immune function for accurate quantification of gene expression by real-time PCR. The analysis confirmed and extended with quantitative data, a number of significant changes in both the CD4+ and CD8+ T-cells subsets from MS post-transplant. Notably, CD8+ T-cells revealed more extensive changes in the expression of genes involved in effector immune responses.

  8. GENIE: a software package for gene-gene interaction analysis in genetic association studies using multiple GPU or CPU cores.

    Science.gov (United States)

    Chikkagoudar, Satish; Wang, Kai; Li, Mingyao

    2011-05-26

    Gene-gene interaction in genetic association studies is computationally intensive when a large number of SNPs are involved. Most of the latest Central Processing Units (CPUs) have multiple cores, whereas Graphics Processing Units (GPUs) also have hundreds of cores and have been recently used to implement faster scientific software. However, currently there are no genetic analysis software packages that allow users to fully utilize the computing power of these multi-core devices for genetic interaction analysis for binary traits. Here we present a novel software package GENIE, which utilizes the power of multiple GPU or CPU processor cores to parallelize the interaction analysis. GENIE reads an entire genetic association study dataset into memory and partitions the dataset into fragments with non-overlapping sets of SNPs. For each fragment, GENIE analyzes: 1) the interaction of SNPs within it in parallel, and 2) the interaction between the SNPs of the current fragment and other fragments in parallel. We tested GENIE on a large-scale candidate gene study on high-density lipoprotein cholesterol. Using an NVIDIA Tesla C1060 graphics card, the GPU mode of GENIE achieves a speedup of 27 times over its single-core CPU mode run. GENIE is open-source, economical, user-friendly, and scalable. Since the computing power and memory capacity of graphics cards are increasing rapidly while their cost is going down, we anticipate that GENIE will achieve greater speedups with faster GPU cards. Documentation, source code, and precompiled binaries can be downloaded from http://www.cceb.upenn.edu/~mli/software/GENIE/.

  9. Implications of climate variability for the detection of multiple equilibria and for rapid transitions in the atmosphere-vegetation system

    Energy Technology Data Exchange (ETDEWEB)

    Bathiany, S. [Max Planck Institute for Meteorology, Hamburg (Germany); Claussen, M. [Max Planck Institute for Meteorology, Hamburg (Germany); Universitaet Hamburg, Meteorologisches Institut, Hamburg (Germany); Fraedrich, K. [Universitaet Hamburg, Meteorologisches Institut, Hamburg (Germany)

    2012-05-15

    Paleoclimatic records indicate a decline of vegetation cover in the Western Sahara at the end of the African Humid Period (about 5,500 years before present). Modelling studies have shown that this phenomenon may be interpreted as a critical transition that results from a bifurcation in the atmosphere-vegetation system. However, the stability properties of this system are closely linked to climate variability and depend on the climate model and the methods of analysis. By coupling the Planet Simulator (PlaSim), an atmosphere model of intermediate complexity, with the simple dynamic vegetation model VECODE, we assess previous methods for the detection of multiple equilibria, and demonstrate their limitations. In particular, a stability diagram can yield misleading results because of spatial interactions, and the system's steady state and its dependency on initial conditions are affected by atmospheric variability and nonlinearities. In addition, we analyse the implications of climate variability for the abruptness of a vegetation decline. We find that a vegetation collapse can happen at different locations at different times. These collapses are possible despite large and uncorrelated climate variability. Because of the nonlinear relation between vegetation dynamics and precipitation the green state is initially stabilised by the high variability. When precipitation falls below a critical threshold, the desert state is stabilised as variability is then also decreased. (orig.)

  10. FCERI and Histamine Metabolism Gene Variability in Selective Responders to NSAIDS.

    Science.gov (United States)

    Amo, Gemma; Cornejo-García, José A; García-Menaya, Jesus M; Cordobes, Concepcion; Torres, M J; Esguevillas, Gara; Mayorga, Cristobalina; Martinez, Carmen; Blanca-Lopez, Natalia; Canto, Gabriela; Ramos, Alfonso; Blanca, Miguel; Agúndez, José A G; García-Martín, Elena

    2016-01-01

    The high-affinity IgE receptor (Fcε RI) is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ, and Fcε RIγ (αβγ2) encoded by three genes designated as FCER1A, FCER1B (MS4A2), and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated) non-steroidal anti-inflammatory (NSAID) hypersensitivity. From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA), propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone, or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837, and rs2251746; FCER1B rs1441586, rs569108, and rs512555; FCER1G rs11587213, rs2070901, and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742, and rs1049793 in the HDC, HNMT, and DAO genes. No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug, or clinical presentation) were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG

  11. FCERI AND HISTAMINE METABOLISM GENE VARIABILITY IN SELECTIVE RESPONDERS TO NSAIDS

    Directory of Open Access Journals (Sweden)

    Gemma Amo

    2016-09-01

    Full Text Available The high-affinity IgE receptor (Fcε RI is a heterotetramer of three subunits: Fcε RIα, Fcε RIβ and Fcε RIγ (αβγ2 encoded by three genes designated as FCER1A, FCER1B (MS4A2 and FCER1G, respectively. Recent evidence points to FCERI gene variability as a relevant factor in the risk of developing allergic diseases. Because Fcε RI plays a key role in the events downstream of the triggering factors in immunological response, we hypothesized that FCERI gene variants might be related with the risk of, or with the clinical response to, selective (IgE mediated non-steroidal anti-inflammatory (NSAID hypersensitivity.From a cohort of 314 patients suffering from selective hypersensitivity to metamizole, ibuprofen, diclofenac, paracetamol, acetylsalicylic acid (ASA, propifenazone, naproxen, ketoprofen, dexketoprofen, etofenamate, aceclofenac, etoricoxib, dexibuprofen, indomethacin, oxyphenylbutazone or piroxicam, and 585 unrelated healthy controls that tolerated these NSAIDs, we analyzed the putative effects of the FCERI SNPs FCER1A rs2494262, rs2427837 and rs2251746; FCER1B rs1441586, rs569108 and rs512555; FCER1G rs11587213, rs2070901 and rs11421. Furthermore, in order to identify additional genetic markers which might be associated with the risk of developing selective NSAID hypersensitivity, or which may modify the putative association of FCERI gene variations with risk, we analyzed polymorphisms known to affect histamine synthesis or metabolism, such as rs17740607, rs2073440, rs1801105, rs2052129, rs10156191, rs1049742 and rs1049793 in the HDC, HNMT and DAO genes.No major genetic associations with risk or with clinical presentation, and no gene-gene interactions, or gene-phenotype interactions (including age, gender, IgE concentration, antecedents of atopy, culprit drug or clinical presentation were identified in patients. However, logistic regression analyses indicated that the presence of antecedents of atopy and the DAO SNP rs2052129 (GG

  12. Phylogenetic Relationships of Pseudorasbora, Pseudopungtungia, and Pungtungia (Teleostei; Cypriniformes; Gobioninae Inferred from Multiple Nuclear Gene Sequences

    Directory of Open Access Journals (Sweden)

    Keun-Yong Kim

    2013-01-01

    Full Text Available Gobionine species belonging to the genera Pseudorasbora, Pseudopungtungia, and Pungtungia (Teleostei; Cypriniformes; Cyprinidae have been heavily studied because of problems on taxonomy, threats of extinction, invasion, and human health. Nucleotide sequences of three nuclear genes, that is, recombination activating protein gene 1 (rag1, recombination activating gene 2 (rag2, and early growth response 1 gene (egr1, from Pseudorasbora, Pseudopungtungia, and Pungtungia species residing in China, Japan, and Korea, were analyzed to elucidate their intergeneric and interspecific phylogenetic relationships. In the phylogenetic tree inferred from their multiple gene sequences, Pseudorasbora, Pseudopungtungia and Pungtungia species ramified into three phylogenetically distinct clades; the “tenuicorpa” clade composed of Pseudopungtungia tenuicorpa, the “parva” clade composed of all Pseudorasbora species/subspecies, and the “herzi” clade composed of Pseudopungtungia nigra, and Pungtungia herzi. The genus Pseudorasbora was recovered as monophyletic, while the genus Pseudopungtungia was recovered as polyphyletic. Our phylogenetic result implies the unstable taxonomic status of the genus Pseudopungtungia.

  13. Resequencing analysis of the candidate tyrosine kinase and RAS pathway gene families in multiple myeloma.

    Science.gov (United States)

    Hucthagowder, Vishwanathan; Meyer, Rekha; Mullins, Chelsea; Nagarajan, Rakesh; DiPersio, John F; Vij, Ravi; Tomasson, Michael H; Kulkarni, Shashikant

    2012-09-01

    Multiple myeloma (MM) is an incurable, B-cell malignancy characterized by the clonal proliferation and accumulation of malignant plasma cells in bone marrow. Despite recent advances in the understanding of genomic aberrations, a comprehensive catalogue of clinically actionable mutations in MM is just beginning to emerge. The tyrosine kinase (TK) and RAS oncogenes, which encode important regulators of various signaling pathways, are among the most frequently altered gene families in cancer. To clarify the role of TK and RAS genes in the pathogenesis of MM, we performed a systematic, targeted screening of mutations on prioritized RAS and TK genes, in CD138-sorted bone marrow specimens from 42 untreated patients. We identified a total of 24 mutations in the KRAS, PIK3CA, INSR, LTK, and MERTK genes. In particular, seven novel mutations in addition to known KRAS mutations were observed. Prediction analysis tools PolyPhen and Sorting Intolerant from Tolerant (SIFT) were used to assess the functional significance of these novel mutations. Our analysis predicted that these mutations may have a deleterious effect, resulting in the functional alteration of proteins involved in the pathogenesis of myeloma. While further investigation is needed to determine the functional consequences of these proteins, mutational testing of the RAS and TK genes in larger myeloma cohorts might also be useful to establish the recurrent nature of these mutations. Copyright © 2012 Elsevier Inc. All rights reserved.

  14. Four genes predict high risk of progression from smoldering to symptomatic multiple myeloma (SWOG S0120).

    Science.gov (United States)

    Khan, Rashid; Dhodapkar, Madhav; Rosenthal, Adam; Heuck, Christoph; Papanikolaou, Xenofon; Qu, Pingping; van Rhee, Frits; Zangari, Maurizio; Jethava, Yogesh; Epstein, Joshua; Yaccoby, Shmuel; Hoering, Antje; Crowley, John; Petty, Nathan; Bailey, Clyde; Morgan, Gareth; Barlogie, Bart

    2015-09-01

    Multiple myeloma is preceded by an asymptomatic phase, comprising monoclonal gammopathy of uncertain significance and smoldering myeloma. Compared to the former, smoldering myeloma has a higher and non-uniform rate of progression to clinical myeloma, reflecting a subset of patients with higher risk. We evaluated the gene expression profile of smoldering myeloma plasma cells among 105 patients enrolled in a prospective observational trial at our institution, with a view to identifying a high-risk signature. Baseline clinical, bone marrow, cytogenetic and radiologic data were evaluated for their potential to predict time to therapy for symptomatic myeloma. A gene signature derived from four genes, at an optimal binary cut-point of 9.28, identified 14 patients (13%) with a 2-year therapy risk of 85.7%. Conversely, a low four-gene score (smoldering myeloma with a 5.0% chance of progression at 2 years. The top 40 probe sets showed concordance with indices of chromosome instability. These data demonstrate high discriminatory power of a gene-based assay and suggest a role for dysregulation of mitotic checkpoints in the context of genomic instability as a hallmark of high-risk smoldering myeloma. Copyright© Ferrata Storti Foundation.

  15. Fractional order Riemann-Liouville integral inclusions with two independent variables and multiple delay

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    Saïd Abbas

    2013-01-01

    Full Text Available In the present paper we investigate the existence of solutions for a system of integral inclusions of fractional order with multiple delay. Our results are obtained upon suitable fixed point theorems, namely the Bohnenblust-Karlin fixed point theorem for the convex case and the Covitz-Nadler for the nonconvex case.

  16. Multiple crown size variables of the upper incisors in patients with supernumerary teeth compared with controls

    NARCIS (Netherlands)

    Khalaf, K.; Smith, R. N.; Elcock, C.; Brook, A. H.

    2009-01-01

    Aims: As part of ongoing studies of the aetiology of dental anomalies the aims of this study were to identify multiple components of tooth size of the upper permanent incisors in 34 patients with supernumerary teeth and to compare them with those in a control group to determine whether the presence

  17. Variable-length coding for short packets over a multiple access channel with feedback

    DEFF Research Database (Denmark)

    Trillingsgaard, Kasper Fløe; Popovski, Petar

    2014-01-01

    We consider a two-user discrete memoryless multiple access channel with a common stop-feedback signal from the receiver to both transmitters. The achievable regions are characterized using joint decoding and successive cancellation decoding and, it is shown that the achievable regions are signifi...

  18. Expression analysis of the Theileria parva subtelomere-encoded variable secreted protein gene family.

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    Jacqueline Schmuckli-Maurer

    Full Text Available The intracellular protozoan parasite Theileria parva transforms bovine lymphocytes inducing uncontrolled proliferation. Proteins released from the parasite are assumed to contribute to phenotypic changes of the host cell and parasite persistence. With 85 members, genes encoding subtelomeric variable secreted proteins (SVSPs form the largest gene family in T. parva. The majority of SVSPs contain predicted signal peptides, suggesting secretion into the host cell cytoplasm.We analysed SVSP expression in T. parva-transformed cell lines established in vitro by infection of T or B lymphocytes with cloned T. parva parasites. Microarray and quantitative real-time PCR analysis revealed mRNA expression for a wide range of SVSP genes. The pattern of mRNA expression was largely defined by the parasite genotype and not by host background or cell type, and found to be relatively stable in vitro over a period of two months. Interestingly, immunofluorescence analysis carried out on cell lines established from a cloned parasite showed that expression of a single SVSP encoded by TP03_0882 is limited to only a small percentage of parasites. Epitope-tagged TP03_0882 expressed in mammalian cells was found to translocate into the nucleus, a process that could be attributed to two different nuclear localisation signals.Our analysis reveals a complex pattern of Theileria SVSP mRNA expression, which depends on the parasite genotype. Whereas in cell lines established from a cloned parasite transcripts can be found corresponding to a wide range of SVSP genes, only a minority of parasites appear to express a particular SVSP protein. The fact that a number of SVSPs contain functional nuclear localisation signals suggests that proteins released from the parasite could contribute to phenotypic changes of the host cell. This initial characterisation will facilitate future studies on the regulation of SVSP gene expression and the potential biological role of these enigmatic

  19. Overexpression of multiple detoxification genes in deltamethrin resistant Laodelphax striatellus (Hemiptera: Delphacidae in China.

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    Lu Xu

    Full Text Available BACKGROUND: The small brown planthopper (SBPH, Laodelphax striatellus (Fallén, is one of the major rice pests in Asia and has developed resistance to multiple classes of insecticides. Understanding resistance mechanisms is essential to the management of this pest. Biochemical and molecular assays were performed in this study to systematically characterize deltamethrin resistance mechanisms with laboratory-selected resistant and susceptible strains of SBPH. METHODOLOGY/PRINCIPAL FINDINGS: Deltamethrin resistant strains of SBPH (JH-del were derived from a field population by continuously selections (up to 30 generations in the laboratory, while a susceptible strain (JHS was obtained from the same population by removing insecticide pressure for 30 generations. The role of detoxification enzymes in the resistance was investigated using synergism and enzyme activity assays with strains of different resistant levels. Furthermore, 71 cytochrome P450, 93 esterases and 12 glutathione-S-transferases cDNAs were cloned based on transcriptome data of a field collected population. Semi-quantitative RT-PCR screening analysis of 176 identified detoxification genes demonstrated that multiple P450 and esterase genes were overexpressed (>2-fold in JH-del strains (G4 and G30 when compared to that in JHS, and the results of quantitative PCR coincided with the semi-quantitative RT-PCR results. Target mutation at IIS3-IIS6 regions encoded by the voltage-gated sodium channel gene was ruled out for conferring the observed resistance. CONCLUSION/SIGNIFICANCE: As the first attempt to discover genes potentially involved in SBPH pyrethroid resistance, this study putatively identified several candidate genes of detoxification enzymes that were significantly overexpressed in the resistant strain, which matched the synergism and enzyme activity testing. The biochemical and molecular evidences suggest that the high level pyrethroid resistance in L. striatellus could be due to

  20. Late multiple organ surge in interferon-regulated target genes characterizes staphylococcal enterotoxin B lethality.

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    Gabriela A Ferreyra

    Full Text Available BACKGROUND: Bacterial superantigens are virulence factors that cause toxic shock syndrome. Here, the genome-wide, temporal response of mice to lethal intranasal staphylococcal enterotoxin B (SEB challenge was investigated in six tissues. RESULTS: The earliest responses and largest number of affected genes occurred in peripheral blood mononuclear cells (PBMC, spleen, and lung tissues with the highest content of both T-cells and monocyte/macrophages, the direct cellular targets of SEB. In contrast, the response of liver, kidney, and heart was delayed and involved fewer genes, but revealed a dominant genetic program that was seen in all 6 tissues. Many of the 85 uniquely annotated transcripts participating in this shared genomic response have not been previously linked to SEB. Nine of the 85 genes were subsequently confirmed by RT-PCR in every tissue/organ at 24 h. These 85 transcripts, up-regulated in all tissues, annotated to the interferon (IFN/antiviral-response and included genes belonging to the DNA/RNA sensing system, DNA damage repair, the immunoproteasome, and the ER/metabolic stress-response and apoptosis pathways. Overall, this shared program was identified as a type I and II interferon (IFN-response and the promoters of these genes were highly enriched for IFN regulatory matrices. Several genes whose secreted products induce the IFN pathway were up-regulated at early time points in PBMCs, spleen, and/or lung. Furthermore, IFN regulatory factors including Irf1, Irf7 and Irf8, and Zbp1, a DNA sensor/transcription factor that can directly elicit an IFN innate immune response, participated in this host-wide SEB signature. CONCLUSION: Global gene-expression changes across multiple organs implicated a host-wide IFN-response in SEB-induced death. Therapies aimed at IFN-associated innate immunity may improve outcome in toxic shock syndromes.

  1. Limited pattern of TCR delta chain gene rearrangement on the RNA level in multiple sclerosis.

    Science.gov (United States)

    Nowak, J; Januszkiewicz, D; Pernak, M; Hertmanowska, H; Nowicka-Kujawska, K; Rembowska, J; Lewandowski, K; Nowak, T; Wender, M

    2001-01-01

    Susceptibility to multiple sclerosis (MS) is most likely affected by a number of genes, including HLA and T-cell receptor (TCR) genes. T cells expressing gamma/delta receptors seem to contribute to autoagression in MS, as evidenced by their localization in the MS plaques in the brain. The aim of this study was to analyse the TCRdelta chain gene rearrangement at the RNA (cDNA) level and compare to the DNA pattern rearrangement. TCRdelta gene rearrangement was analysed in MS patients and healthy individuals with the use of primers specific for Vdelta1-6 and Jdelta1 genes (at the DNA level) and specific for Vdelta1-6 and Cdelta1 genes (at the cDNA level). The size of PCR products was analysed on agarose gel and by ALF-Express (Pharmacia). Additionally, the lymphocyte surface immunophenotype was studied with specific monoclonal antibodies. At the DNA level a restricted pattern of Vdelta3-Jdelta1 and Vdelta5-Jdelta1 was found only in MS patients. Contrary to DNA, mono-, oligoclonal RNA (cDNA) rearrangements were limited to Vdelta1-Cdelta1, Vdelta2-Cdelta1 and Vdelta3-Cdelta1 only in MS patients as well. Surface immunophenotype analysis revealed in MS a much higher frequency of activated gamma/delta T lymphocytes, i.e. expressing HLA-DR and CD25. An elevated level of CD56 positive cells in MS was recorded. Mono-oligoclonal pattern of TCRdelta gene rearrangement at the RNA level, along with increase in activated gamma/delta T cells, strongly argue for a significant role of gamma/delta T lymphocytes in the pathogenesis of MS.

  2. Effect of Interaction between Chromatin Loops on Cell-to-Cell Variability in Gene Expression.

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    Tuoqi Liu

    2016-05-01

    Full Text Available According to recent experimental evidence, the interaction between chromatin loops, which can be characterized by three factors-connection pattern, distance between regulatory elements, and communication form, play an important role in determining the level of cell-to-cell variability in gene expression. These quantitative experiments call for a corresponding modeling effect that addresses the question of how changes in these factors affect variability at the expression level in a systematic rather than case-by-case fashion. Here we make such an effort, based on a mechanic model that maps three fundamental patterns for two interacting DNA loops into a 4-state model of stochastic transcription. We first show that in contrast to side-by-side loops, nested loops enhance mRNA expression and reduce expression noise whereas alternating loops have just opposite effects. Then, we compare effects of facilitated tracking and direct looping on gene expression. We find that the former performs better than the latter in controlling mean expression and in tuning expression noise, but this control or tuning is distance-dependent, remarkable for moderate loop lengths, and there is a limit loop length such that the difference in effect between two communication forms almost disappears. Our analysis and results justify the facilitated chromatin-looping hypothesis.

  3. Variable clinical expression in patients with a germline MEN1 disease gene mutation: clues to a genotype-phenotype correlation

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    Cornelis J. Lips

    2012-01-01

    Full Text Available Multiple endocrine neoplasia type 1 is an inherited endocrine tumor syndrome, predominantly characterized by tumors of the parathyroid glands, gastroenteropancreatic tumors, pituitary adenomas, adrenal adenomas, and neuroendocrine tumors of the thymus, lungs or stomach. Multiple endocrine neoplasia type 1 is caused by germline mutations of the multiple endocrine neoplasia type 1 tumor suppressor gene. The initial germline mutation, loss of the wild-type allele, and modifying genetic and possibly epigenetic and environmental events eventually result in multiple endocrine neoplasia type 1 tumors. Our understanding of the function of the multiple endocrine neoplasia type 1 gene product, menin, has increased significantly over the years. However, to date, no clear genotype-phenotype correlation has been established. In this review we discuss reports on exceptional clinical presentations of multiple endocrine neoplasia type 1, which may provide more insight into the pathogenesis of this disorder and offer clues for a possible genotype-phenotype correlation.

  4. Whole tree xylem sap flow responses to multiple environmental variables in a wet tropical forest

    Science.gov (United States)

    J.J. O' Brien; S.F. Oberbauer; D.B. Clark

    2004-01-01

    In order to quantify and characterize the variance in rain-forest tree physiology, whole tree sap flow responses to local environmental conditions were investigated in 10 species of trees with diverse traits at La Selva Biological Station, Costa Rica. A simple model was developed to predict tree sap flow responses to a synthetic environmental variable generated by a...

  5. Multiple timescales of stochastically forced North Atlantic Ocean variability: A model study

    Science.gov (United States)

    Mecking, Jennifer V.; Keenlyside, Noel S.; Greatbatch, Richard J.

    2015-09-01

    The Atlantic meridional overturning circulation (AMOC) and the subpolar gyre (SPG) are important elements in mechanisms for multidecadal variability in models in the North Atlantic Ocean. In this study, a 2000-year long global ocean model integration forced with the atmospheric patterns associated with a white noise North Atlantic Oscillation (NAO) index is shown to have three distinct timescales of North Atlantic Ocean variability. First, an interannual timescale with variability shorter than 15 years, that can be related to Ekman dynamics. Second, a multidecadal timescale, on the 15- to 65-year range, that is mainly concentrated in the SPG region and is controlled by constructive interference between density anomalies around the gyre and the changing NAO forcing. Finally, the centennial timescales, with variability longer than 65 years, that can be attributed to the ocean being in a series of quasi-equilibrium states. The relationship between the ocean's response and the NAO index differs for each timescale; the 15-year and shorter timescales are directly related to the NAO of the same year, 15- to 65-year timescales are dependent on the NAO index in the last 25-30 years in a sinusoidal sense while the 65-year and longer timescales relate to a sum of the last 50-80 years of the NAO index.

  6. Using Derivative Estimates to Describe Intraindividual Variability at Multiple Time Scales

    Science.gov (United States)

    Deboeck, Pascal R.; Montpetit, Mignon A.; Bergeman, C. S.; Boker, Steven M.

    2009-01-01

    The study of intraindividual variability is central to the study of individuals in psychology. Previous research has related the variance observed in repeated measurements (time series) of individuals to traitlike measures that are logically related. Intraindividual measures, such as intraindividual standard deviation or the coefficient of…

  7. Multiplicity Results for Variable-Coefficient Singular Third-Order Differential Equation with a Parameter

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    Zhibo Cheng

    2014-01-01

    Full Text Available We investigate a class of variable coefficients singular third-order differential equation with superlinearity or sublinearity assumptions at infinity for an appropriately chosen parameter. By applications of Green’s function and the Krasnoselskii fixed point theorem, sufficient conditions for the existence of positive periodic solutions are established.

  8. Nucleotide variability and linkage disequilibrium patterns in the porcine MUC4 gene

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    Yang Ming

    2012-07-01

    Full Text Available Abstract Background MUC4 is a type of membrane anchored glycoprotein and serves as the major constituent of mucus that covers epithelial surfaces of many tissues such as trachea, colon and cervix. MUC4 plays important roles in the lubrication and protection of the surface epithelium, cell proliferation and differentiation, immune response, cell adhesion and cancer development. To gain insights into the evolution of the porcine MUC4 gene, we surveyed the nucleotide variability and linkage disequilibrium (LD within this gene in Chinese indigenous breeds and Western commercial breeds. Results A total of 53 SNPs covering the MUC4 gene were genotyped on 5 wild boars and 307 domestic pigs representing 11 Chinese breeds and 3 Western breeds. The nucleotide variability, haplotype phylogeny and LD extent of MUC4 were analyzed in these breeds. Both Chinese and Western breeds had considerable nucleotide diversity at the MUC4 locus. Western pig breeds like Duroc and Large White have comparable nucleotide diversity as many of Chinese breeds, thus artificial selection for lean pork production have not reduced the genetic variability of MUC4 in Western commercial breeds. Haplotype phylogeny analyses indicated that MUC4 had evolved divergently in Chinese and Western pigs. The dendrogram of genetic differentiation between breeds generally reflected demographic history and geographical distribution of these breeds. LD patterns were unexpectedly similar between Chinese and Western breeds, in which LD usually extended less than 20 kb. This is different from the presumed high LD extent (more than 100 kb in Western commercial breeds. The significant positive Tajima’D, and Fu and Li’s D statistics in a few Chinese and Western breeds implied that MUC4 might undergo balancing selection in domestic breeds. Nevertheless, we cautioned that the significant statistics could be upward biased by SNP ascertainment process. Conclusions Chinese and Western breeds have

  9. Handling multiple testing while interpreting microarrays with the Gene Ontology Database

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    Zhao Hongyu

    2004-09-01

    Full Text Available Abstract Background The development of software tools that analyze microarray data in the context of genetic knowledgebases is being pursued by multiple research groups using different methods. A common problem for many of these tools is how to correct for multiple statistical testing since simple corrections are overly conservative and more sophisticated corrections are currently impractical. A careful study of the nature of the distribution one would expect by chance, such as by a simulation study, may be able to guide the development of an appropriate correction that is not overly time consuming computationally. Results We present the results from a preliminary study of the distribution one would expect for analyzing sets of genes extracted from Drosophila, S. cerevisiae, Wormbase, and Gramene databases using the Gene Ontology Database. Conclusions We found that the estimated distribution is not regular and is not predictable outside of a particular set of genes. Permutation-based simulations may be necessary to determine the confidence in results of such analyses.

  10. Genetic diversity and population structure of Lantana camara in India indicates multiple introductions and gene flow.

    Science.gov (United States)

    Ray, A; Quader, S

    2014-05-01

    Lantana camara is a highly invasive plant, which has spread over 60 countries and island groups of Asia, Africa and Australia. In India, it was introduced in the early nineteenth century, since when it has expanded and gradually established itself in almost every available ecosystem. We investigated the genetic diversity and population structure of this plant in India in order to understand its introduction, subsequent range expansion and gene flow. A total of 179 individuals were sequenced at three chloroplast loci and 218 individuals were genotyped for six nuclear microsatellites. Both chloroplasts (nine haplotypes) and microsatellites (83 alleles) showed high genetic diversity. Besides, each type of marker confirmed the presence of private polymorphism. We uncovered low to medium population structure in both markers, and found a faint signal of isolation by distance with microsatellites. Bayesian clustering analyses revealed multiple divergent genetic clusters. Taken together, these findings (i.e. high genetic diversity with private alleles and multiple genetic clusters) suggest that Lantana was introduced multiple times and gradually underwent spatial expansion with recurrent gene flow. © 2013 German Botanical Society and The Royal Botanical Society of the Netherlands.

  11. Transcriptome analysis reveals crosstalk of responsive genes to multiple abiotic stresses in cotton (Gossypium hirsutum L..

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    Ya-Na Zhu

    Full Text Available Abiotic stress is a major environmental factor that limits cotton growth and yield, moreover, this problem has become more and more serious recently, as multiple stresses often occur simultaneously due to the global climate change and environmental pollution. In this study, we sought to identify genes involved in diverse stresses including abscisic acid (ABA, cold, drought, salinity and alkalinity by comparative microarray analysis. Our result showed that 5790, 3067, 5608, 778 and 6148 transcripts, were differentially expressed in cotton seedlings under treatment of ABA (1 μM ABA, cold (4°C, drought (200 mM mannitol, salinity (200 mM NaCl and alkalinity (pH=11 respectively. Among the induced or suppressed genes, 126 transcripts were shared by all of the five kinds of abiotic stresses, with 64 up-regulated and 62 down-regulated. These common members are grouped as stress signal transduction, transcription factors (TFs, stress response/defense proteins, metabolism, transport facilitation, as well as cell wall/structure, according to the function annotation. We also noticed that large proportion of significant differentially expressed genes specifically regulated in response to different stress. Nine of the common transcripts of multiple stresses were selected for further validation with quantitative real time RT-PCR (qRT-PCR. Furthermore, several well characterized TF families, for example, WRKY, MYB, NAC, AP2/ERF and zinc finger were shown to be involved in different stresses. As an original report using comparative microarray to analyze transcriptome of cotton under five abiotic stresses, valuable information about functional genes and related pathways of anti-stress, and/or stress tolerance in cotton seedlings was unveiled in our result. Besides this, some important common factors were focused for detailed identification and characterization. According to our analysis, it suggested that there was crosstalk of responsive genes or pathways to

  12. A large-scale study of the random variability of a coding sequence: a study on the CFTR gene.

    Science.gov (United States)

    Modiano, Guido; Bombieri, Cristina; Ciminelli, Bianca Maria; Belpinati, Francesca; Giorgi, Silvia; Georges, Marie des; Scotet, Virginie; Pompei, Fiorenza; Ciccacci, Cinzia; Guittard, Caroline; Audrézet, Marie Pierre; Begnini, Angela; Toepfer, Michael; Macek, Milan; Ferec, Claude; Claustres, Mireille; Pignatti, Pier Franco

    2005-02-01

    Coding single nucleotide substitutions (cSNSs) have been studied on hundreds of genes using small samples (n(g) approximately 100-150 genes). In the present investigation, a large random European population sample (average n(g) approximately 1500) was studied for a single gene, the CFTR (Cystic Fibrosis Transmembrane conductance Regulator). The nonsynonymous (NS) substitutions exhibited, in accordance with previous reports, a mean probability of being polymorphic (q > 0.005), much lower than that of the synonymous (S) substitutions, but they showed a similar rate of subpolymorphic (q < 0.005) variability. This indicates that, in autosomal genes that may have harmful recessive alleles (nonduplicated genes with important functions), genetic drift overwhelms selection in the subpolymorphic range of variability, making disadvantageous alleles behave as neutral. These results imply that the majority of the subpolymorphic nonsynonymous alleles of these genes are selectively negative or even pathogenic.

  13. Tools to minimize interlaboratory variability in vitellogenin gene expression monitoring programs

    Science.gov (United States)

    Jastrow, Aaron; Gordon, Denise A.; Auger, Kasie M.; Punska, Elizabeth C.; Arcaro, Kathleen F.; Keteles, Kristen; Winkelman, Dana L.; Lattier, David; Biales, Adam; Lazorchak, James M.

    2017-01-01

    The egg yolk precursor protein vitellogenin is widely used as a biomarker of estrogen exposure in male fish. However, standardized methodology is lacking and little is known regarding the reproducibility of results among laboratories using different equipment, reagents, protocols, and data analysis programs. To address this data gap we tested the reproducibility across laboratories to evaluate vitellogenin gene (vtg) expression and assessed the value of using a freely available software data analysis program. Samples collected from studies of male fathead minnows (Pimephales promelas) exposed to 17α-ethinylestradiol (EE2) and minnows exposed to processed wastewater effluent were evaluated for vtg expression in 4 laboratories. Our results indicate reasonable consistency among laboratories if the free software for expression analysis LinRegPCR is used, with 3 of 4 laboratories detecting vtg in fish exposed to 5 ng/L EE2 (n = 5). All 4 laboratories detected significantly increased vtg levels in 15 male fish exposed to wastewater effluent compared with 15 male fish held in a control stream. Finally, we were able to determine that the source of high interlaboratory variability from complementary deoxyribonucleic acid (cDNA) to quantitative polymerase chain reaction (qPCR) analyses was the expression analysis software unique to each real-time qPCR machine. We successfully eliminated the interlaboratory variability by reanalyzing raw fluorescence data with independent freeware, which yielded cycle thresholds and polymerase chain reaction (PCR) efficiencies that calculated results independently of proprietary software. Our results suggest that laboratories engaged in monitoring programs should validate their PCR protocols and analyze their gene expression data following the guidelines established in the present study for all gene expression biomarkers. 

  14. Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

    Directory of Open Access Journals (Sweden)

    Mishra Bikash K

    2007-07-01

    Full Text Available Abstract Background Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire. Results We genotyped a total of 121 single nucleotide polymorphisms (SNPs in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor α1 subunit, GABA-A receptor α2 subunit, GABA-A receptor β1 subunit, α-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor β1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025 almost strong enough to correct for testing 22 haplotype blocks. Conclusion If confirmed, the current results may suggest that a common haplotype in the GABA-A β1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of

  15. IGF-I gene variability is associated with an increased risk for AD.

    Science.gov (United States)

    Vargas, Teo; Martinez-Garcia, Ana; Antequera, Desiree; Vilella, Elisabet; Clarimon, Jordi; Mateo, Ignacio; Sanchez-Juan, Pascual; Rodriguez-Rodriguez, Eloy; Frank, Ana; Rosich-Estrago, Marcel; Lleo, Alberto; Molina-Porcel, Laura; Blesa, Rafael; Gomez-Isla, Teresa; Combarros, Onofre; Bermejo-Pareja, Felix; Valdivieso, Fernando; Bullido, Maria Jesus; Carro, Eva

    2011-03-01

    Insulin-like growth factor I (IGF-I), a neuroprotective factor with a wide spectrum of actions in the adult brain, is involved in the pathogenesis of Alzheimer's disease (AD). Circulating levels of IGF-I change in AD patients and are implicated in the clearance of brain amyloid beta (Aβ) complexes. To investigate this hypothesis, we screened the IGF-I gene for various well known single nucleotide polymorphisms (SNPs) covering % of the gene variability in a population of 2352 individuals. Genetic analysis indicated different distribution of genotypes of 1 single nucleotide polymorphism, and 1 extended haplotype in the AD population compared with healthy control subjects. In particular, the frequency of rs972936 GG genotype was significantly greater in AD patients than in control subjects (63% vs. 55%). The rs972936 GG genotype was associated with an increased risk for disease, independently of apolipoprotein E genotype, and with enhanced circulating levels of IGF-I. These findings suggest that polymorphisms within the IGF-I gene could infer greater risk for AD through their effect on IGF-I levels, and confirm the physiological role IGF-I in the pathogenesis of AD. Copyright © 2011 IBRO. Published by Elsevier Inc. All rights reserved.

  16. Variability of Pasteurella multocida isolated from Icelandic sheep and detection of the toxA gene.

    Science.gov (United States)

    Einarsdottir, Thorbjorg; Gunnarsson, Eggert; Sigurdardottir, Olof G; Jorundsson, Einar; Fridriksdottir, Vala; Thorarinsdottir, Gudridur E; Hjartardottir, Sigridur

    2016-09-01

    Pasteurella multocida can be part of the upper respiratory flora of animals, but under conditions of stress or immunocompromisation, the bacteria can cause severe respiratory symptoms. In this study, we compared 10 P. multocida isolates from Icelandic sheep with respiratory symptoms and 19 isolates from apparently healthy abattoir sheep. We examined capsule type, genetic variability and the presence of the toxA gene in the two groups. Surprisingly, we found that all ovine P. multocida isolates examined in this study carried the toxA gene, which markedly differs from what has been published from other studies. Interestingly, all isolates from abattoir animals were capsule type D, whilst bacteria isolated from animals with clinical respiratory symptoms had capsule type A, D or F. Examination of seven housekeeping genes indicated that the clinical respiratory isolates were significantly more heterogeneous than the abattoir isolates (Pmultocida in sheep - a genetically homogeneous group that resides in the respiratory tract and a genetically heterogeneous group that is the predominant cause of disease.

  17. Recombination between an expressed immunoglobulin heavy-chain gene and a germline variable gene segment in a Ly 1+ B-cell lymphoma.

    Science.gov (United States)

    Kleinfield, R; Hardy, R R; Tarlinton, D; Dangl, J; Herzenberg, L A; Weigert, M

    The early stages of murine B-cell differentiation are characterized by a series of immunoglobulin gene rearrangements which are required for the assembly of heavy(H) and light(L)-chain variable regions from germline gene segments. Rearrangement at the heavy-chain locus is initiated first and consists of the joining of a diversity (DH) gene segment to a joining (JH) gene segment. This forms a DJH intermediate to which a variable (VH) gene segment is subsequently added. Light-chain gene rearrangement follows and consists of the joining of a VL gene segment to a JL gene segment: once a productive light-chain gene has been formed the cell initiates synthesis of surface immunoglobulin M (sIgM) receptors (reviewed in ref. 1). These receptors are clonally distributed and may undergo further diversification either by somatic mutation or possibly by continued recombinational events. Such recombinational events have been detected in the Ly 1+ B-cell lymphoma NFS-5, which has been shown to rearrange both lambda and H-chain genes subsequent to the formation of sIgM (mu kappa) molecules. Here we have analysed a rearrangement of the productive allele of NFS-5 and found that it is due to a novel recombination event between VH genes which results in the replacement of most or all of the coding sequence of the initial VHQ52 rearrangement by a germline VH7183 gene. Embedded in the VH coding sequence close to the site of the cross-over is the sequence 5' TACTGTG 3', which is identical to the signal heptamer found 5' of many DH gene segments. This embedded heptamer is conserved in over 70% of known VH genes. We suggest that this heptamer mediates VH gene replacement and may play an important part in the development of the antibody repertoire.

  18. A multiple-time-scale turbulence model based on variable partitioning of turbulent kinetic energy spectrum

    Science.gov (United States)

    Kim, S.-W.; Chen, C.-P.

    1988-01-01

    The paper presents a multiple-time-scale turbulence model of a single point closure and a simplified split-spectrum method. Consideration is given to a class of turbulent boundary layer flows and of separated and/or swirling elliptic turbulent flows. For the separated and/or swirling turbulent flows, the present turbulence model yielded significantly improved computational results over those obtained with the standard k-epsilon turbulence model.

  19. Analysis of biological and technical variability in gene expression assays from formalin-fixed paraffin-embedded classical Hodgkin lymphomas.

    Science.gov (United States)

    Vera-Lozada, Gabriela; Scholl, Vanesa; Barros, Mário Henrique M; Sisti, Davide; Guescini, Michele; Stocchi, Vilberto; Stefanoff, Claudio Gustavo; Hassan, Rocio

    2014-12-01

    Formalin-fixed paraffin-embedded (FFPE) tissues are invaluable sources of biological material for research and diagnostic purposes. In this study, we aimed to identify biological and technical variability in RT-qPCR TaqMan® assays performed with FFPE-RNA from lymph nodes of classical Hodgkin lymphoma samples. An ANOVA-nested 6-level design was employed to evaluate BCL2, CASP3, IRF4, LYZ and STAT1 gene expression. The most variable genes were CASP3 (low expression) and LYZ (high expression). Total variability decreased after normalization for all genes, except by LYZ. Genes with moderate and low expression were identified and suffered more the effects of the technical manipulation than high-expression genes. Pre-amplification was shown to introduce significant technical variability, which was partially alleviated by lowering to a half the amount of input RNA. Ct and Cy0 quantification methods, based on cycle-threshold and the kinetic of amplification curves, respectively, were compared. Cy0 method resulted in higher quantification values, leading to the decrease of total variability in CASP3 and LYZ genes. The mean individual noise was 0.45 (0.31 to 0.61 SD), indicating a variation of gene expression over ~1.5 folds from one case to another. We showed that total variability in RT-qPCR from FFPE-RNA is not higher than that reported for fresh complex tissues, and identified gene-, and expression level-sources of biological and technical variability, which can allow better strategies for designing RT-qPCR assays from highly degraded and inhibited samples. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Multivariate quantile mapping bias correction: An N-dimensional probability density function transform for climate model simulations of multiple variables

    Science.gov (United States)

    Cannon, Alex

    2017-04-01

    Most bias correction algorithms used in climatology, for example quantile mapping, are applied to univariate time series. They neglect the dependence between different variables. Those that are multivariate often correct only limited measures of joint dependence, such as Pearson or Spearman rank correlation. Here, an image processing technique designed to transfer colour information from one image to another - the N-dimensional probability density function transform - is adapted for use as a multivariate bias correction algorithm (MBCn) for climate model projections/predictions of multiple climate variables. MBCn is a multivariate generalization of quantile mapping that transfers all aspects of an observed continuous multivariate distribution to the corresponding multivariate distribution of variables from a climate model. When applied to climate model projections, changes in quantiles of each variable between the historical and projection period are also preserved. The MBCn algorithm is demonstrated on three case studies. First, the method is applied to an image processing example with characteristics that mimic a climate projection problem. Second, MBCn is used to correct a suite of 3-hourly surface meteorological variables from the Canadian Centre for Climate Modelling and Analysis Regional Climate Model (CanRCM4) across a North American domain. Components of the Canadian Forest Fire Weather Index (FWI) System, a complicated set of multivariate indices that characterizes the risk of wildfire, are then calculated and verified against observed values. Third, MBCn is used to correct biases in the spatial dependence structure of CanRCM4 precipitation fields. Results are compared against a univariate quantile mapping algorithm, which neglects the dependence between variables, and two multivariate bias correction algorithms, each of which corrects a different form of inter-variable correlation structure. MBCn outperforms these alternatives, often by a large margin

  1. Exclusion of the phosphatidylinositol-specific phospholipase C beta 3 (PLC beta 3) gene as candidate for the multiple endocrine neoplasia type 1 (MEN 1) gene

    NARCIS (Netherlands)

    de Wit, M J; Landsvater, R M; Sinke, R J; Geurts van Kessel, A; Lips, C J; Höppener, J W

    Multiple endocrine neoplasia type 1 (MEN 1) is inherited as an autosomal dominant disorder, characterized by hyperplasia and neoplasia in several endocrine organs. The MEN 1 gene, which is most probably a tumor suppressor gene, has been localized to a 900-kb region on chromosome 11q13. The human

  2. Genetic variability and mRNA editing frequencies of the phosphoprotein genes of wild-type measles viruses.

    Science.gov (United States)

    Bankamp, B; Lopareva, E N; Kremer, J R; Tian, Y; Clemens, M S; Patel, R; Fowlkes, A L; Kessler, J R; Muller, C P; Bellini, W J; Rota, P A

    2008-08-01

    The sequences of the nucleoprotein (N) and hemagglutinin (H) genes are routinely used for molecular epidemiologic studies of measles virus (MV). However, the amount of genetic diversity contained in other genes of MV has not been thoroughly evaluated. In this report, the nucleotide sequences of the phosphoprotein (P) genes from 34 wild-type strains representing 15 genotypes of MV were analyzed and found to be almost as variable as the H genes but less variable than the N genes. Deduced amino acid sequences of the three proteins encoded by the P gene, P, V and C, demonstrated considerably higher variability than the H proteins. Phylogenetic analysis showed the same tree topography for the P gene sequences as previously seen for the N and H genes. RNA editing of P gene transcripts affects the relative ratios of P and V proteins, which may have consequences for pathogenicity. Wild-type isolates produced more transcripts with more than one G insertion; however, there was no significant difference in the use of P and V open reading frames, suggesting that the relative amounts of P and V proteins in infected cells would be similar for both vaccine and wild-type strains.

  3. Multiple cis-elements mediate shear stress-induced gene expression.

    Science.gov (United States)

    Shyy, J Y; Li, Y S; Lin, M C; Chen, W; Yuan, S; Usami, S; Chien, S

    1995-12-01

    Fluid shear stress activates the expression of immediate early (IE) genes in vascular endothelial cells. The transcriptional regulation can be mediated through the shear stress-sensitive cis-acting elements at the 5' promoter regions of various IE genes such as the monocyte chemotactic protein-1 (MCP-1) gene. We linked wild-type and mutated MCP-1 promoters to the reporter gene luciferase and used such constructs to investigate the role of the phorbol ester TPA responsive element (TRE) in the shear-induced MCP-1 gene expression in vascular endothelial cells. Functional analysis showed that TGACTCC (a divergent TRE) located at nt -54 to -60 is necessary for shear-inducibility in bovine aortic endothelial cells (BAEC). The induction of the wild-type MCP-1 promoter construct by shear stress was attenuated by pretreating the cells with 1 microM dexamethasone or 1 microM retinoic acid 12 h before the shear stress experiments. The induction by shear stress reduced from 13-fold in the untreated cells to 7- and 3-folds in the dexamethasone- and retinoic acid-treated cells, respectively. These results demonstrate that the glucocorticoid receptor and retinoic acid receptor may interfere with the shear stress-activated AP-1/TRE. The reporter activity of HIV(LTR), which is a plasmid construct of the long terminal repeats of the human immunodeficiency virus and contains a kappa B enhancer element, was also activated by shear stress. The results of our investigations indicate that the shear stress-induced IE gene expression can be mediated through multiple cis-elements.

  4. Biomaterial constructs for delivery of multiple therapeutic genes: a spatiotemporal evaluation of efficacy using molecular beacons.

    Directory of Open Access Journals (Sweden)

    Jennifer C Alexander

    Full Text Available Gene therapy is emerging as a potential therapeutic approach for cardiovascular pathogenesis. An appropriate therapy may require multiple genes to enhance therapeutic outcome by modulating inflammatory response and angiogenesis in a controlled and time-dependent manner. Thus, the aim of this research was to assess the spatiotemporal efficacy of a dual-gene therapy model based on 3D collagen scaffolds loaded with the therapeutic genes interleukin 10 (IL-10, a potent anti-inflammatory cytokine, and endothelial nitric oxide synthase (eNOS, a promoter of angiogenesis. A collagen-based scaffold loaded with plasmid IL-10 polyplexes and plasmid eNOS polyplexes encapsulated into microspheres was used to transfect HUVECs and HMSCs cells.The therapeutic efficacy of the system was monitored at 2, 7 and 14 days for eNOS and IL-10 mRNA expression using RT-PCR and live cell imaging molecular beacon technology. The dual gene releasing collagen-based scaffold provided both sustained and delayed release of functional polyplexes in vitro over a 14 day period which was corroborated with variation in expression levels seen using RT-PCR and MB imaging. Maximum fold increases in IL-10 mRNA and eNOS mRNA expression levels occurred at day 7 in HMSCs and HUVECs. However, IL-10 mRNA expression levels seemed dependent on frequency of media changes and/or ease of transfection of the cell type. It was demonstrated that molecular beacons are able to monitor changes in mRNA levels at various time points, in the presence of a 3D scaffolding gene carrier system and the results complemented those of RT-PCR.

  5. Pareto evolution of gene networks: an algorithm to optimize multiple fitness objectives.

    Science.gov (United States)

    Warmflash, Aryeh; Francois, Paul; Siggia, Eric D

    2012-10-01

    The computational evolution of gene networks functions like a forward genetic screen to generate, without preconceptions, all networks that can be assembled from a defined list of parts to implement a given function. Frequently networks are subject to multiple design criteria that cannot all be optimized simultaneously. To explore how these tradeoffs interact with evolution, we implement Pareto optimization in the context of gene network evolution. In response to a temporal pulse of a signal, we evolve networks whose output turns on slowly after the pulse begins, and shuts down rapidly when the pulse terminates. The best performing networks under our conditions do not fall into categories such as feed forward and negative feedback that also encode the input-output relation we used for selection. Pareto evolution can more efficiently search the space of networks than optimization based on a single ad hoc combination of the design criteria.

  6. Gene expression risk signatures maintain prognostic power in multiple myeloma despite microarray probe set translation

    DEFF Research Database (Denmark)

    Hermansen, N E U; Borup, R; Andersen, M K

    2016-01-01

    INTRODUCTION: Gene expression profiling (GEP) risk models in multiple myeloma are based on 3'-end microarrays. We hypothesized that GEP risk signatures could retain prognostic power despite being translated and applied to whole-transcript microarray data. METHODS: We studied CD138-positive bone...... marrow plasma cells in a prospective cohort of 59 samples from newly diagnosed patients eligible for high-dose therapy (HDT) and 67 samples from previous HDT patients with progressive disease. We used Affymetrix Human Gene 1.1 ST microarrays for GEP. Nine GEP risk signatures were translated by probe set...... match and applied to our data in multivariate Cox regression analysis for progression-free survival and overall survival in combination with clinical, cytogenetic and biochemical risk markers, including the International Staging System (ISS). RESULTS: Median follow-up was 66 months (range 42...

  7. Experimental cancer gene therapy by multiple anti-survivin hammerhead ribozymes.

    Science.gov (United States)

    Fei, Qi; Zhang, Hongyu; Fu, Lili; Dai, Xinlan; Gao, Baomei; Ni, Min; Ge, Chao; Li, Jinjun; Ding, Xia; Ke, Yuwen; Yao, Xuebiao; Zhu, Jingde

    2008-06-01

    To improve the efficacy of gene therapy for cancer, we designed four hammerhead ribozyme adenoviruses (R1 to R4) targeting the exposed regions of survivin mRNA. In addition to the in vitro characterization, which included a determination of the sequence specificity of cleavage by primer extension, assays for cell proliferation and for in vivo tumor growth were used to score for ribozyme efficiency. The resulting suppression of survivin expression induced mitotic catastrophe and cell death via the caspase-3-dependent pathway. Importantly, administration of the ribozyme adenoviruses inhibited tumor growth in a hepatocellular carcinoma xenograft mouse model. Co-expression of R1, R3 and R4 ribozymes synergistically suppressed survivin and, as this combination targets all major forms of the survivin transcripts, produced the most potent anti-cancer effects. The adenoviruses carrying the multiple hammerhead ribozymes described in this report offered a robust gene therapy strategy against cancer.

  8. The multiple sulfatase deficiency gene encodes an essential and limiting factor for the activity of sulfatases.

    Science.gov (United States)

    Cosma, Maria Pia; Pepe, Stefano; Annunziata, Ida; Newbold, Robert F; Grompe, Markus; Parenti, Giancarlo; Ballabio, Andrea

    2003-05-16

    In multiple sulfatase deficiency (MSD), a human inherited disorder, the activities of all sulfatases are impaired due to a defect in posttranslational modification. Here we report the identification, by functional complementation using microcell-mediated chromosome transfer, of a gene that is mutated in MSD and is able to rescue the enzymatic deficiency in patients' cell lines. Functional conservation of this gene was observed among distantly related species, suggesting a critical biological role. Coexpression of SUMF1 with sulfatases results in a strikingly synergistic increase of enzymatic activity, indicating that SUMF1 is both an essential and a limiting factor for sulfatases. These data have profound implications on the feasibility of enzyme replacement therapy for eight distinct inborn errors of metabolism.

  9. The Use of Multiple Correspondence Analysis to Explore Associations between Categories of Qualitative Variables in Healthy Ageing

    Directory of Open Access Journals (Sweden)

    Patrício Soares Costa

    2013-01-01

    Full Text Available The main focus of this study was to illustrate the applicability of multiple correspondence analysis (MCA in detecting and representing underlying structures in large datasets used to investigate cognitive ageing. Principal component analysis (PCA was used to obtain main cognitive dimensions, and MCA was used to detect and explore relationships between cognitive, clinical, physical, and lifestyle variables. Two PCA dimensions were identified (general cognition/executive function and memory, and two MCA dimensions were retained. Poorer cognitive performance was associated with older age, less school years, unhealthier lifestyle indicators, and presence of pathology. The first MCA dimension indicated the clustering of general/executive function and lifestyle indicators and education, while the second association was between memory and clinical parameters and age. The clustering analysis with object scores method was used to identify groups sharing similar characteristics. The weaker cognitive clusters in terms of memory and executive function comprised individuals with characteristics contributing to a higher MCA dimensional mean score (age, less education, and presence of indicators of unhealthier lifestyle habits and/or clinical pathologies. MCA provided a powerful tool to explore complex ageing data, covering multiple and diverse variables, showing if a relationship exists and how variables are related, and offering statistical results that can be seen both analytically and visually.

  10. Serum complement factor H and Tyr402 His gene polymorphism among Egyptians with multiple sclerosis.

    Science.gov (United States)

    Abdel Rasol, Hoiyda A; Helmy, Hanan; Aziz, Margeret A

    2015-10-01

    Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system. A contribution from complement has long been suspected. We investigated the association of complement factor H (CFH) Tyr402 His gene polymorphism and serum level in Egyptian patients with MS to examine whether complement might identify or predict specific pathological processes and outcomes in MS. This case-control study was performed during 2013 on MS subjects who attended the Department of Neurology, Cairo University Teaching Hospital. The study included 86 subjects with MS and 74 healthy controls (HC). They were divided into two sets of patients: we measured serum CFH level in 42 patients and 34 HC, and CFH Tyr402 His gene polymorphism in 44 MS patients and 40 HC. Serum CFH was measured by an enzyme-linked immunosorbent assay. Complement factor H Tyr402 His gene polymorphism was detected using polymerase chain reaction followed by restriction fragment length polymorphism analysis. Serum CFH levels were significantly higher in the MS group and subgroups (P His genotypes and alleles between MS patients and healthy controls. There was evidence that serum CFH level may be associated with disease risk. There was no evidence that CFH Tyr402 His gene polymorphism is associated with disease risk.

  11. A novel hybrid gene prediction method employing protein multiple sequence alignments.

    Science.gov (United States)

    Keller, Oliver; Kollmar, Martin; Stanke, Mario; Waack, Stephan

    2011-03-15

    As improved DNA sequencing techniques have increased enormously the speed of producing new eukaryotic genome assemblies, the further development of automated gene prediction methods continues to be essential. While the classification of proteins into families is a task heavily relying on correct gene predictions, it can at the same time provide a source of additional information for the prediction, complementary to those presently used. We extended the gene prediction software AUGUSTUS by a method that employs block profiles generated from multiple sequence alignments as a protein signature to improve the accuracy of the prediction. Equipped with profiles modelling human dynein heavy chain (DHC) proteins and other families, AUGUSTUS was run on the genomic sequences known to contain members of these families. Compared with AUGUSTUS' ab initio version, the rate of genes predicted with high accuracy showed a dramatic increase. The AUGUSTUS project web page is located at http://augustus.gobics.de, with the executable program as well as the source code available for download.

  12. Terbinafine resistance conferred by multiple copies of the salicylate 1-monooxygenase gene in Trichophyton rubrum.

    Science.gov (United States)

    Santos, Hemelin L; Lang, Elza A S; Segato, Fernando; Rossi, Antonio; Martinez-Rossi, Nilce M

    2017-06-02

    Resistance to antifungals is a leading concern in the treatment of human mycoses. We demonstrate that the salA gene, encoding salicylate 1-monooxygenase, is involved in resistance of the dermatophyte Trichophyton rubrum to terbinafine, one of the most effective antifungal drugs against dermatophytes. A strain with multiple copies of salA was constructed and exhibited elevated expression of salA and increased terbinafine resistance. This reflects a mechanism not yet reported in a pathogenic fungus. © The Author 2017. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Identification of the Functional Initiation Codons of a Phase-Variable Gene of Haemophilus influenzae, lic2A, with the Potential for Differential Expression▿

    Science.gov (United States)

    Dixon, Kevin; Bayliss, Christopher D.; Makepeace, Katherine; Moxon, E. Richard; Hood, Derek W.

    2007-01-01

    Simple sequence repeats located within reading frames mediate phase-variable ON/OFF switches in gene expression by generating frameshifts. Multiple translation initiation codons in different reading frames are found upstream of most Haemophilus influenzae tetranucleotide repeat tracts, raising the possibility of multiple active reading frames and more than two levels of gene expression for these loci. Phase variation between three levels of gene expression (strong, weak, and none) was observed when lic2A was fused to a lacZ reporter gene. The lic2A 5′ CAAT repeat tract is preceded by four 5′ ATG codons (x, y, z1, and z2) in two reading frames. Each of these initiation codons was inactivated by site-directed mutagenesis. Strong expression from frame 1 was associated with x but not y. Weak expression from frame 2 was mainly dependent on the z2 codon, and there was no expression from frame 3. Using monoclonal antibodies specific for a digalactoside epitope of lipopolysaccharide whose synthesis requires Lic2A, two levels (strong and undetectable) of antibody reactivity were detected, suggesting that weak expression of lic2A is not discernible at the phenotypic level. Inactivation of the x initiation codon resulted in loss of strong expression of the digalactoside epitope and elevated killing by human serum. The failure to detect more than two phenotypes for lic2A, despite clear evidence of weak expression from the z1/z2 initiation codons, leaves open the question of whether or not multiple initiation codons are associated with more complex patterns of phenotypic variation rather than classical phase-variable switching between two phenotypes. PMID:17098909

  14. Association of a novel point mutation in MSH2 gene with familial multiple primary cancers

    Directory of Open Access Journals (Sweden)

    Hai Hu

    2017-10-01

    Full Text Available Abstract Background Multiple primary cancers (MPC have been identified as two or more cancers without any subordinate relationship that occur either simultaneously or metachronously in the same or different organs of an individual. Lynch syndrome is an autosomal dominant genetic disorder that increases the risk of many types of cancers. Lynch syndrome patients who suffer more than two cancers can also be considered as MPC; patients of this kind provide unique resources to learn how genetic mutation causes MPC in different tissues. Methods We performed a whole genome sequencing on blood cells and two tumor samples of a Lynch syndrome patient who was diagnosed with five primary cancers. The mutational landscape of the tumors, including somatic point mutations and copy number alternations, was characterized. We also compared Lynch syndrome with sporadic cancers and proposed a model to illustrate the mutational process by which Lynch syndrome progresses to MPC. Results We revealed a novel pathologic mutation on the MSH2 gene (G504 splicing that associates with Lynch syndrome. Systematical comparison of the mutation landscape revealed that multiple cancers in the proband were evolutionarily independent. Integrative analysis showed that truncating mutations of DNA mismatch repair (MMR genes were significantly enriched in the patient. A mutation progress model that included germline mutations of MMR genes, double hits of MMR system, mutations in tissue-specific driver genes, and rapid accumulation of additional passenger mutations was proposed to illustrate how MPC occurs in Lynch syndrome patients. Conclusion Our findings demonstrate that both germline and somatic alterations are driving forces of carcinogenesis, which may resolve the carcinogenic theory of Lynch syndrome.

  15. Screening of point mutations by multiple SSCP analysis in the dystrophin gene

    Energy Technology Data Exchange (ETDEWEB)

    Lasa, A.; Baiget, M.; Gallano, P. [Hospital Sant Pau, Barcelona (Spain)

    1994-09-01

    Duchenne muscular dystrophy (DMD) is a lethal, X-linked neuromuscular disorder. The population frequency of DMD is one in approximately 3500 boys, of which one third is thought to be a new mutant. The DMD gene is the largest known to date, spanning over 2,3 Mb in band Xp21.2; 79 exons are transcribed into a 14 Kb mRNA coding for a protein of 427 kD which has been named dystrophin. It has been shown that about 65% of affected boys have a gene deletion with a wide variation in localization and size. The remaining affected individuals who have no detectable deletions or duplications would probably carry more subtle mutations that are difficult to detect. These mutations occur in several different exons and seem to be unique to single patients. Their identification represents a formidable goal because of the large size and complexity of the dystrophin gene. SSCP is a very efficient method for the detection of point mutations if the parameters that affect the separation of the strands are optimized for a particular DNA fragment. The multiple SSCP allows the simultaneous study of several exons, and implies the use of different conditions because no single set of conditions will be optimal for all fragments. Seventy-eight DMD patients with no deletion or duplication in the dystrophin gene were selected for the multiple SSCP analysis. Genomic DNA from these patients was amplified using the primers described for the diagnosis procedure (muscle promoter and exons 3, 8, 12, 16, 17, 19, 32, 45, 48 and 51). We have observed different mobility shifts in bands corresponding to exons 8, 12, 43 and 51. In exons 17 and 45, altered electrophoretic patterns were found in different samples identifying polymorphisms already described.

  16. Microarray test results should not be compensated for multiplicity of gene contents

    Directory of Open Access Journals (Sweden)

    Konishi Tomokazu

    2011-12-01

    Full Text Available Abstract Background Microarray technology has enabled the measurement of comprehensive transcriptomic information. However, each data entry may reflect trivial individual differences among samples and also contain technical noise. Therefore, the certainty of each observed difference should be confirmed at earlier steps of the analyses, and statistical tests are frequently used for this purpose. Since microarrays analyze a huge number of genes simultaneously, concerns of multiplicity, i.e. the family wise error rate (FWER and false discovery rate (FDR, have been raised in testing the data. To deal with these concerns, several compensation methodologies have been proposed, making the tests very conservative to the extent that arbitrary tuning of the threshold has been introduced to relax the conditions. Unexpectedly, however, the appropriateness of the test methodologies, the concerns of multiplicity, and the compensation methodologies have not been sufficiently confirmed. Results The appropriateness was checked by means of coincidence between the methodologies' premises and the statistical characteristics of data found in two typical microarray platforms. As expected, normality was observed in within-group data differences, supporting application of t-test and F-test statistics. However, genes displayed their own tendencies in the magnitude of variations, and the distributions of p-values were rather complex. These characteristics are inconsistent with premises underlying the compensation methodologies, which assume that most of the null hypotheses are true. The evidence also raised concerns about multiplicity. In transcriptomic studies, FWER should not be critical, as analyses at higher levels would not be influenced by a few false positives. Additionally, the concerns for FDR are not suitable for the sharp null hypotheses on expression levels. Conclusions Therefore, although compensation methods have been recommended to deal with the problem of

  17. Recurrent Rearrangements of Human Amylase Genes Create Multiple Independent CNV Series.

    Science.gov (United States)

    Shwan, Nzar A A; Louzada, Sandra; Yang, Fengtang; Armour, John A L

    2017-05-01

    The human amylase gene cluster includes the human salivary (AMY1) and pancreatic amylase genes (AMY2A and AMY2B), and is a highly variable and dynamic region of the genome. Copy number variation (CNV) of AMY1 has been implicated in human dietary adaptation, and in population association with obesity, but neither of these findings has been independently replicated. Despite these functional implications, the structural genomic basis of CNV has only been defined in detail very recently. In this work, we use high-resolution analysis of copy number, and analysis of segregation in trios, to define new, independent allelic series of amylase CNVs in sub-Saharan Africans, including a series of higher-order expansions of a unit consisting of one copy each of AMY1, AMY2A, and AMY2B. We use fiber-FISH (fluorescence in situ hybridization) to define unexpected complexity in the accompanying rearrangements. These findings demonstrate recurrent involvement of the amylase gene region in genomic instability, involving at least five independent rearrangements of the pancreatic amylase genes (AMY2A and AMY2B). Structural features shared by fundamentally distinct lineages strongly suggest that the common ancestral state for the human amylase cluster contained more than one, and probably three, copies of AMY1. © 2017 WILEY PERIODICALS, INC.

  18. Esterase isozymes in a solitary bee, Megachile rotundata (Fab.): characterization, developmental multiplicity, and adult variability.

    Science.gov (United States)

    Frohlich, D R; Brindley, W A; Burris, T E; Youssef, N N

    1990-08-01

    This study describes the biochemical characterization and genetic variation of cytosolic esterases in the alfalfa leafcutting bee, Megachile rotundata (Fab.). Esterase isozymes were separated by nondenaturing polyacrylamide gel electrophoresis and isoelectric focusing and characterized by inhibition with eserine sulfate, EDTA, paraoxon, and p-hydroxymercuribenzoate. Based on inhibition patterns and substrate specificity, there are major differences between adults and immature forms and more subtle differences between male and female adults. M. rotundata esterases are largely organophosphate sensitive and the two major adult allozymes were highly variable within the population examined. Differences in esterase expression between life stages with respect to niche and the occurrence of diploid males are discussed.

  19. Variability in multiple paternity rates for grey reef sharks (Carcharhinus amblyrhynchos) and scalloped hammerheads (Sphyrna lewini).

    Science.gov (United States)

    Green, M E; Appleyard, S A; White, W; Tracey, S; Ovenden, J

    2017-05-08

    This study assessed the presence and prevalence of multiple paternity (MP) in litters of grey reef sharks (Carcharhinus amblyrhynchos) and scalloped hammerheads (Sphyrna lewini) opportunistically caught in Papua New Guinea (PNG). Litter size between species were significantly different with an average of 3.3 pups for grey reef sharks and 17.2 pups for scalloped hammerhead. Using 14 and 10 microsatellite loci respectively, we identified MP in 66% of grey reef sharks (4 out of 6 litters) and 100% MP in scalloped hammerheads (5 litters). We found high paternal skew (the uneven contribution of sires per litter) and a positive correlation between female adult size and litter size in scalloped hammerheads but not in grey reef sharks. Differences in the frequency of MP between species and the identification of paternal skew may be linked with mating strategies and post-copulatory mechanisms. Multiple paternity is thought to benefit populations by enhancing genetic diversity therefore increasing the population's genetic resilience to extrinsic pressures. The identification of MP in two shark species reported here, further elucidates the complex breeding strategies elasmobranchs undertake.

  20. Clinical application of gamma knife dose verification method in multiple brain tumors : modified variable ellipsoid modeling technique.

    Science.gov (United States)

    Hur, Beong Ik; Lee, Jae Min; Cho, Won Ho; Kang, Dong Wan; Kim, Choong Rak; Choi, Byung Kwan

    2013-02-01

    The Leksell Gamma Knife® (LGK) is based on a single-fraction high dose treatment strategy. Therefore, independent verification of the Leksell GammaPlan® (LGP) is important for ensuring patient safety and minimizing the risk of treatment errors. Although several verification techniques have been previously developed and reported, no method has ever been tested statistically on multiple LGK target treatments. The purpose of this study was to perform and to evaluate the accuracy of a verification method (modified variable ellipsoid modeling technique, MVEMT) for multiple target treatments. A total of 500 locations in 10 consecutive patients with multiple brain tumor targets were included in this study. We compared the data from an LGP planning system and MVEMT in terms of dose at random points, maximal dose points, and target volumes. All data was analyzed by t-test and the Bland-Altman plot, which are statistical methods used to compare two different measurement techniques. No statistical difference in dose at the 500 random points was observed between LGP and MVEMT. Differences in maximal dose ranged from -2.4% to 6.1%. An average distance of 1.6 mm between the maximal dose points was observed when comparing the two methods. Statistical analyses demonstrated that MVEMT was in excellent agreement with LGP when planning for radiosurgery involving multiple target treatments. MVEMT is a useful, independent tool for planning multiple target treatment that provides statistically identical data to that produced by LGP. Findings from the present study indicate that MVEMT can be used as a reference dose verification system for multiple tumors.

  1. Prediction of high- and low-risk multiple myeloma based on gene expression and the International Staging System

    NARCIS (Netherlands)

    R. Kuiper (Ruud); M. van Duin (Mark); M.H. van Vliet (Martin); A. Broijl (Annemiek); B. van der Holt (Bronno); L.E. Jarari (Laila El); E.H. van Beers (Erik); G. Mulligan (George); H. Avet-Loiseau (Hervé); W. Gregory (W.); G. Morgan (Gareth); H. Goldschmidt (Hartmut); H.M. Lokhorst (Henk); P. Sonneveld (Pieter)

    2015-01-01

    textabstractPatients with multiple myeloma have variable survival and require reliable prognostic and predictive scoring systems. Currently, clinical and biological risk markers are used independently. Here, International Staging System (ISS), fluorescence in situ hybridization (FISH) markers, and

  2. FIRE: an SPSS program for variable selection in multiple linear regression analysis via the relative importance of predictors.

    Science.gov (United States)

    Lorenzo-Seva, Urbano; Ferrando, Pere J

    2011-03-01

    We provide an SPSS program that implements currently recommended techniques and recent developments for selecting variables in multiple linear regression analysis via the relative importance of predictors. The approach consists of: (1) optimally splitting the data for cross-validation, (2) selecting the final set of predictors to be retained in the equation regression, and (3) assessing the behavior of the chosen model using standard indices and procedures. The SPSS syntax, a short manual, and data files related to this article are available as supplemental materials from brm.psychonomic-journals.org/content/supplemental.

  3. Sum of ratios of products forα-μ random variables in wireless multihop relaying and multiple scattering

    KAUST Repository

    Wang, Kezhi

    2014-09-01

    The sum of ratios of products of independent 2642 2642α-μ random variables (RVs) is approximated by using the Generalized Gamma ratio approximation (GGRA) with Gamma ratio approximation (GRA) as a special case. The proposed approximation is used to calculate the outage probability of the equal gain combining (EGC) or maximum ratio combining (MRC) receivers for wireless multihop relaying or multiple scattering systems considering interferences. Numerical results show that the newly derived approximation works very well verified by the simulation, while GRA has a slightly worse performance than GGRA when outage probability is below 0.1 but with a more simplified form.

  4. The Gene, Environment Association Studies consortium (GENEVA): maximizing the knowledge obtained from GWAS by collaboration across studies of multiple conditions.

    Science.gov (United States)

    Cornelis, Marilyn C; Agrawal, Arpana; Cole, John W; Hansel, Nadia N; Barnes, Kathleen C; Beaty, Terri H; Bennett, Siiri N; Bierut, Laura J; Boerwinkle, Eric; Doheny, Kimberly F; Feenstra, Bjarke; Feingold, Eleanor; Fornage, Myriam; Haiman, Christopher A; Harris, Emily L; Hayes, M Geoffrey; Heit, John A; Hu, Frank B; Kang, Jae H; Laurie, Cathy C; Ling, Hua; Manolio, Teri A; Marazita, Mary L; Mathias, Rasika A; Mirel, Daniel B; Paschall, Justin; Pasquale, Louis R; Pugh, Elizabeth W; Rice, John P; Udren, Jenna; van Dam, Rob M; Wang, Xiaojing; Wiggs, Janey L; Williams, Kayleen; Yu, Kai

    2010-05-01

    Genome-wide association studies (GWAS) have emerged as powerful means for identifying genetic loci related to complex diseases. However, the role of environment and its potential to interact with key loci has not been adequately addressed in most GWAS. Networks of collaborative studies involving different study populations and multiple phenotypes provide a powerful approach for addressing the challenges in analysis and interpretation shared across studies. The Gene, Environment Association Studies (GENEVA) consortium was initiated to: identify genetic variants related to complex diseases; identify variations in gene-trait associations related to environmental exposures; and ensure rapid sharing of data through the database of Genotypes and Phenotypes. GENEVA consists of several academic institutions, including a coordinating center, two genotyping centers and 14 independently designed studies of various phenotypes, as well as several Institutes and Centers of the National Institutes of Health led by the National Human Genome Research Institute. Minimum detectable effect sizes include relative risks ranging from 1.24 to 1.57 and proportions of variance explained ranging from 0.0097 to 0.02. Given the large number of research participants (N>80,000), an important feature of GENEVA is harmonization of common variables, which allow analyses of additional traits. Environmental exposure information available from most studies also enables testing of gene-environment interactions. Facilitated by its sizeable infrastructure for promoting collaboration, GENEVA has established a unified framework for genotyping, data quality control, analysis and interpretation. By maximizing knowledge obtained through collaborative GWAS incorporating environmental exposure information, GENEVA aims to enhance our understanding of disease etiology, potentially identifying opportunities for intervention. (c) 2010 Wiley-Liss, Inc.

  5. Characters with multiple usages- phenotypic variability analysis at Echinacea purpurea (L. Moench species

    Directory of Open Access Journals (Sweden)

    Mihai Radu POP

    2010-11-01

    Full Text Available Merging aesthetics with utility, some medicinal plants can benefit both of a high production and decoration potential. This calls for diversification of improvement directions of the species. Through this article we suggest one of these species, Echinacea purpurea (L. Moench. This is considered to be important at this time, acquisition of new biological forms - varieties in this species, which show multiple attributes utility based on key biological characteristics, agronomic, physiological, biochemical and agrochemical (medicinal, decorative, culinary etc.. To achieve this goal, studies were undertaken, given in this article, which is the starting point for selecting characters representative for our targets.The results presented in this study reveal a pronounced genetic polymorphism showing the selection operation can use the original material for a quantitative and qualitative differentiation of valuable genotypes that could be approved.

  6. Genetic variability in the methylenetetrahydrofolate reductase gene (MTHFR) affects clinical expression of Wilson's disease.

    Science.gov (United States)

    Gromadzka, Grażyna; Rudnicka, Magdalena; Chabik, Grzegorz; Przybyłkowski, Adam; Członkowska, Anna

    2011-10-01

    Wilson's disease (WND) is an autosomal recessive disorder of copper (Cu) transport, resulting from pathogenic mutations in the ATP7B gene. The reason for the high variability in phenotypic expressions of WND is unknown. Hepatotoxic and neurotoxic effects of homocysteine (Hcy), as well as interrelationships between Hcy and Cu toxicity, were documented. We genotyped the two 5,10-methylenetetrahydrofolate reductase (one of the key folate/Hcy pathway enzymes) gene (MTHFR) polymorphisms: C677T and A1298C in 245 WND patients. Next, we tested the modulation of WND phenotypes by genotypes of MTHFR. MTHFR C677T genotype distribution deviated from that expected from a population in Hardy-Weinberg equilibrium (C677T, χ(2) = 12.14, p = 0.0005). Patients with the MTHFR 1298C allele were younger at symptoms' onset than those without this allele (median (IQR) age, 24.9 (14.0) years vs. 28.5 (12.0) years, p = 0.006). Carriers of MTHFR "high activity" diplotype (double wild-type homozygotes 677CC/1298AA) manifested WND at older age, than non-carriers (median (IQR) age, 33.5 (9.0) years vs. 25.0 (13.0) years, p = 0.0009). Patients with the MTHFR 677T allele less frequently exhibited the neurological WND phenotype (31 (29.5%) vs. 36 (48.0%)), and more frequently presented with hepatic WND (44 (41.9%) vs. 22 (29.3%)), compared with subjects MTHFR 677T(-). We postulate that MTHFR polymorphism contributes to the phenotypic variability of WND. Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  7. Stressing "Escherichia coli" to Educate Students about Research: A CURE to Investigate Multiple Levels of Gene Regulation

    Science.gov (United States)

    McDonough, Janet; Goudsouzian, Lara K.; Papaj, Agllai; Maceli, Ashley R.; Klepac-Ceraj, Vanja; Peterson, Celeste N.

    Course-based undergraduate research experiences (CUREs) have been shown to increase student retention and learning in the biological sciences. Most CURES cover only one aspect of gene regulation, such as transcriptional control. Here we present a new inquiry-based lab that engages understanding of gene expression from multiple perspectives.…

  8. Stressing "Escherichia coli" to Educate Students about Research: A CURE to Investigate Multiple Levels of Gene Regulation

    Science.gov (United States)

    McDonough, Janet; Goudsouzian, Lara K.; Papaj, Agllai; Maceli, Ashley R.; Klepac-Ceraj, Vanja; Peterson, Celeste N.

    2017-01-01

    Course-based undergraduate research experiences (CUREs) have been shown to increase student retention and learning in the biological sciences. Most CURES cover only one aspect of gene regulation, such as transcriptional control. Here we present a new inquiry-based lab that engages understanding of gene expression from multiple perspectives.…

  9. Development of the Multiple Gene Knockout System with One-Step PCR in Thermoacidophilic Crenarchaeon Sulfolobus acidocaldarius

    Directory of Open Access Journals (Sweden)

    Shoji Suzuki

    2017-01-01

    Full Text Available Multiple gene knockout systems developed in the thermoacidophilic crenarchaeon Sulfolobus acidocaldarius are powerful genetic tools. However, plasmid construction typically requires several steps. Alternatively, PCR tailing for high-throughput gene disruption was also developed in S. acidocaldarius, but repeated gene knockout based on PCR tailing has been limited due to lack of a genetic marker system. In this study, we demonstrated efficient homologous recombination frequency (2.8 × 104 ± 6.9 × 103 colonies/μg DNA by optimizing the transformation conditions. This optimized protocol allowed to develop reliable gene knockout via double crossover using short homologous arms and to establish the multiple gene knockout system with one-step PCR (MONSTER. In the MONSTER, a multiple gene knockout cassette was simply and rapidly constructed by one-step PCR without plasmid construction, and the PCR product can be immediately used for target gene deletion. As an example of the applications of this strategy, we successfully made a DNA photolyase- (phr- and arginine decarboxylase- (argD- deficient strain of S. acidocaldarius. In addition, an agmatine selection system consisting of an agmatine-auxotrophic strain and argD marker was also established. The MONSTER provides an alternative strategy that enables the very simple construction of multiple gene knockout cassettes for genetic studies in S. acidocaldarius.

  10. Vascular endothelial growth factor (VEGF) gene polymorphisms may influence the efficacy of thalidomide in multiple myeloma

    DEFF Research Database (Denmark)

    Andersen, Niels Frost; Vogel, Ulla Birgitte; Klausen, Tobias W

    2012-01-01

    and prognosis. In this study, we evaluated the association between genetic variations in the VEGF gene in patients with multiple myeloma and time to treatment failure (TTF) after high-dose melphalan and stem cell support (HDT), overall survival (OS) and efficacy of the anti-angiogenic drug thalidomide....... Retrospectively, the SNPs -2,578C>A (rs699947), -460C>T (rs833061), +405G>C (rs2010963) and +936C>T (rs3025039) in the VEGF gene were examined in 348 patients with newly diagnosed multiple myeloma initially treated with HDT, where 176 patients were treated with thalidomide at relapse. None of the examined geno......- or haplotypes was associated with differences in TTF after initial therapy or OS. A possible relation between the haplotype -2,578A/-460C/+405G (ACG) and effect of thalidomide was seen. Patients with no copies of the haplotype ACG had a longer time to next treatment than patients with one or two copies...

  11. Vitamin D receptor gene is epigenetically altered and transcriptionally up-regulated in multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Teresa Ayuso

    Full Text Available Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR gene to identify genomic regulatory elements relevant to MS pathogenesis.Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls.An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2% compared to controls (18.75%, 9.5%, p-value<0.05. Moreover, a 6.5-fold increase in VDR mRNA levels was found in RRMS patients compared to controls (p-value<0.001.An alternative promoter of the VDR gene shows altered DNA methylation levels in patients with multiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis.

  12. Analyzing Multiple-Probe Microarray: Estimation and Application of Gene Expression Indexes

    KAUST Repository

    Maadooliat, Mehdi

    2012-07-26

    Gene expression index estimation is an essential step in analyzing multiple probe microarray data. Various modeling methods have been proposed in this area. Amidst all, a popular method proposed in Li and Wong (2001) is based on a multiplicative model, which is similar to the additive model discussed in Irizarry et al. (2003a) at the logarithm scale. Along this line, Hu et al. (2006) proposed data transformation to improve expression index estimation based on an ad hoc entropy criteria and naive grid search approach. In this work, we re-examined this problem using a new profile likelihood-based transformation estimation approach that is more statistically elegant and computationally efficient. We demonstrate the applicability of the proposed method using a benchmark Affymetrix U95A spiked-in experiment. Moreover, We introduced a new multivariate expression index and used the empirical study to shows its promise in terms of improving model fitting and power of detecting differential expression over the commonly used univariate expression index. As the other important content of the work, we discussed two generally encountered practical issues in application of gene expression index: normalization and summary statistic used for detecting differential expression. Our empirical study shows somewhat different findings from the MAQC project (MAQC, 2006).

  13. Associations between multiple dimensions of schizotypy and sociodemographic variables in a nonpsychiatric sample of young adults.

    Science.gov (United States)

    Goulding, Sandra M; McClure-Tone, Erin; Compton, Michael T

    2009-10-01

    In several prior studies, self-reported schizotypy has been documented to vary by gender, age, race/ethnicity, and measures of social engagement. In this study, undergraduate students participated in an online survey, and data from 825 students were used to examine sociodemographic characteristics and past mental health treatment history as predictors of 6 schizotypy measures. History of mental health treatment was a significant independent predictor of paranoid, cognitive-perceptual, and interpersonal schizotypy; race, relationship status, and mental health treatment history were significant independent predictors of disorganized schizotypy; race was an independent significant predictor of perceptual aberrations; and race and gender were significant independent predictors of social anhedonia. These results suggest that basic demographics, relationship status, and history of mental health treatment may be important variables to consider in studies of schizotypy. Furthermore, differences across studies could be driven by race/ethnicity and cultural factors that may affect the reporting of unusual or distorted perceptions.

  14. Discrimination of multiple stress levels in virtual reality environments using heart rate variability.

    Science.gov (United States)

    Jinsil Ham; Dongrae Cho; Jooyoung Oh; Boreom Lee

    2017-07-01

    People are suffering from various stress during daily living. Stress can cause a variety of symptoms, and in severe cases, it can lead to a dangerous disease. For this reason, it is essential to develop a simple method to evaluate stress level precisely. Popularly, heart rate variability (HRV) is used because it can reflect autonomic nervous system (ANS) activity. On the other hand, virtual reality (VR), which can provide environments similar to reality, is widely used in laboratory-based experiments. In this paper, we analyzed the HRV of healthy people by using the photoplethysmogram (PPG) while providing diverse stress situations. To detect and classify the exact stress levels, extracted HRV features and linear discriminant analysis (LDA) were utilized. As a result, high multi-class classification accuracy was obtained: Baseline (74%), mild stress (81%), and severe stress (82%).

  15. Biofilm formation and genetic variability of BCR1 gene in the Candida parapsilosis complex.

    Science.gov (United States)

    Treviño-Rangel, Rogelio de J; Rodríguez-Sánchez, Irám P; Rosas-Taraco, Adrián G; Hernández-Bello, Romel; González, José G; González, Gloria M

    2015-01-01

    Candida parapsilosis sensu stricto, Candida orthopsilosis, and Candida metapsilosis are cryptic species that belong to the C. parapsilosis complex, which has been increasingly associated to fungemia in various geographic regions, principally due to the capability of these yeasts to form biofilms on indwelling medical devices. BCR1 is one of the most studied genes related to Candida spp. biofilms. To evaluate the biofilm forming capability of a subset of 65 clinical isolates of the C. parapsilosis complex using two conventional approaches, and to look for an association between the biofilm forming phenotype and genetic variants of a fragment of BCR1. The biofilm determination was carried out by crystal violet staining and tetrazolium reduction assay. On the other hand, a segment of BCR1 gene was sequenced by Sanger methodology. C. parapsilosis sensu stricto was statistically associated with a low biofilm production phenotype, while C. orthopsilosis was significantly associated with both phenotypes (high and low biofilm producers). According to the BCR1 sequence analysis, genetic variability was detected in C. orthopsilosis and C. metapsilosis without a particular biofilm formation phenotype association. Under the adopted experimental design, C. parapsilosis sensu stricto was associated with the low biofilm phenotype and C. orthopsilosis with both phenotypes (high and low biofilm producers). On the other hand, an association between a biofilm forming phenotype and a particular genetic variant of the analyzed BCR1 fragment was not found. Copyright © 2014 Revista Iberoamericana de Micología. Published by Elsevier Espana. All rights reserved.

  16. Clinicopathological variables predicting HER-2 gene status in immunohistochemistry-equivocal (2+) invasive breast cancer.

    Science.gov (United States)

    Ji, Yongling; Sheng, Liming; Du, Xianghui; Qiu, Guoqin; Chen, Bo; Wang, Xiaojia

    2014-07-01

    Human epidermal growth factor receptor-2 (HER-2) gene status is crucial to guide treatment decisions regarding the use of HER-2-targeted therapies in breast cancer. An invasive breast cancer with HER-2 2+ score is regarded as HER-2 status equivocal and should further determine by fluorescent in situ hybridization (FISH), which is considered the standard test for HER-2 status. Here, we aimed to establish a risk score to allow for prediction of the presence of HER-2 gene status. A total of 182 HER-2 2+ by immunohistochemistry (IHC) invasive breast cancer cases were enrolled in this study. The association between clinicopathological variables like age, sex, tumor grade, hormone receptor (HR) status, P53 and proliferation index (Ki67), and FISH result using US Food and Drug Administration (FDA) criteria was evaluated. Also, we compared the HER-2 FISH results using FDA criteria and 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline. The study population had a median age of 48 years (range, 29-78 years). Estrogen receptor (ER) was expressed in 131 (72.0%) patients. 73.1% of patients (133/182) were progesterone receptor (PR) positive. The median Ki67 value was 20% (range, 3-90%). There was good agreement between the FDA and 2013 ASCO/CAP guideline. Sixty-three of all patients were HER-2 FISH amplified (positive) based on FDA criteria. Tumors with HER-2 amplified were more likely to harbor ER negative (58.8% vs. 25.2%, PHER-2 amplified groups (P=0.006). We created a risk score that comprised HR, P53 and Ki67. A significant association between risk score and HER-2 FISH amplification was observed (χ(2)=30.41, PHER-2 gene status in invasive breast cancer.

  17. Genetic association between polymorphisms in the ADAMTS14 gene and multiple sclerosis.

    Science.gov (United States)

    Goertsches, Robert; Comabella, Manuel; Navarro, Arcadi; Perkal, Hector; Montalban, Xavier

    2005-07-01

    ADAMTS14 is a novel member of the ADAMTS (a disintegrin-like and metalloproteinase domain with thrombospondin type 1 modules) metalloproteinase family which processes extracellular matrix proteins. In the present study we performed a comprehensive investigation of the ADAMTS14 as a candidate gene for susceptibility to multiple sclerosis (MS). Eight single nucleotide polymorphisms (SNPs) were analyzed in a case-control study of 287 patients with MS [192 with relapsing-remitting MS (RRMS) and 95 with primary-progressive MS (PPMS)], and 285 age- and sex-matched controls. Allele and genotype frequencies were compared between controls and the MS subgroups, and gene-based haplotypes were reconstructed by computational procedures. Pairwise linkage disequilibrium values (D') suggested that three locus pairs (SNPs 3 through 5) had alleles in strong disequilibrium and constituted a haplotype block spanning 14 kb. Overall comparisons of allele and genotype frequencies showed association for SNPs 3 and 6 with MS. Stratification of MS patients according to major clinical forms revealed an increased frequency of both allele C (p = 0.006) and CC homozygosity (p = 0.008) at SNP6 in RRMS patients compared with controls. PPMS was associated with allele A at SNP2 compared with RRMS (p = 0.003) and controls (p = 0.009), and with CG heterozygosity at SNP3 compared with controls (p = 0.005). Haplotype frequency comparisons showed significant association between PPMS and the AGGGC haplotype compared with controls (p = 0.0004), and negative association between RRMS and the GGAGT haplotype compared with controls (p = 0.0026). No association was detected between different genotypes and disease severity measured by the Multiple Sclerosis Severity Score (MSSS). These findings suggest a potentially important role for the ADAMTS14 gene in predisposition to MS.

  18. Kidney adysplasia and variable hydronephrosis, a new mutation affecting the odd-skipped related 1 gene in the mouse, causes variable defects in kidney development and hydronephrosis.

    Science.gov (United States)

    Davisson, Muriel T; Cook, Susan A; Akeson, Ellen C; Liu, Don; Heffner, Caleb; Gudis, Polyxeni; Fairfield, Heather; Murray, Stephen A

    2015-06-15

    Many genes, including odd-skipped related 1 (Osr1), are involved in regulation of mammalian kidney development. We describe here a new recessive mutation (kidney adysplasia and variable hydronephrosis, kavh) in the mouse that leads to downregulation of Osr1 transcript, causing several kidney defects: agenesis, hypoplasia, and hydronephrosis with variable age of onset. The mutation is closely associated with a reciprocal translocation, T(12;17)4Rk, whose Chromosome 12 breakpoint is upstream from Osr1. The kavh/kavh mutant provides a model to study kidney development and test therapies for hydronephrosis. Copyright © 2015 the American Physiological Society.

  19. From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A

    Directory of Open Access Journals (Sweden)

    Tone Berge

    2013-02-01

    Full Text Available Multiple sclerosis (MS is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals, probably triggered by common environmental factors. Human leukocyte antigen (HLA loci were early shown to confer the strongest genetic associations in MS. Now, more than 50 non-HLA MS susceptibility loci are identified, of which the majority are located in immune-regulatory genes. Single nucleotide polymorphisms (SNPs in the C-type lectin-like domain family 16A (CLEC16A gene were among the first non-HLA genetic variants that were confirmed to be associated with MS. Fine-mapping has indicated a primary association in MS and also other autoimmune diseases to intronic CLEC16A SNPs. Here, we review the identification of MS susceptibility variants in the CLEC16A gene region, functional studies of the CLEC16A molecule and the recent progress in understanding the implications thereof for MS development. This may serve as an example of the importance for further molecular investigation of the loci identified in genetic studies, with the aim to translate this knowledge into the clinic.

  20. Using cases and parents to study multiplicative gene-by-environment interaction.

    Science.gov (United States)

    Kistner, Emily O; Shi, Min; Weinberg, Clarice R

    2009-08-01

    With case-parent triads, one can estimate genotype relative risks by measuring the apparent overtransmission of susceptibility genotypes from parents to affected offspring. Results obtained using such designs, properly analyzed, resist both bias due to population structure and bias due to self-selection. Most diseases are not purely genetic, and environmental cofactors can also be important. In this paper, the authors describe how a polytomous logistic regression method previously developed for studying genetic effects on a quantitative trait can be used with case-parent data to study multiplicative gene-by-environment interaction. The idea is that if the joint effect of exposure and genotype on risk is submultiplicative or supermultiplicative, then, conditional on the parental genotypes, inheritance of a susceptibility genotype by affected offspring will appear to have been influenced by the offspring's exposure level. The authors' approach tolerates exposure-complicated genetic population structure, and simulations suggest power and Type I error rates comparable to those of competitors. With this approach, one can estimate the usual interaction parameters under a much less stringent assumption than gene-environment independence in the source population. Incompletely genotyped triads can contribute through an expectation-maximization algorithm. To illustrate, the authors consider polymorphisms in detoxification pathway genes and maternal smoking in relation to the birth defect oral cleft.

  1. Vitamin D receptor gene polymorphisms in multiple sclerosis patients in northwest Greece

    Directory of Open Access Journals (Sweden)

    Georgiou Ioannis

    2011-05-01

    Full Text Available Abstract Background Polymorphisms of the vitamin D receptor (VDR gene have been linked to both multiple sclerosis (MS and osteoporosis. We examined the frequency of the Taq-I and Bsm-I polymorphisms of the vitamin D receptor (VDR gene in 69 patients with MS and 81 age and sex-matched healthy individuals. Genotyping of Taq-I (rs731236 and Bsm-I (rs1544410 was performed using TaqMan® SNP Genotyping Assay. All patients and controls had determination of body mass index (BMI, bone mineral density (BMD and smoking history. Results The mean age of patients was 39 ± 10.5 years compared to 38.7 ± 10.7 years of the controls (p = 0.86, the BMI was 24.8 ± 4.2 kg/m2 compared to 25.7 ± 4.8 kg/m2 of the controls (p = 0.23, the BMD in the lumbar spine 0.981 ± 0.15 compared to 1.025 ± 013 of the controls (p = 0.06 and the total hip BMD was 0.875 ± 0.14 compared to 0.969 ± 0.12 of the controls (p Conclusions This study suggests that the Taq-I and Bsm-I polymorphisms of the VDR gene are not associated with MS risk, BMI or BMD in the Greek population studied.

  2. Architectural roles of multiple chromatin insulators at the human apolipoprotein gene cluster

    Science.gov (United States)

    Mishiro, Tsuyoshi; Ishihara, Ko; Hino, Shinjiro; Tsutsumi, Shuichi; Aburatani, Hiroyuki; Shirahige, Katsuhiko; Kinoshita, Yoshikazu; Nakao, Mitsuyoshi

    2009-01-01

    Long-range regulatory elements and higher-order chromatin structure coordinate the expression of multiple genes in cluster, and CTCF/cohesin-mediated chromatin insulator may be a key in this regulation. The human apolipoprotein (APO) A1/C3/A4/A5 gene region, whose alterations increase the risk of dyslipidemia and atherosclerosis, is partitioned at least by three CTCF-enriched sites and three cohesin protein RAD21-enriched sites (two overlap with the CTCF sites), resulting in the formation of two transcribed chromatin loops by interactions between insulators. The C3 enhancer and APOC3/A4/A5 promoters reside in the same loop, where the APOC3/A4 promoters are pointed towards the C3 enhancer, whereas the APOA1 promoter is present in the different loop. The depletion of either CTCF or RAD21 disrupts the chromatin loop structure, together with significant changes in the APO expression and the localization of transcription factor hepatocyte nuclear factor (HNF)-4α and transcriptionally active form of RNA polymerase II at the APO promoters. Thus, CTCF/cohesin-mediated insulators maintain the chromatin loop formation and the localization of transcriptional apparatus at the promoters, suggesting an essential role of chromatin insulation in controlling the expression of clustered genes. PMID:19322193

  3. Bayesian inference based modelling for gene transcriptional dynamics by integrating multiple source of knowledge

    Directory of Open Access Journals (Sweden)

    Wang Shu-Qiang

    2012-07-01

    Full Text Available Abstract Background A key challenge in the post genome era is to identify genome-wide transcriptional regulatory networks, which specify the interactions between transcription factors and their target genes. Numerous methods have been developed for reconstructing gene regulatory networks from expression data. However, most of them are based on coarse grained qualitative models, and cannot provide a quantitative view of regulatory systems. Results A binding affinity based regulatory model is proposed to quantify the transcriptional regulatory network. Multiple quantities, including binding affinity and the activity level of transcription factor (TF are incorporated into a general learning model. The sequence features of the promoter and the possible occupancy of nucleosomes are exploited to estimate the binding probability of regulators. Comparing with the previous models that only employ microarray data, the proposed model can bridge the gap between the relative background frequency of the observed nucleotide and the gene's transcription rate. Conclusions We testify the proposed approach on two real-world microarray datasets. Experimental results show that the proposed model can effectively identify the parameters and the activity level of TF. Moreover, the kinetic parameters introduced in the proposed model can reveal more biological sense than previous models can do.

  4. Hairpin RNA Targeting Multiple Viral Genes Confers Strong Resistance to Rice Black-Streaked Dwarf Virus

    Directory of Open Access Journals (Sweden)

    Fangquan Wang

    2016-05-01

    Full Text Available Rice black-streaked dwarf virus (RBSDV belongs to the genus Fijivirus in the family of Reoviridae and causes severe yield loss in rice-producing areas in Asia. RNA silencing, as a natural defence mechanism against plant viruses, has been successfully exploited for engineering virus resistance in plants, including rice. In this study, we generated transgenic rice lines harbouring a hairpin RNA (hpRNA construct targeting four RBSDV genes, S1, S2, S6 and S10, encoding the RNA-dependent RNA polymerase, the putative core protein, the RNA silencing suppressor and the outer capsid protein, respectively. Both field nursery and artificial inoculation assays of three generations of the transgenic lines showed that they had strong resistance to RBSDV infection. The RBSDV resistance in the segregating transgenic populations correlated perfectly with the presence of the hpRNA transgene. Furthermore, the hpRNA transgene was expressed in the highly resistant transgenic lines, giving rise to abundant levels of 21–24 nt small interfering RNA (siRNA. By small RNA deep sequencing, the RBSDV-resistant transgenic lines detected siRNAs from all four viral gene sequences in the hpRNA transgene, indicating that the whole chimeric fusion sequence can be efficiently processed by Dicer into siRNAs. Taken together, our results suggest that long hpRNA targeting multiple viral genes can be used to generate stable and durable virus resistance in rice, as well as other plant species.

  5. Multiple genes of apparent algal origin suggest ciliates may once have been photosynthetic.

    Science.gov (United States)

    Reyes-Prieto, Adrian; Moustafa, Ahmed; Bhattacharya, Debashish

    2008-07-08

    Plantae (as defined by Cavalier-Smith, 1981) plastids evolved via primary endosymbiosis whereby a heterotrophic protist enslaved a photosynthetic cyanobacterium. This "primary" plastid spread into other eukaryotes via secondary endosymbiosis. An important but contentious theory in algal evolution is the chromalveolate hypothesis that posits chromists (cryptophytes, haptophytes, and stramenopiles) and alveolates (ciliates, apicomplexans, and dinoflagellates) share a common ancestor that contained a red-algal-derived "secondary" plastid. Under this view, the existence of several later-diverging plastid-lacking chromalveolates such as ciliates and oomycetes would be explained by plastid loss in these lineages. To test the idea of a photosynthetic ancestry for ciliates, we used the 27,446 predicted proteins from the macronuclear genome of Tetrahymena thermophila to query prokaryotic and eukaryotic genomes. We identified 16 proteins of possible algal origin in the ciliates Tetrahymena and Paramecium tetraurelia. Fourteen of these are present in other chromalveolates. Here we compare and contrast the likely scenarios for algal-gene origin in ciliates either via multiple rounds of horizontal gene transfer (HGT) from algal prey or symbionts, or through endosymbiotic gene transfer (EGT) during a putative photosynthetic phase in their evolution.

  6. Fast sparse matrix-vector multiplication by exploiting variable block structure

    Energy Technology Data Exchange (ETDEWEB)

    Vuduc, R W; Moon, H

    2005-07-07

    We improve the performance of sparse matrix-vector multiply (SpMV) on modern cache-based superscalar machines when the matrix structure consists of multiple, irregularly aligned rectangular blocks. Matrices from finite element modeling applications often have this kind of structure. Our technique splits the matrix, A, into a sum, A{sub 1} + A{sub 2} + ... + A{sub s}, where each term is stored in a new data structure, unaligned block compressed sparse row (UBCSR) format . The classical alternative approach of storing A in a block compressed sparse row (BCSR) format yields limited performance gains because it imposes a particular alignment of the matrix non-zero structure, leading to extra work from explicitly padded zeros. Combining splitting and UBCSR reduces this extra work while retaining the generally lower memory bandwidth requirements and register-level tiling opportunities of BCSR. Using application test matrices, we show empirically that speedups can be as high as 2.1x over not blocking at all, and as high as 1.8x over the standard BCSR implementation used in prior work. When performance does not improve, split UBCSR can still significantly reduce matrix storage. Through extensive experiments, we further show that the empirically optimal number of splittings s and the block size for each matrix term A{sub i} will in practice depend on the matrix and hardware platform. Our data lay a foundation for future development of fully automated methods for tuning these parameters.

  7. A multiple-time-scale turbulence model based on variable partitioning of the turbulent kinetic energy spectrum

    Science.gov (United States)

    Kim, S.-W.; Chen, C.-P.

    1989-01-01

    A multiple-time-scale turbulence model of a single point closure and a simplified split-spectrum method is presented. In the model, the effect of the ratio of the production rate to the dissipation rate on eddy viscosity is modeled by use of the multiple-time-scales and a variable partitioning of the turbulent kinetic energy spectrum. The concept of a variable partitioning of the turbulent kinetic energy spectrum and the rest of the model details are based on the previously reported algebraic stress turbulence model. Example problems considered include: a fully developed channel flow, a plane jet exhausting into a moving stream, a wall jet flow, and a weakly coupled wake-boundary layer interaction flow. The computational results compared favorably with those obtained by using the algebraic stress turbulence model as well as experimental data. The present turbulence model, as well as the algebraic stress turbulence model, yielded significantly improved computational results for the complex turbulent boundary layer flows, such as the wall jet flow and the wake boundary layer interaction flow, compared with available computational results obtained by using the standard kappa-epsilon turbulence model.

  8. Improvement of the R-SWAT-FME framework to support multiple variables and multi-objective functions

    Science.gov (United States)

    Wu, Yiping; Liu, Shu-Guang

    2014-01-01

    Application of numerical models is a common practice in the environmental field for investigation and prediction of natural and anthropogenic processes. However, process knowledge, parameter identifiability, sensitivity, and uncertainty analyses are still a challenge for large and complex mathematical models such as the hydrological/water quality model, Soil and Water Assessment Tool (SWAT). In this study, the previously developed R program language-SWAT-Flexible Modeling Environment (R-SWAT-FME) was improved to support multiple model variables and objectives at multiple time steps (i.e., daily, monthly, and annually). This expansion is significant because there is usually more than one variable (e.g., water, nutrients, and pesticides) of interest for environmental models like SWAT. To further facilitate its easy use, we also simplified its application requirements without compromising its merits, such as the user-friendly interface. To evaluate the performance of the improved framework, we used a case study focusing on both streamflow and nitrate nitrogen in the Upper Iowa River Basin (above Marengo) in the United States. Results indicated that the R-SWAT-FME performs well and is comparable to the built-in auto-calibration tool in multi-objective model calibration. Overall, the enhanced R-SWAT-FME can be useful for the SWAT community, and the methods we used can also be valuable for wrapping potential R packages with other environmental models.

  9. Variability in the elastic properties of bovine dentin at multiple length scales.

    Science.gov (United States)

    Deymier-Black, A C; Almer, J D; Stock, S R; Dunand, D C

    2012-01-01

    Various methods are used to investigate the variability in elastic properties across a population of deciduous bovine incisor root dentin samples spanning different animals, incisor types, and locations within teeth. First, measurements of elastic strains by high-energy synchrotron X-ray scattering during compressive loading of dentin specimens provided the effective modulus--the ratio of applied stress to elastic phase strain--for the two main phases of dentin (hydroxyapatite crystals and mineralized collagen fibrils), shedding light on load transfer operating at the nanoscale between collagen and mineral phases. Second, Young's moduli were measured at the macroscale by ultrasonic time-of-flight measurements. Third, thermogravimetry quantified the volume fractions of hydroxyapatite, protein and water at the macroscale. Finally, micro-Computed Tomography determined spatial variations of the mineral at the sub-millimeter scale. Statistical comparison of the above properties reveals: (i) no significant differences for dentin samples taken from different animals or different incisor types but (ii) significant differences for samples taken from the cervical or apical root sections as well as from different locations between buccal and lingual edges. Copyright © 2011 Elsevier Ltd. All rights reserved.

  10. Utilizing multiple state variables to improve the dynamic range of analog switching in a memristor

    Energy Technology Data Exchange (ETDEWEB)

    Jeong, YeonJoo; Kim, Sungho; Lu, Wei D., E-mail: wluee@eecs.umich.edu [Department of Electrical Engineering and Computer Science, University of Michigan, Ann Arbor, 48109 (United States)

    2015-10-26

    Memristors and memristive systems have been extensively studied for data storage and computing applications such as neuromorphic systems. To act as synapses in neuromorphic systems, the memristor needs to exhibit analog resistive switching (RS) behavior with incremental conductance change. In this study, we show that the dynamic range of the analog RS behavior can be significantly enhanced in a tantalum-oxide-based memristor. By controlling different state variables enabled by different physical effects during the RS process, the gradual filament expansion stage can be selectively enhanced without strongly affecting the abrupt filament length growth stage. Detailed physics-based modeling further verified the observed experimental effects and revealed the roles of oxygen vacancy drift and diffusion processes, and how the diffusion process can be selectively enhanced during the filament expansion stage. These findings lead to more desirable and reliable memristor behaviors for analog computing applications. Additionally, the ability to selectively control different internal physical processes demonstrated in the current study provides guidance for continued device optimization of memristor devices in general.

  11. Apnea-hypopnea index as the outcome variable in multiple linear regression analysis: statistical issues.

    Science.gov (United States)

    Chan, Chung-hong; Ng, Daniel K

    2007-08-01

    It is common for apnea-hypopnea index (AHI) to be used as an outcome variable in ordinary least squares linear regression. However, the distribution of AHI is not tested. The assumption of ordinary least squares linear regression may be violated. The distribution of AHI from a pediatric sleep laboratory was assessed by Kolomgorov-Smirnov test. Transformation of AHI was attempted. In addition, we fitted an ordinary linear regression model (OLSM) and negative binomial regression model (NBRM) of the relationship between body mass index and the rate of apnea and hypopnea events. OLSM and NBRM were evaluated by residuals analysis. AHI from the studied population deviated significantly from normal distribution. Commonly used transformation algorithm could not transform AHI to normal distribution. In addition, OLSM violated the underlying statistical assumptions of homogeneity of variance and normality of error. NBRM, on the other hand, was not restricted by these assumptions. The current study suggested AHI is not likely to be normally distributed and its distribution cannot be transformed to normal. Negative binomial regression of the total number of apnea and hypopnea with an offset of log TST should be used in data analysis. 2007 Wiley-Liss, Inc.

  12. Supervised pre-processing approaches in multiple class variables classification for fish recruitment forecasting

    KAUST Repository

    Fernandes, José Antonio

    2013-02-01

    A multi-species approach to fisheries management requires taking into account the interactions between species in order to improve recruitment forecasting of the fish species. Recent advances in Bayesian networks direct the learning of models with several interrelated variables to be forecasted simultaneously. These models are known as multi-dimensional Bayesian network classifiers (MDBNs). Pre-processing steps are critical for the posterior learning of the model in these kinds of domains. Therefore, in the present study, a set of \\'state-of-the-art\\' uni-dimensional pre-processing methods, within the categories of missing data imputation, feature discretization and feature subset selection, are adapted to be used with MDBNs. A framework that includes the proposed multi-dimensional supervised pre-processing methods, coupled with a MDBN classifier, is tested with synthetic datasets and the real domain of fish recruitment forecasting. The correctly forecasting of three fish species (anchovy, sardine and hake) simultaneously is doubled (from 17.3% to 29.5%) using the multi-dimensional approach in comparison to mono-species models. The probability assessments also show high improvement reducing the average error (estimated by means of Brier score) from 0.35 to 0.27. Finally, these differences are superior to the forecasting of species by pairs. © 2012 Elsevier Ltd.

  13. Analysis of multiple transcriptomes of the African oil palm (Elaeis guineensis) to identify reference genes for RT-qPCR.

    Science.gov (United States)

    Xia, Wei; Mason, Annaliese S; Xiao, Yong; Liu, Zheng; Yang, Yaodong; Lei, Xintao; Wu, Xiaoming; Ma, Zilong; Peng, Ming

    2014-08-20

    The African oil palm (Elaeis guineensis), which is grown in tropical and subtropical regions, is a highly productive oil-bearing crop. For gene expression-based analyses such as reverse transcription-quantitative real time PCR (RT-qPCR), reference genes are essential to provide a baseline with which to quantify relative gene expression. Normalization using reliable reference genes is critical in correctly interpreting expression data from RT-qPCR. In order to identify suitable reference genes in African oil palm, 17 transcriptomes of different tissues obtained from NCBI were systematically assessed for gene expression variation. In total, 53 putative candidate reference genes with coefficient of variation values <3.0 were identified: 18 in reproductive tissue and 35 in vegetative tissue. Analysis for enriched functions showed that approximately 90% of identified genes were clustered in cell component gene functions, and 12 out of 53 genes were traditional housekeeping genes. We selected and validated 16 reference genes chosen from leaf tissue transcriptomes by using RT-qPCR in sets of cold, drought and high salinity treated samples, and ranked expression stability using statistical algorithms geNorm, Normfinder and Bestkeeper. Genes encoding actin, adenine phosphoribosyltransferase and eukaryotic initiation factor 4A genes were the most stable genes over the cold, drought and high salinity stresses. Identification of stably expressed genes as reference gene candidates from multiple transcriptome datasets was found to be reliable and efficient, and some traditional housekeeping genes were more stably expressed than others. We provide a useful molecular genetic resource for future gene expression studies in African oil palm, facilitating molecular genetics approaches for crop improvement in this species. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Mapping of Variable DNA Methylation Across Multiple Cell Types Defines a Dynamic Regulatory Landscape of the Human Genome.

    Science.gov (United States)

    Gu, Junchen; Stevens, Michael; Xing, Xiaoyun; Li, Daofeng; Zhang, Bo; Payton, Jacqueline E; Oltz, Eugene M; Jarvis, James N; Jiang, Kaiyu; Cicero, Theodore; Costello, Joseph F; Wang, Ting

    2016-04-07

    DNA methylation is an important epigenetic modification involved in many biological processes and diseases. Many studies have mapped DNA methylation changes associated with embryogenesis, cell differentiation, and cancer at a genome-wide scale. Our understanding of genome-wide DNA methylation changes in a developmental or disease-related context has been steadily growing. However, the investigation of which CpGs are variably methylated in different normal cell or tissue types is still limited. Here, we present an in-depth analysis of 54 single-CpG-resolution DNA methylomes of normal human cell types by integrating high-throughput sequencing-based methylation data. We found that the ratio of methylated to unmethylated CpGs is relatively constant regardless of cell type. However, which CpGs made up the unmethylated complement was cell-type specific. We categorized the 26,000,000 human autosomal CpGs based on their methylation levels across multiple cell types to identify variably methylated CpGs and found that 22.6% exhibited variable DNA methylation. These variably methylated CpGs formed 660,000 variably methylated regions (VMRs), encompassing 11% of the genome. By integrating a multitude of genomic data, we found that VMRs enrich for histone modifications indicative of enhancers, suggesting their role as regulatory elements marking cell type specificity. VMRs enriched for transcription factor binding sites in a tissue-dependent manner. Importantly, they enriched for GWAS variants, suggesting that VMRs could potentially be implicated in disease and complex traits. Taken together, our results highlight the link between CpG methylation variation, genetic variation, and disease risk for many human cell types. Copyright © 2016 Gu et al.

  15. Positive selection of Plasmodium falciparum parasites with multiple var2csa-type PfEMP1 genes during the course of infection in pregnant women

    DEFF Research Database (Denmark)

    Sander, Adam F; Salanti, Ali; Lavstsen, Thomas

    2011-01-01

    multiple genes coding for different VAR2CSA proteins, and parasites with >1 var2csa gene appear to be more common in pregnant women with placental malaria than in nonpregnant individuals. We present evidence that, in pregnant women, parasites containing multiple var2csa-type genes possess a selective...... advantage over parasites with a single var2csa gene. Accumulation of parasites with multiple copies of the var2csa gene during the course of pregnancy was also correlated with the development of antibodies involved in blocking VAR2CSA adhesion. The data suggest that multiplicity of var2csa-type genes...

  16. Interleukin 35 and Hepatocyte Growth Factor; as a novel combined immune gene therapy for Multiple Sclerosis disease.

    Science.gov (United States)

    Moghadam, Samira; Erfanmanesh, Maryam; Esmaeilzadeh, Abdolreza

    2017-11-01

    An autoimmune demyelination disease of the Central Nervous System, Multiple Sclerosis, is a chronic inflammation which mostly involves young adults. Suffering people face functional loss with a severe pain. Most current MS treatments are focused on the immune response suppression. Approved drugs suppress the inflammatory process, but factually, there is no definite cure for Multiple Sclerosis. Recently developed knowledge has demonstrated that gene and cell therapy as a hopeful approach in tissue regeneration. The authors propose a novel combined immune gene therapy for Multiple Sclerosis treatment using anti-inflammatory and remyelination of Interleukine-35 and Hepatocyte Growth Factor properties, respectively. In this hypothesis Interleukine-35 and Hepatocyte Growth Factor introduce to Mesenchymal Stem Cells of EAE mouse model via an adenovirus based vector. It is expected that Interleukine-35 and Hepatocyte Growth Factor genes expressed from MSCs could effectively perform in immunotherapy of Multiple Sclerosis. Copyright © 2017. Published by Elsevier Ltd.

  17. Assessing variability and long-term trends in burned area by merging multiple satellite fire products

    Directory of Open Access Journals (Sweden)

    L. Giglio

    2010-03-01

    Full Text Available Long term, high quality estimates of burned area are needed for improving both prognostic and diagnostic fire emissions models and for assessing feedbacks between fire and the climate system. We developed global, monthly burned area estimates aggregated to 0.5° spatial resolution for the time period July 1996 through mid-2009 using four satellite data sets. From 2001–2009, our primary data source was 500-m burned area maps produced using Moderate Resolution Imaging Spectroradiometer (MODIS surface reflectance imagery; more than 90% of the global area burned during this time period was mapped in this fashion. During times when the 500-m MODIS data were not available, we used a combination of local regression and regional regression trees developed over periods when burned area and Terra MODIS active fire data were available to indirectly estimate burned area. Cross-calibration with fire observations from the Tropical Rainfall Measuring Mission (TRMM Visible and Infrared Scanner (VIRS and the Along-Track Scanning Radiometer (ATSR allowed the data set to be extended prior to the MODIS era. With our data set we estimated that the global annual area burned for the years 1997–2008 varied between 330 and 431 Mha, with the maximum occurring in 1998. We compared our data set to the recent GFED2, L3JRC, GLOBCARBON, and MODIS MCD45A1 global burned area products and found substantial differences in many regions. Lastly, we assessed the interannual variability and long-term trends in global burned area over the past 13 years. This burned area time series serves as the basis for the third version of the Global Fire Emissions Database (GFED3 estimates of trace gas and aerosol emissions.

  18. Role of Metastasis in Hypertabastic Survival Analysis of Breast Cancer: Interaction with Clinical and Gene Expression Variables

    Directory of Open Access Journals (Sweden)

    Mohammad A. Tabatabai Ph.D.

    2012-01-01

    Full Text Available This paper analyzes the survival of breast cancer patients, exploring the role of a metastasis variable in combination with clinical and gene expression variables. We use the hypertabastic model in a detailed analysis of 295 breast cancer patients from the Netherlands Cancer Institute given in. 1 In comparison to Cox regression the increase in accuracy is complemented by the ability to analyze the time course of the disease progression using the explicitly described hazard and survival curves. We also demonstrate the ability to compute deciles for survival and probability of survival to a given time. Our primary concern in this article is the introduction of a variable representing the existence of metastasis and the effects on the other clinical and gene expression variables. In addition to making a quantitative assessment of the impact of metastasis on the prospects for survival, we are able to look at its interactions with the other prognostic variables. The estrogen receptor status increase in importance, while the significance of the gene expression variables used in the combined model diminishes. When considering only the subgroup of patients who experienced metastasis, the covariates in the model are only the clinical variables for estrogen receptor status and tumor grade.

  19. Land use regression modeling of intra-urban residential variability in multiple traffic-related air pollutants.

    Science.gov (United States)

    Clougherty, Jane E; Wright, Rosalind J; Baxter, Lisa K; Levy, Jonathan I

    2008-05-16

    There is a growing body of literature linking GIS-based measures of traffic density to asthma and other respiratory outcomes. However, no consensus exists on which traffic indicators best capture variability in different pollutants or within different settings. As part of a study on childhood asthma etiology, we examined variability in outdoor concentrations of multiple traffic-related air pollutants within urban communities, using a range of GIS-based predictors and land use regression techniques. We measured fine particulate matter (PM2.5), nitrogen dioxide (NO2), and elemental carbon (EC) outside 44 homes representing a range of traffic densities and neighborhoods across Boston, Massachusetts and nearby communities. Multiple three to four-day average samples were collected at each home during winters and summers from 2003 to 2005. Traffic indicators were derived using Massachusetts Highway Department data and direct traffic counts. Multivariate regression analyses were performed separately for each pollutant, using traffic indicators, land use, meteorology, site characteristics, and central site concentrations. PM2.5 was strongly associated with the central site monitor (R2 = 0.68). Additional variability was explained by total roadway length within 100 m of the home, smoking or grilling near the monitor, and block-group population density (R2 = 0.76). EC showed greater spatial variability, especially during winter months, and was predicted by roadway length within 200 m of the home. The influence of traffic was greater under low wind speed conditions, and concentrations were lower during summer (R2 = 0.52). NO2 showed significant spatial variability, predicted by population density and roadway length within 50 m of the home, modified by site characteristics (obstruction), and with higher concentrations during summer (R2 = 0.56). Each pollutant examined displayed somewhat different spatial patterns within urban neighborhoods, and were differently related to

  20. Land use regression modeling of intra-urban residential variability in multiple traffic-related air pollutants

    Directory of Open Access Journals (Sweden)

    Baxter Lisa K

    2008-05-01

    Full Text Available Abstract Background There is a growing body of literature linking GIS-based measures of traffic density to asthma and other respiratory outcomes. However, no consensus exists on which traffic indicators best capture variability in different pollutants or within different settings. As part of a study on childhood asthma etiology, we examined variability in outdoor concentrations of multiple traffic-related air pollutants within urban communities, using a range of GIS-based predictors and land use regression techniques. Methods We measured fine particulate matter (PM2.5, nitrogen dioxide (NO2, and elemental carbon (EC outside 44 homes representing a range of traffic densities and neighborhoods across Boston, Massachusetts and nearby communities. Multiple three to four-day average samples were collected at each home during winters and summers from 2003 to 2005. Traffic indicators were derived using Massachusetts Highway Department data and direct traffic counts. Multivariate regression analyses were performed separately for each pollutant, using traffic indicators, land use, meteorology, site characteristics, and central site concentrations. Results PM2.5 was strongly associated with the central site monitor (R2 = 0.68. Additional variability was explained by total roadway length within 100 m of the home, smoking or grilling near the monitor, and block-group population density (R2 = 0.76. EC showed greater spatial variability, especially during winter months, and was predicted by roadway length within 200 m of the home. The influence of traffic was greater under low wind speed conditions, and concentrations were lower during summer (R2 = 0.52. NO2 showed significant spatial variability, predicted by population density and roadway length within 50 m of the home, modified by site characteristics (obstruction, and with higher concentrations during summer (R2 = 0.56. Conclusion Each pollutant examined displayed somewhat different spatial patterns

  1. Holocene seasonal variability inferred from multiple proxy records from Crevice Lake, Yellowstone National Park, USA

    Science.gov (United States)

    Whitlock, Cathy; Dean, Walter E.; Fritz, Sherilyn C.; Stevens, Lora R.; Stone, Jeffery R.; Power, Mitchell J.; Rosenbaum, Joseph R.; Pierce, Kenneth L.; Bracht-Flyr, Brandi B.

    2012-01-01

    the Roman Warm Period (~ 2000 cal yr BP) and Medieval Climate Anomaly (1200–800 cal yr BP). Long springs and mild summers occurred during the Little Ice Age, and these conditions persist to the present. Although the proxy data indicate effectively wet summer conditions in the early Holocene and drier conditions in the middle and late Holocene, none point specifically to changes in summer precipitation as the cause. Instead, summer conditions were governed by multi-seasonal controls on effective moisture that operated over multiple time scales.

  2. Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci

    Science.gov (United States)

    Asselbergs, Folkert W.; Guo, Yiran; van Iperen, Erik P.A.; Sivapalaratnam, Suthesh; Tragante, Vinicius; Lanktree, Matthew B.; Lange, Leslie A.; Almoguera, Berta; Appelman, Yolande E.; Barnard, John; Baumert, Jens; Beitelshees, Amber L.; Bhangale, Tushar R.; Chen, Yii-Der Ida; Gaunt, Tom R.; Gong, Yan; Hopewell, Jemma C.; Johnson, Toby; Kleber, Marcus E.; Langaee, Taimour Y.; Li, Mingyao; Li, Yun R.; Liu, Kiang; McDonough, Caitrin W.; Meijs, Matthijs F.L.; Middelberg, Rita P.S.; Musunuru, Kiran; Nelson, Christopher P.; O’Connell, Jeffery R.; Padmanabhan, Sandosh; Pankow, James S.; Pankratz, Nathan; Rafelt, Suzanne; Rajagopalan, Ramakrishnan; Romaine, Simon P.R.; Schork, Nicholas J.; Shaffer, Jonathan; Shen, Haiqing; Smith, Erin N.; Tischfield, Sam E.; van der Most, Peter J.; van Vliet-Ostaptchouk, Jana V.; Verweij, Niek; Volcik, Kelly A.; Zhang, Li; Bailey, Kent R.; Bailey, Kristian M.; Bauer, Florianne; Boer, Jolanda M.A.; Braund, Peter S.; Burt, Amber; Burton, Paul R.; Buxbaum, Sarah G.; Chen, Wei; Cooper-DeHoff, Rhonda M.; Cupples, L. Adrienne; deJong, Jonas S.; Delles, Christian; Duggan, David; Fornage, Myriam; Furlong, Clement E.; Glazer, Nicole; Gums, John G.; Hastie, Claire; Holmes, Michael V.; Illig, Thomas; Kirkland, Susan A.; Kivimaki, Mika; Klein, Ronald; Klein, Barbara E.; Kooperberg, Charles; Kottke-Marchant, Kandice; Kumari, Meena; LaCroix, Andrea Z.; Mallela, Laya; Murugesan, Gurunathan; Ordovas, Jose; Ouwehand, Willem H.; Post, Wendy S.; Saxena, Richa; Scharnagl, Hubert; Schreiner, Pamela J.; Shah, Tina; Shields, Denis C.; Shimbo, Daichi; Srinivasan, Sathanur R.; Stolk, Ronald P.; Swerdlow, Daniel I.; Taylor, Herman A.; Topol, Eric J.; Toskala, Elina; van Pelt, Joost L.; van Setten, Jessica; Yusuf, Salim; Whittaker, John C.; Zwinderman, A.H.; Anand, Sonia S.; Balmforth, Anthony J.; Berenson, Gerald S.; Bezzina, Connie R.; Boehm, Bernhard O.; Boerwinkle, Eric; Casas, Juan P.; Caulfield, Mark J.; Clarke, Robert; Connell, John M.; Cruickshanks, Karen J.; Davidson, Karina W.; Day, Ian N.M.; de Bakker, Paul I.W.; Doevendans, Pieter A.; Dominiczak, Anna F.; Hall, Alistair S.; Hartman, Catharina A.; Hengstenberg, Christian; Hillege, Hans L.; Hofker, Marten H.; Humphries, Steve E.; Jarvik, Gail P.; Johnson, Julie A.; Kaess, Bernhard M.; Kathiresan, Sekar; Koenig, Wolfgang; Lawlor, Debbie A.; März, Winfried; Melander, Olle; Mitchell, Braxton D.; Montgomery, Grant W.; Munroe, Patricia B.; Murray, Sarah S.; Newhouse, Stephen J.; Onland-Moret, N. Charlotte; Poulter, Neil; Psaty, Bruce; Redline, Susan; Rich, Stephen S.; Rotter, Jerome I.; Schunkert, Heribert; Sever, Peter; Shuldiner, Alan R.; Silverstein, Roy L.; Stanton, Alice; Thorand, Barbara; Trip, Mieke D.; Tsai, Michael Y.; van der Harst, Pim; van der Schoot, Ellen; van der Schouw, Yvonne T.; Verschuren, W.M. Monique; Watkins, Hugh; Wilde, Arthur A.M.; Wolffenbuttel, Bruce H.R.; Whitfield, John B.; Hovingh, G. Kees; Ballantyne, Christie M.; Wijmenga, Cisca; Reilly, Muredach P.; Martin, Nicholas G.; Wilson, James G.; Rader, Daniel J.; Samani, Nilesh J.; Reiner, Alex P.; Hegele, Robert A.; Kastelein, John J.P.; Hingorani, Aroon D.; Talmud, Philippa J.; Hakonarson, Hakon; Elbers, Clara C.; Keating, Brendan J.; Drenos, Fotios

    2012-01-01

    Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom ∼50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering ∼2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids. PMID:23063622

  3. Multiple driving factors explain spatial and temporal variability in coral calcification rates on the Bermuda platform

    Science.gov (United States)

    Venti, A.; Andersson, A.; Langdon, C.

    2014-12-01

    Experimental studies have shown that coral calcification rates are dependent on light, nutrients, food availability, temperature, and seawater aragonite saturation ( Ω arag), but the relative importance of each parameter in natural settings remains uncertain. In this study, we applied Calcein fluorescent dyes as time indicators within the skeleton of coral colonies ( n = 3) of Porites astreoides and Diploria strigosa at three study sites distributed across the northern Bermuda coral reef platform. We evaluated the correlation between seasonal average growth rates based on coral density and extension rates with average temperature, light, and seawater Ω arag in an effort to decipher the relative importance of each parameter. The results show significant seasonal differences among coral calcification rates ranging from summer maximums of 243 ± 58 and 274 ± 57 mmol CaCO3 m-2 d-1 to winter minimums of 135 ± 39 and 101 ± 34 mmol CaCO3 m-2 d-1 for P. astreoides and D. strigosa, respectively. We also placed small coral colonies ( n = 10) in transparent chambers and measured the instantaneous rate of calcification under light and dark treatments at the same study sites. The results showed that the skeletal growth of D. strigosa and P. astreoides, whether hourly or seasonal, was highly sensitive to Ω arag. We believe this high sensitivity, however, is misleading, due to covariance between light and Ω arag, with the former being the strongest driver of calcification variability. For the seasonal data, we assessed the impact that the observed seasonal differences in temperature (4.0 °C), light (5.1 mol photons m-2 d-1), and Ω arag (0.16 units) would have on coral growth rates based on established relationships derived from laboratory studies and found that they could account for approximately 44, 52, and 5 %, respectively, of the observed seasonal change of 81 ± 14 mmol CaCO3 m-2 d-1. Using short-term light and dark incubations, we show how the covariance of light

  4. GAP1, a novel selection and counter-selection marker for multiple gene disruptions in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Regenberg, Birgitte; Hansen, J.

    2000-01-01

    We report on the use of a new homologous marker for use in multiple gene deletions in S, cerevisiae, the general amino acid permease gene (GAP1), A GAP1 strain can utilize L-citrulline as the sole nitrogen source but cannot grow in the presence of the toxic amino acid D-histidine, L-citrulline as......We report on the use of a new homologous marker for use in multiple gene deletions in S, cerevisiae, the general amino acid permease gene (GAP1), A GAP1 strain can utilize L-citrulline as the sole nitrogen source but cannot grow in the presence of the toxic amino acid D-histidine, L...... flanked by short (60 bp) stretches of the gene in question. Through homologous recombination, the cassette will integrate into the target gene, which is thus replaced by GAP1, and mutants are selected for on minimal L-citrulline medium. When propagated under non-selective conditions, some cells will lose...... the GAP1 gene. This is caused by recombination between two Salmonella typuimurium hisG direct repeats embracing GAP1, and will result in a sub-population of gap1 cells. Such cells are selected on a medium containing D-histidine, and may subsequently be used for a second gene disruption. Hence, multiple...

  5. Glatiramer acetate antibodies, gene expression and disease activity in multiple sclerosis

    DEFF Research Database (Denmark)

    Sellebjerg, Finn Thorup; Hedegaard, Chris Juul; Krakauer, M

    2011-01-01

    Background: Glatiramer acetate (GA) treatment suppresses disease activity in multiple sclerosis (MS). The immunological response to treatment may differ in patients who are stable on GA therapy and patients with breakthrough disease activity, but the results of previous studies are inconsistent....... Objectives: We studied the immunological response to GA and its relationship with disease activity. Methods: Anti-GA antibodies in plasma and the expression of genes encoding cytokines and T-cell-polarizing transcription factors in blood cells were analysed by flow cytometric bead array and polymerase chain...... and transcription factors was reduced during long-term treatment, but there was no relationship between the expression of cytokines and transcription factors and anti-GA antibodies. High expression of mRNA encoding GATA3 and lymphotoxin-β (LT-β) was associated with low disease activity in Gd-enhanced MRI studies...

  6. Genetic variants of CC chemokine genes in experimental autoimmune encephalomyelitis, multiple sclerosis and rheumatoid arthritis

    DEFF Research Database (Denmark)

    Ockinger, J; Stridh, P; Beyeen, A D

    2010-01-01

    Multiple sclerosis (MS) is a complex disorder of the central nervous system, causing inflammation, demyelination and axonal damage. A limited number of genetic risk factors for MS have been identified, but the etiology of the disease remains largely unknown. For the identification of genes...... regulating neuroinflammation we used a rat model of MS, myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE), and carried out a linkage analysis in an advanced intercross line (AIL). We thereby redefine the Eae18b locus to a 0.88 Mb region, including a cluster....... A haplotype in CCL2 and rs3136682 in CCL1 show a protective association to MS, whereas a haplotype in CCL13 is disease predisposing. In the HLA-DRB1* 15 positive subgroup, we also identified an association to a risk haplotype in CCL2, suggesting an influence from the human leukocyte antigen (HLA) locus. We...

  7. Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma

    DEFF Research Database (Denmark)

    Kristensen, Ida B; Christensen, Jacob Haaber; Lyng, Maria Bibi

    2014-01-01

    of osteoclast regulators (RANK, RANKL, OPG, TRAIL, MIP1A), Wnt inhibitors (DKK1, SFRP2, SFRP3, sclerostin, WIF1) and osteoblast transcription factors (RUNX2, osterix) by quantitative reverse transcriptase polymerase chain reaction (RT-PCR) in the bone marrow (BM) microenvironment using snap-frozen BM biopsies......Multiple myeloma (MM) lytic bone disease (LBD) is caused by osteoclast activation and osteoblast inhibition. RANK/RANKL/OPG play central roles in osteoclast activation and Wnt inhibitor DKK1 in osteoblast inhibition. The role of other Wnt inhibitors is less clear. We evaluated gene expression...... radiographs and the bone resorption marker CTX-1. Protein levels were evaluated by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry. Among Wnt inhibitors, only SFRP3 and DKK1 were significantly overexpressed in advanced LBD, correlating with protein levels. SFRP3 correlated with CTX-1. Our...

  8. Genome of Thysanoplusia orichalcea multiple nucleopolyhedrovirus lacks the superoxide dismutase gene.

    Science.gov (United States)

    Wang, Yun-Sheng; Huang, Guo-Hua; Cheng, Xin-Hua; Wang, Xing; Garretson, Tyler A; Dai, Liang-Ying; Zhang, Chuan-Xi; Cheng, Xiao-Wen

    2012-11-01

    Thysanoplusia orichalcea multiple nucleopolyhedrovirus (ThorMNPV) has high virulence to Trichoplusia ni and Pseudoplusia includens larvae, with a potential for biological control of insect pests. The genome of ThorMNPV was sequenced and found to be 132,978 bp, with a G+C content of 37.9%. There are 145 predicted open reading frames (ORFs), encoding proteins of 50 or more amino acid residues with minimal overlap. Of the 145 ORFs, 141 appeared to be homologous to those of Autographa californica MNPV (AcMNPV). In comparison to AcMNPV, 9 ORFs of AcMNPV were absent in ThorMNPV, including the superoxide dismutase (sod) gene.

  9. Relationship between rice yield and climate variables in southwest Nigeria using multiple linear regression and support vector machine analysis.

    Science.gov (United States)

    Oguntunde, Philip G; Lischeid, Gunnar; Dietrich, Ottfried

    2017-10-14

    This study examines the variations of climate variables and rice yield and quantifies the relationships among them using multiple linear regression, principal component analysis, and support vector machine (SVM) analysis in southwest Nigeria. The climate and yield data used was for a period of 36 years between 1980 and 2015. Similar to the observed decrease (P yield, pan evaporation, solar radiation, and wind speed declined significantly. Eight principal components exhibited an eigenvalue > 1 and explained 83.1% of the total variance of predictor variables. The SVM regression function using the scores of the first principal component explained about 75% of the variance in rice yield data and linear regression about 64%. SVM regression between annual solar radiation values and yield explained 67% of the variance. Only the first component of the principal component analysis (PCA) exhibited a clear long-term trend and sometimes short-term variance similar to that of rice yield. Short-term fluctuations of the scores of the PC1 are closely coupled to those of rice yield during the 1986-1993 and the 2006-2013 periods thereby revealing the inter-annual sensitivity of rice production to climate variability. Solar radiation stands out as the climate variable of highest influence on rice yield, and the influence was especially strong during monsoon and post-monsoon periods, which correspond to the vegetative, booting, flowering, and grain filling stages in the study area. The outcome is expected to provide more in-depth regional-specific climate-rice linkage for screening of better cultivars that can positively respond to future climate fluctuations as well as providing information that may help optimized planting dates for improved radiation use efficiency in the study area.

  10. Relationship between rice yield and climate variables in southwest Nigeria using multiple linear regression and support vector machine analysis

    Science.gov (United States)

    Oguntunde, Philip G.; Lischeid, Gunnar; Dietrich, Ottfried

    2017-10-01

    This study examines the variations of climate variables and rice yield and quantifies the relationships among them using multiple linear regression, principal component analysis, and support vector machine (SVM) analysis in southwest Nigeria. The climate and yield data used was for a period of 36 years between 1980 and 2015. Similar to the observed decrease (P 1 and explained 83.1% of the total variance of predictor variables. The SVM regression function using the scores of the first principal component explained about 75% of the variance in rice yield data and linear regression about 64%. SVM regression between annual solar radiation values and yield explained 67% of the variance. Only the first component of the principal component analysis (PCA) exhibited a clear long-term trend and sometimes short-term variance similar to that of rice yield. Short-term fluctuations of the scores of the PC1 are closely coupled to those of rice yield during the 1986-1993 and the 2006-2013 periods thereby revealing the inter-annual sensitivity of rice production to climate variability. Solar radiation stands out as the climate variable of highest influence on rice yield, and the influence was especially strong during monsoon and post-monsoon periods, which correspond to the vegetative, booting, flowering, and grain filling stages in the study area. The outcome is expected to provide more in-depth regional-specific climate-rice linkage for screening of better cultivars that can positively respond to future climate fluctuations as well as providing information that may help optimized planting dates for improved radiation use efficiency in the study area.

  11. Hidden variability of floral homeotic B genes in Solanaceae provides a molecular basis for the evolution of novel functions.

    Science.gov (United States)

    Geuten, Koen; Irish, Vivian

    2010-08-01

    B-class MADS box genes specify petal and stamen identities in several core eudicot species. Members of the Solanaceae possess duplicate copies of these genes, allowing for diversification of function. To examine the changing roles of such duplicate orthologs, we assessed the functions of B-class genes in Nicotiana benthamiana and tomato (Solanum lycopersicum) using virus-induced gene silencing and RNA interference approaches. Loss of function of individual duplicates can have distinct phenotypes, yet complete loss of B-class gene function results in extreme homeotic transformations of petal and stamen identities. We also show that these duplicate gene products have qualitatively different protein-protein interaction capabilities and different regulatory roles. Thus, compensatory changes in B-class MADS box gene duplicate function have occurred in the Solanaceae, in that individual gene roles are distinct, but their combined functions are equivalent. Furthermore, we show that species-specific differences in the stamen regulatory network are associated with differences in the expression of the microRNA miR169. Whereas there is considerable plasticity in individual B-class MADS box transcription factor function, there is overall conservation in the roles of the multimeric MADS box B-class protein complexes, providing robustness in the specification of petal and stamen identities. Such hidden variability in gene function as we observe for individual B-class genes can provide a molecular basis for the evolution of regulatory functions that result in novel morphologies.

  12. High variability of expression profiles of homeologous genes for Wnt, Hh, Notch, and Hippo signaling pathways in Xenopus laevis.

    Science.gov (United States)

    Michiue, Tatsuo; Yamamoto, Takayoshi; Yasuoka, Yuuri; Goto, Toshiyasu; Ikeda, Takafumi; Nagura, Kei; Nakayama, Takuya; Taira, Masanori; Kinoshita, Tsutomu

    2017-06-15

    Cell signaling pathways, such as Wnt, Hedgehog (Hh), Notch, and Hippo, are essential for embryogenesis, organogenesis, and tissue homeostasis. In this study, we analyzed 415 genes involved in these pathways in the allotetraploid frog, Xenopus laevis. Most genes are retained in two subgenomes called L and S (193 homeologous gene pairs and 29 singletons). This conservation rate of homeologs is much higher than that of all genes in the X. laevis genome (86.9% vs 60.2%). Among singletons, 24 genes are retained in the L subgenome, a rate similar to the average for all genes (82.8% vs 74.6%). In addition, as general components of signal transduction, we also analyzed 32 heparan sulfate proteoglycan (HSPG)-related genes and eight TLE/Groucho transcriptional corepressors-related genes. In these gene sets, all homeologous pairs have been retained. Transcriptome analysis using RNA-seq data from developmental stages and adult tissues demonstrated that most homeologous pairs of signaling components have variable expression patterns, in contrast to the conservative expression profiles of homeologs for transcription factors. Our results indicate that homeologous gene pairs for cell signaling regulation have tended to become subfunctionalized after allotetraploidization. Diversification of signaling pathways by subfunctionalization of homeologs may enhance environmental adaptability. These results provide insights into the evolution of signaling pathways after polyploidization. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. The removal of multiplicative, systematic bias allows integration of breast cancer gene expression datasets – improving meta-analysis and prediction of prognosis

    Directory of Open Access Journals (Sweden)

    Pepper Stuart D

    2008-09-01

    Full Text Available Abstract Background The number of gene expression studies in the public domain is rapidly increasing, representing a highly valuable resource. However, dataset-specific bias precludes meta-analysis at the raw transcript level, even when the RNA is from comparable sources and has been processed on the same microarray platform using similar protocols. Here, we demonstrate, using Affymetrix data, that much of this bias can be removed, allowing multiple datasets to be legitimately combined for meaningful meta-analyses. Results A series of validation datasets comparing breast cancer and normal breast cell lines (MCF7 and MCF10A were generated to examine the variability between datasets generated using different amounts of starting RNA, alternative protocols, different generations of Affymetrix GeneChip or scanning hardware. We demonstrate that systematic, multiplicative biases are introduced at the RNA, hybridization and image-capture stages of a microarray experiment. Simple batch mean-centering was found to significantly reduce the level of inter-experimental variation, allowing raw transcript levels to be compared across datasets with confidence. By accounting for dataset-specific bias, we were able to assemble the largest gene expression dataset of primary breast tumours to-date (1107, from six previously published studies. Using this meta-dataset, we demonstrate that combining greater numbers of datasets or tumours leads to a greater overlap in differentially expressed genes and more accurate prognostic predictions. However, this is highly dependent upon the composition of the datasets and patient characteristics. Conclusion Multiplicative, systematic biases are introduced at many stages of microarray experiments. When these are reconciled, raw data can be directly integrated from different gene expression datasets leading to new biological findings with increased statistical power.

  14. Iron-related gene variants and brain iron in multiple sclerosis and healthy individuals.

    Science.gov (United States)

    Hagemeier, Jesper; Ramanathan, Murali; Schweser, Ferdinand; Dwyer, Michael G; Lin, Fuchun; Bergsland, Niels; Weinstock-Guttman, Bianca; Zivadinov, Robert

    2018-01-01

    Brain iron homeostasis is known to be disturbed in multiple sclerosis (MS), yet little is known about the association of common gene variants linked to iron regulation and pathological tissue changes in the brain. In this study, we investigated the association of genetic determinants linked to iron regulation with deep gray matter (GM) magnetic susceptibility in both healthy controls (HC) and MS patients. Four hundred (400) patients with MS and 150 age- and sex-matched HCs were enrolled and obtained 3 T MRI examination. Three (3) single nucleotide polymorphisms (SNPs) associated with iron regulation were genotyped: two SNPs in the human hereditary hemochromatosis protein gene HFE : rs1800562 (C282Y mutation) and rs1799945 (H63D mutation), as well as the rs1049296 SNP in the transferrin gene (C2 mutation). The effects of disease and genetic status were studied using quantitative susceptibility mapping (QSM) voxel-based analysis (VBA) and region-of-interest (ROI) analysis of the deep GM. The general linear model framework was used to compare groups. Analyses were corrected for age and sex, and adjusted for false discovery rate. We found moderate increases in susceptibility in the right putamen of participants with the C282Y (+ 6.1 ppb) and H63D (+ 6.9 ppb) gene variants vs. non-carriers, as well as a decrease in thalamic susceptibility of progressive MS patients with the C282Y mutation (left: - 5.3 ppb, right: - 6.7 ppb, p < 0.05). Female MS patients had lower susceptibility in the caudate (- 6.0 ppb) and putamen (left: - 3.9 ppb, right: - 4.6 ppb) than men, but only when they had a wild-type allele (p < 0.05). Iron-gene linked increases in putamen susceptibility (in HC and relapsing remitting MS) and decreases in thalamus susceptibility (in progressive MS), coupled with apparent sex interactions, indicate that brain iron in healthy and disease states may be influenced by genetic factors.

  15. Identification of gene expression patterns crucially involved in experimental autoimmune encephalomyelitis and multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Martin M. Herrmann

    2016-10-01

    Full Text Available After encounter with a central nervous system (CNS-derived autoantigen, lymphocytes leave the lymph nodes and enter the CNS. This event leads only rarely to subsequent tissue damage. Genes relevant to CNS pathology after cell infiltration are largely undefined. Myelin-oligodendrocyte-glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE is an animal model of multiple sclerosis (MS, a chronic autoimmune disease of the CNS that results in disability. To assess genes that are involved in encephalitogenicity and subsequent tissue damage mediated by CNS-infiltrating cells, we performed a DNA microarray analysis from cells derived from lymph nodes and eluted from CNS in LEW.1AV1 (RT1av1 rats immunized with MOG 91-108. The data was compared to immunizations with adjuvant alone or naive rats and to immunizations with the immunogenic but not encephalitogenic MOG 73-90 peptide. Here, we show involvement of Cd38, Cxcr4 and Akt and confirm these findings by the use of Cd38-knockout (B6.129P2-Cd38tm1Lnd/J mice, S1P-receptor modulation during EAE and quantitative expression analysis in individuals with MS. The hereby-defined underlying pathways indicate cellular activation and migration pathways mediated by G-protein-coupled receptors as crucial events in CNS tissue damage. These pathways can be further explored for novel therapeutic interventions.

  16. Involvement of Multiple Gene-Silencing Pathways in a Paramutation-like Phenomenon in Arabidopsis

    Directory of Open Access Journals (Sweden)

    Zhimin Zheng

    2015-05-01

    Full Text Available Paramutation is an epigenetic phenomenon that has been observed in a number of multicellular organisms. The epigenetically silenced state of paramutated alleles is not only meiotically stable but also “infectious” to active homologous alleles. The molecular mechanism of paramutation remains unclear, but components involved in RNA-directed DNA methylation (RdDM are required. Here, we report a multi-copy pRD29A-LUC transgene in Arabidopsis thaliana that behaves like a paramutation locus. The silent state of LUC is induced by mutations in the DNA glycosylase gene ROS1. The silent alleles of LUC are not only meiotically stable but also able to transform active LUC alleles into silent ones, in the absence of ros1 mutations. Maintaining silencing at the LUC gene requires action of multiple pathways besides RdDM. Our study identified specific factors that are involved in the paramutation-like phenomenon and established a model system for the study of paramutation in Arabidopsis.

  17. Multiple Genes Cause Postmating Prezygotic Reproductive Isolation in the Drosophila virilis Group

    Directory of Open Access Journals (Sweden)

    Yasir H. Ahmed-Braimah

    2016-12-01

    Full Text Available Understanding the genetic basis of speciation is a central problem in evolutionary biology. Studies of reproductive isolation have provided several insights into the genetic causes of speciation, especially in taxa that lend themselves to detailed genetic scrutiny. Reproductive barriers have usually been divided into those that occur before zygote formation (prezygotic and after (postzygotic, with the latter receiving a great deal of attention over several decades. Reproductive barriers that occur after mating but before zygote formation [postmating prezygotic (PMPZ] are especially understudied at the genetic level. Here, I present a phenotypic and genetic analysis of a PMPZ reproductive barrier between two species of the Drosophila virilis group: D. americana and D. virilis. This species pair shows strong PMPZ isolation, especially when D. americana males mate with D. virilis females: ∼99% of eggs laid after these heterospecific copulations are not fertilized. Previous work has shown that the paternal loci contributing to this incompatibility reside on two chromosomes, one of which (chromosome 5 likely carries multiple factors. The other (chromosome 2 is fixed for a paracentric inversion that encompasses nearly half the chromosome. Here, I present two results. First, I show that PMPZ in this species cross is largely due to defective sperm storage in heterospecific copulations. Second, using advanced intercross and backcross mapping approaches, I identify genomic regions that carry genes capable of rescuing heterospecific fertilization. I conclude that paternal incompatibility between D. americana males and D. virilis females is underlain by four or more genes on chromosomes 2 and 5.

  18. Retinyl Palmitate Supplementation Modulates T-bet and Interferon Gamma Gene Expression in Multiple Sclerosis Patients.

    Science.gov (United States)

    Mohammadzadeh Honarvar, Niyaz; Harirchian, Mohammad Hossein; Abdolahi, Mina; Abedi, Elahe; Bitarafan, Sama; Koohdani, Fariba; Siassi, Feridoun; Sahraian, Mohammad Ali; Chahardoli, Reza; Zareei, Mahnaz; Salehi, Eisa; Geranmehr, Maziyar; Saboor-Yaraghi, Ali Akbar

    2016-07-01

    Vitamin A derivatives such as retinoic acid may improve the impaired balance of CD4+ T cells in autoimmune and inflammatory diseases. This study is a double-blind randomized trial to evaluate the effect of vitamin A (as form of retinyl palmitate) supplementation on multiple sclerosis (MS) patients. Thirty-nine patients were enrolled and randomly assigned to two groups. Both groups were followed for 6 months. The experimental group received 25,000 IU of retinyl palmitate daily, while the control group received a placebo. Before and after the study, the expression of interferon gamma (IFN-γ) and T-bet genes was evaluated in peripheral blood mononuclear cells of patients by RT-PCR. The results showed that after 6 months of supplementation, expression of IFN-γ and T-bet was significantly decreased. These data suggest that retinyl palmitate supplementation can modulate the impaired balance of Th1 and Th2 cells and vitamin A products that may be involved in the therapeutic mechanism of vitamin A in MS patients. This study provides information regarding the decreased gene expression of IFN-γ and T-bet in MS by retinyl palmitate supplementation.

  19. Multiple genetic interaction experiments provide complementary information useful for gene function prediction.

    Directory of Open Access Journals (Sweden)

    Magali Michaut

    Full Text Available Genetic interactions help map biological processes and their functional relationships. A genetic interaction is defined as a deviation from the expected phenotype when combining multiple genetic mutations. In Saccharomyces cerevisiae, most genetic interactions are measured under a single phenotype - growth rate in standard laboratory conditions. Recently genetic interactions have been collected under different phenotypic readouts and experimental conditions. How different are these networks and what can we learn from their differences? We conducted a systematic analysis of quantitative genetic interaction networks in yeast performed under different experimental conditions. We find that networks obtained using different phenotypic readouts, in different conditions and from different laboratories overlap less than expected and provide significant unique information. To exploit this information, we develop a novel method to combine individual genetic interaction data sets and show that the resulting network improves gene function prediction performance, demonstrating that individual networks provide complementary information. Our results support the notion that using diverse phenotypic readouts and experimental conditions will substantially increase the amount of gene function information produced by genetic interaction screens.

  20. Multiple Linear Regression for Reconstruction of Gene Regulatory Networks in Solving Cascade Error Problems

    Science.gov (United States)

    Zainudin, Suhaila; Arif, Shereena M.

    2017-01-01

    Gene regulatory network (GRN) reconstruction is the process of identifying regulatory gene interactions from experimental data through computational analysis. One of the main reasons for the reduced performance of previous GRN methods had been inaccurate prediction of cascade motifs. Cascade error is defined as the wrong prediction of cascade motifs, where an indirect interaction is misinterpreted as a direct interaction. Despite the active research on various GRN prediction methods, the discussion on specific methods to solve problems related to cascade errors is still lacking. In fact, the experiments conducted by the past studies were not specifically geared towards proving the ability of GRN prediction methods in avoiding the occurrences of cascade errors. Hence, this research aims to propose Multiple Linear Regression (MLR) to infer GRN from gene expression data and to avoid wrongly inferring of an indirect interaction (A → B → C) as a direct interaction (A → C). Since the number of observations of the real experiment datasets was far less than the number of predictors, some predictors were eliminated by extracting the random subnetworks from global interaction networks via an established extraction method. In addition, the experiment was extended to assess the effectiveness of MLR in dealing with cascade error by using a novel experimental procedure that had been proposed in this work. The experiment revealed that the number of cascade errors had been very minimal. Apart from that, the Belsley collinearity test proved that multicollinearity did affect the datasets used in this experiment greatly. All the tested subnetworks obtained satisfactory results, with AUROC values above 0.5. PMID:28250767

  1. Simultaneous Targeting of Multiple Gene Homeologs to Alter Seed Oil Production in Camelina sativa.

    Science.gov (United States)

    Aznar-Moreno, J A; Durrett, T P

    2017-07-01

    The ability to transform Camelina sativa easily with biosynthetic enzymes derived from other plants has made this oil seed crop an ideal platform for the production of unusual lipids valuable for different applications. However, in addition to expressing transgenic enzymes, the suppression of endogenous enzyme activity to reduce competition for common substrates or cofactors is also required to enhance the production of target compounds. As camelina possesses a relatively undifferentiated hexaploid genome, up to three gene homeologs can code for any particular enzymatic activity, complicating efforts to alter endogenous biosynthetic pathways. New genome editing technologies, such as that offered by the CRISPR/Cas (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein) system, offer the capability to introduce mutations into specifically targeted genomic sites. Here, by using a carefully designed guide RNA identical to all three homeologs, we demonstrate the ability of the CRISPR/Cas genome editing system to introduce mutations in all three CsDGAT1 or CsPDAT1 homeologous genes important for triacylglycerol (TAG) synthesis in developing seeds. Sequence analysis from transgenic T1 plants revealed that each CsDGAT1 or each CsPDAT1 homeolog was altered by multiple mutations, resulting in a genetic mosaic in the plants. Interestingly, seed harvested from both CsDGAT1- and CsPDAT1-targeted lines was often shrunken and wrinkled. Further, lipid analysis revealed that many lines produced seed with reduced oil content and altered fatty acid composition, consistent with the role of the targeted genes in seed oil biosynthesis. The CRISPR/Cas system therefore represents a useful method to alter endogenous biosynthetic pathways efficiently in polyploid species such as camelina. © The Author 2017. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  2. Multiple Linear Regression for Reconstruction of Gene Regulatory Networks in Solving Cascade Error Problems.

    Science.gov (United States)

    Salleh, Faridah Hani Mohamed; Zainudin, Suhaila; Arif, Shereena M

    2017-01-01

    Gene regulatory network (GRN) reconstruction is the process of identifying regulatory gene interactions from experimental data through computational analysis. One of the main reasons for the reduced performance of previous GRN methods had been inaccurate prediction of cascade motifs. Cascade error is defined as the wrong prediction of cascade motifs, where an indirect interaction is misinterpreted as a direct interaction. Despite the active research on various GRN prediction methods, the discussion on specific methods to solve problems related to cascade errors is still lacking. In fact, the experiments conducted by the past studies were not specifically geared towards proving the ability of GRN prediction methods in avoiding the occurrences of cascade errors. Hence, this research aims to propose Multiple Linear Regression (MLR) to infer GRN from gene expression data and to avoid wrongly inferring of an indirect interaction (A → B → C) as a direct interaction (A → C). Since the number of observations of the real experiment datasets was far less than the number of predictors, some predictors were eliminated by extracting the random subnetworks from global interaction networks via an established extraction method. In addition, the experiment was extended to assess the effectiveness of MLR in dealing with cascade error by using a novel experimental procedure that had been proposed in this work. The experiment revealed that the number of cascade errors had been very minimal. Apart from that, the Belsley collinearity test proved that multicollinearity did affect the datasets used in this experiment greatly. All the tested subnetworks obtained satisfactory results, with AUROC values above 0.5.

  3. Sox10 controls migration of B16F10 melanoma cells through multiple regulatory target genes.

    Directory of Open Access Journals (Sweden)

    Ikjoo Seong

    Full Text Available It is believed that the inherent differentiation program of melanocytes during embryogenesis predisposes melanoma cells to high frequency of metastasis. Sox10, a transcription factor expressed in neural crest stem cells and a subset of progeny lineages, plays a key role in the development of melanocytes. We show that B16F10 melanoma cells transfected with siRNAs specific for Sox10 display reduced migratory activity which in turn indicated that a subset of transcriptional regulatory target genes of Sox10 is likely to be involved in migration and metastasis of melanoma cells. We carried out a microarray-based gene expression profiling using a Sox10-specific siRNA to identify relevant regulatory targets and found that multiple genes including melanocortin-1 receptor (Mc1r partake in the regulation of migration. We provide evidences that the effect of Sox10 on migration is mediated in large part by Mitf, a transcription factor downstream to Sox10. Among the mouse melanoma cell lines examined, however, only B16F10 showed robust down-regulation of Sox10 and inhibition of cell migration indicating that further dissection of dosage effects and/or cell line-specific regulatory networks is necessary. The involvement of Mc1r in migration was studied in detail in vivo using a murine metastasis model. Specifically, B16F10 melanoma cells treated with a specific siRNA showed reduced tendency in metastasizing to and colonizing the lung after being injected in the tail vein. These data reveal a cadre of novel regulators and mediators involved in migration and metastasis of melanoma cells that represents potential targets of therapeutic intervention.

  4. Multiple Linear Regression for Reconstruction of Gene Regulatory Networks in Solving Cascade Error Problems

    Directory of Open Access Journals (Sweden)

    Faridah Hani Mohamed Salleh

    2017-01-01

    Full Text Available Gene regulatory network (GRN reconstruction is the process of identifying regulatory gene interactions from experimental data through computational analysis. One of the main reasons for the reduced performance of previous GRN methods had been inaccurate prediction of cascade motifs. Cascade error is defined as the wrong prediction of cascade motifs, where an indirect interaction is misinterpreted as a direct interaction. Despite the active research on various GRN prediction methods, the discussion on specific methods to solve problems related to cascade errors is still lacking. In fact, the experiments conducted by the past studies were not specifically geared towards proving the ability of GRN prediction methods in avoiding the occurrences of cascade errors. Hence, this research aims to propose Multiple Linear Regression (MLR to infer GRN from gene expression data and to avoid wrongly inferring of an indirect interaction (A → B → C as a direct interaction (A → C. Since the number of observations of the real experiment datasets was far less than the number of predictors, some predictors were eliminated by extracting the random subnetworks from global interaction networks via an established extraction method. In addition, the experiment was extended to assess the effectiveness of MLR in dealing with cascade error by using a novel experimental procedure that had been proposed in this work. The experiment revealed that the number of cascade errors had been very minimal. Apart from that, the Belsley collinearity test proved that multicollinearity did affect the datasets used in this experiment greatly. All the tested subnetworks obtained satisfactory results, with AUROC values above 0.5.

  5. A polymorphism in the HLA-DPB1 gene is associated with susceptibility to multiple sclerosis.

    Directory of Open Access Journals (Sweden)

    Judith Field

    2010-10-01

    Full Text Available We conducted an association study across the human leukocyte antigen (HLA complex to identify loci associated with multiple sclerosis (MS. Comparing 1927 SNPs in 1618 MS cases and 3413 controls of European ancestry, we identified seven SNPs that were independently associated with MS conditional on the others (each P ≤ 4 x 10(-6. All associations were significant in an independent replication cohort of 2212 cases and 2251 controls (P ≤ 0.001 and were highly significant in the combined dataset (P ≤ 6 x 10(-8. The associated SNPs included proxies for HLA-DRB1*15:01 and HLA-DRB1*03:01, and SNPs in moderate linkage disequilibrium (LD with HLA-A*02:01, HLA-DRB1*04:01 and HLA-DRB1*13:03. We also found a strong association with rs9277535 in the class II gene HLA-DPB1 (discovery set P = 9 x 10(-9, replication set P = 7 x 10(-4, combined P = 2 x 10(-10. HLA-DPB1 is located centromeric of the more commonly typed class II genes HLA-DRB1, -DQA1 and -DQB1. It is separated from these genes by a recombination hotspot, and the association is not affected by conditioning on genotypes at DRB1, DQA1 and DQB1. Hence rs9277535 represents an independent MS-susceptibility locus of genome-wide significance. It is correlated with the HLA-DPB1*03:01 allele, which has been implicated previously in MS in smaller studies. Further genotyping in large datasets is required to confirm and resolve this association.

  6. The Variability of Growth Hormone Gene Associated with Ultrasound Imaging of Longissimus dorsi Muscle and Perirenal Fat in Rabbits

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    T. I. Amalianingsih

    2014-04-01

    Full Text Available Identification of genes in rabbits correlated to economic traits were intended to improve and develop their genetic quality. The objective of this research was to analyze the variability of growth hormone gene (GH in three rabbit breeds, i.e. Rex, Satin, and Reza (Rex and Satin crosses then was associated with ultrasound imaging of Longissimus dorsi muscle and perirenal fat thickness. Identification of the variability of growth hormone gene was analyzed using PCR RFLP technique from blood samples of 33 mature male rabbits in Indonesian Research Institute for Animal Production (IRIAP. Thickness of Longissimus dorsi muscle and perirenal fat were imaged and measured by using ultrasound unit at 2nd to 3rd lumbar vertebrae in the left body side. PCR product of GH gene fragment (231 base pair /bp was digested with restriction enzyme Bsh1236I. PCR-RFLP patterns were allele T resulted in an undigested fragment of 231 bp; allele C resulted in fragment of 169 bp and 62 bp. The result showed that Bsh1236I GH gene had three genotypes, i.e. CC, TT, and CT. There were signifficant association of Longissimus dorsi muscle thickness between rabbit breed (P<0.05. There was no significant association between GH Bsh1236I gene polymorphism and imaging ultrasound of Longissimus dorsi muscle and perirenal fat thickness. The association of characteristic genotype of GH|Bsh1236I gene with measurement phenotype was not significant, however it had potency as marker assisted selection (MAS.

  7. Determining the spatial and seasonal variability in OM/OC ratios across the US using multiple regression

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    H. Simon

    2011-03-01

    Full Text Available Data from the Interagency Monitoring of Protected Visual Environments (IMPROVE network are used to estimate organic mass to organic carbon (OM/OC ratios across the United States by extending previously published multiple regression techniques. Our new methodology addresses common pitfalls of multiple regression including measurement uncertainty, colinearity of covariates, dataset selection, and model selection. As expected, summertime OM/OC ratios are larger than wintertime values across the US with all regional median OM/OC values tightly confined between 1.80 and 1.95. Further, we find that OM/OC ratios during the winter are distinctly larger in the eastern US than in the West (regional medians are 1.58, 1.64, and 1.85 in the great lakes, southeast, and northeast regions, versus 1.29 and 1.32 in the western and central states. We find less spatial variability in long-term averaged OM/OC ratios across the US (90% of our multiyear regressions estimate OM/OC ratios between 1.37 and 1.94 than previous studies (90% fell between 1.30 and 2.10. We attribute this difference largely to the inclusion of EC as a covariate in previous regression studies. Due to the colinearity of EC and OC, we find that up to one-quarter of the OM/OC estimates in a previous study are biased low. Assumptions about OC measurement artifacts add uncertainty to our estimates of OM/OC. In addition to estimating OM/OC ratios, our technique reveals trends that may be contrasted with conventional assumptions regarding nitrate, sulfate, and soil across the IMPROVE network. For example, our regressions show pronounced seasonal and spatial variability in both nitrate volatilization and sulfate neutralization and hydration.

  8. Assessment of PD-1 gene variation in patients with multiple sclerosis

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    Shadmehri AA

    2010-05-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin:0cm; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Multiple sclerosis (MS is a chronic inflammatory demyelinating disease of the central nervous system with presumed autoimmune origin. T cells are considered to play a pivotal role in orchestrating the self-reactive immune responses in multiple sclerosis (MS. This study was performed to investigate the role of polymorphisms of the programmed cell death 1 (PD-1 gene on susceptibility to ankylosing spondylitis. This gene codes an immunoreceptor named PD-1, which has a cytoplasmic domain containing two tyrosine residues located within immunoreceptor tyrosine-based inhibitory and switch motifs (ITIM and ITSM, suggesting that PD-1 is predominantly inhibitory which responsible for the negative regulation in T cell activation and peripheral tolerance. We investigated whether PD-1 gene polymorphism is a genetic modifier for risk and progression of MS."n"n Methods: Blood samples from 150 Iranian Relapsing-Remitting MS patients (mean age, 34.98 years and 202 healthy controls (mean age, 30 years were enrolled in this study. The PD-1.3 (7146 G/A Intron 4 and PD-1.9 (7625 C/T Exon 5 polymorphisms were detected by Polymerase Chain Reaction and Restriction Enzyme digestion or Restriction Fragment Length Polymorphism (PCR

  9. Network-based analysis of differentially expressed genes in cerebrospinal fluid (CSF and blood reveals new candidate genes for multiple sclerosis

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    Nahid Safari-Alighiarloo

    2016-12-01

    Full Text Available Background The involvement of multiple genes and missing heritability, which are dominant in complex diseases such as multiple sclerosis (MS, entail using network biology to better elucidate their molecular basis and genetic factors. We therefore aimed to integrate interactome (protein–protein interaction (PPI and transcriptomes data to construct and analyze PPI networks for MS disease. Methods Gene expression profiles in paired cerebrospinal fluid (CSF and peripheral blood mononuclear cells (PBMCs samples from MS patients, sampled in relapse or remission and controls, were analyzed. Differentially expressed genes which determined only in CSF (MS vs. control and PBMCs (relapse vs. remission separately integrated with PPI data to construct the Query-Query PPI (QQPPI networks. The networks were further analyzed to investigate more central genes, functional modules and complexes involved in MS progression. Results The networks were analyzed and high centrality genes were identified. Exploration of functional modules and complexes showed that the majority of high centrality genes incorporated in biological pathways driving MS pathogenesis. Proteasome and spliceosome were also noticeable in enriched pathways in PBMCs (relapse vs. remission which were identified by both modularity and clique analyses. Finally, STK4, RB1, CDKN1A, CDK1, RAC1, EZH2, SDCBP genes in CSF (MS vs. control and CDC37, MAP3K3, MYC genes in PBMCs (relapse vs. remission were identified as potential candidate genes for MS, which were the more central genes involved in biological pathways. Discussion This study showed that network-based analysis could explicate the complex interplay between biological processes underlying MS. Furthermore, an experimental validation of candidate genes can lead to identification of potential therapeutic targets.

  10. Bypassing hazard of housekeeping genes: Their evaluation in rat granule neurons treated with cerebrospinal fluid of Multiple Sclerosis subjects

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    Deepali eMathur

    2015-09-01

    Full Text Available Gene expression studies employing real-time PCR has become an intrinsic part of biomedical research. Appropriate normalization of target gene transcript(s based on stably expressed housekeeping genes is crucial in individual experimental conditions to obtain accurate results. In multiple sclerosis (MS, several gene expression studies have been undertaken, however, the suitability of housekeeping genes to express stably in this disease is not yet explored. Recent research suggests that their expression level may vary under different experimental conditions. Hence it is indispensible to evaluate their expression stability to accurately normalize target gene transcripts. The present study aims to evaluate the expression stability of seven housekeeping genes in rat granule neurons treated with cerebrospinal fluid of MS patients. The selected reference genes were quantified by real time PCR and their expression stability was assessed using GeNorm and NormFinder algorithms. Both methods reported transferrin receptor (Tfrc and microglobulin beta-2 (B2m the most stable genes whereas beta-actin (ActB and glyceraldehyde-3-phosphate-dehydrogenase (Gapdh the most fluctuated ones. Altogether our data demonstrate the significance of pre-validation of housekeeping genes for accurate normalization and indicates Tfrc and B2m as best endogenous controls in MS. ActB and Gapdh are not recommended in gene expression studies related to the current one.

  11. Statistics of α-μ Random Variables and Their Applications inWireless Multihop Relaying and Multiple Scattering Channels

    KAUST Repository

    Wang, Kezhi

    2015-06-01

    Exact results for the probability density function (PDF) and cumulative distribution function (CDF) of the sum of ratios of products (SRP) and the sum of products (SP) of independent α-μ random variables (RVs) are derived. They are in the form of 1-D integral based on the existing works on the products and ratios of α-μ RVs. In the derivation, generalized Gamma (GG) ratio approximation (GGRA) is proposed to approximate SRP. Gamma ratio approximation (GRA) is proposed to approximate SRP and the ratio of sums of products (RSP). GG approximation (GGA) and Gamma approximation (GA) are used to approximate SP. The proposed results of the SRP can be used to calculate the outage probability (OP) for wireless multihop relaying systems or multiple scattering channels with interference. The proposed results of the SP can be used to calculate the OP for these systems without interference. In addition, the proposed approximate result of the RSP can be used to calculate the OP of the signal-To-interference ratio (SIR) in a multiple scattering system with interference. © 1967-2012 IEEE.

  12. Periodic population codes: From a single circular variable to higher dimensions, multiple nested scales, and conceptual spaces.

    Science.gov (United States)

    Herz, Andreas Vm; Mathis, Alexander; Stemmler, Martin

    2017-10-01

    Across the nervous system, neurons often encode circular stimuli using tuning curves that are not sine or cosine functions, but that belong to the richer class of von Mises functions, which are periodic variants of Gaussians. For a population of neurons encoding a single circular variable with such canonical tuning curves, computing a simple population vector is the optimal read-out of the most likely stimulus. We argue that the advantages of population vector read-outs are so compelling that even the neural representation of the outside world's flat Euclidean geometry is curled up into a torus (a circle times a circle), creating the hexagonal activity patterns of mammalian grid cells. Here, the circular scale is not set a priori, so the nervous system can use multiple scales and gain fields to overcome the ambiguity inherent in periodic representations of linear variables. We review the experimental evidence for this framework and discuss its testable predictions and generalizations to more abstract grid-like neural representations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  13. Characterization of Brachyspira hyodysenteriae isolates from Italy by multilocus sequence typing and multiple locus variable number tandem repeat analysis.

    Science.gov (United States)

    Gasparrini, S; Alborali, G L; Pitozzi, A; Guarneri, F; Giacomini, E; Baldo, V; Scali, F; Lazzaro, M; Boniotti, M B

    2017-08-01

    To evaluate and compare the capabilities of multilocus sequence typing (MLST) and multiple locus variable number tandem repeat analysis (MLVA) techniques to characterize Brachyspira hyodysenteriae isolates and to investigate the relationship between pleuromutilin resistance and genetic variability. MLST genotyping was performed on 180 B. hyodysenteriae isolates, and the results were evaluated considering profiles from 108 other strains previously reported in the database. In total, 37 sequence types were obtained. The MLVA approach completely characterized 172 strains and grouped the isolates into 22 different profiles. The combination of MLST and MLVA showed a slight increase in the discriminatory power, identifying 33 joint profiles. An antibiotic resistance analysis showed a reduction in the susceptibility to pleuromutilins over time, and a weak association between susceptibility to valnemulin and inclusion in clonal complex 4. MLST and MLVA are reliable methods for characterizing B. hyodysenteriae strains and they have comparable discriminatory power. The genotyping of B. hyodysenteriae isolates and a database of all the genetic profiles collected during the diagnostic activities could support traditional epidemiological investigations in identifying infection sources and routes of transmission among herds, and in developing more effective control measures. © 2017 The Society for Applied Microbiology.

  14. Development and validation of a single-tube multiple-locus variable number tandem repeat analysis for Klebsiella pneumoniae.

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    Antoinette A T P Brink

    Full Text Available Genotyping of Klebsiella pneumoniae is indispensable for management of nosocomial infections, monitoring of emerging strains--including extended-spectrum beta-lactamase (ESBL producers-, and general epidemiology. Such objectives require a high-resolution genotyping method with a fixed scheme that allows (1 long-term retrospective and prospective assessment, (2 objective result readout and (3 library storage for database development and exchangeable results. We have developed a multiple-locus variable number tandem repeat analysis (MLVA using a single-tube fluorescently primed multiplex PCR for 8 Variable Number Tandem Repeats (VNTRs and automated fragment size analysis. The type allocation scheme was optimized using 224 K. pneumoniae clinical isolates, which yielded 101 MLVA types. The method was compared to the gold standard multilocus sequence typing (MLST using a subset of these clinical isolates (n = 95 and found to be highly concordant, with at least as high a resolution but with considerably less hands-on time. Our results position this MLVA scheme as an appropriate, high-throughput and relatively low-cost tool for K. pneumoniae epidemiology.

  15. Impacts of process variability of alternating-material self-aligned multiple patterning on SRAM circuit performance

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    Han, Ting; Hong, Chuyang; Cheng, Qi; Chen, Yijian

    2016-03-01

    In this paper, we propose a novel modular patterning technology to reduce the edge-placement errors (EPE) significantly by combining alternating-material self-aligned multiple patterning (altSAMP) and selective etching processes. It is assumed that gates and fins are fabricated by the same type of altSAMP process as mixing two different processing techniques will drive up the manufacturing costs. Process variability induced circuit performance degradation is shown to be a serious issue as FinFET devices are scaled down to sub-10nm. We analyze the dependence of FinFET-based SRAM circuit performance on supply voltage, fin-width and gate-length variations. Improved device control with narrower fins helps to increase the static noise margin (SNM) in all SRAM cell designs. Higher supply voltage is also beneficial to the SNM performance. Our simulation results show that 6-T SRAM circuit design does not meet the six-sigma yield requirement when the half pitch is scaled down to sub-7 nm. To reduce the SRAM circuit variability, we study an 8-T SRAM cell and show that it significantly improves the SRAM performance.

  16. Relationship between expanded health belief model variables and mammography screening adherence in women with multiple sclerosis: a pilot study.

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    Paraska, Karen

    2012-01-01

    People with disabilities often find it more difficult to access health-care services than the general population, further jeopardizing their health and well-being. The purpose of this descriptive pilot study was to explore the relationship between variables of the Expanded Health Belief Model (EHBM) and adherence to mammography screening in a sample of homebound women with MS after completion of a National Multiple Sclerosis Society (NMSS) intervention, known as the "Home-Based Health Maintenance Program for Women with MS," that was conducted in Allegheny County, Pennsylvania. The intervention was conducted in the patients' homes and included education of the women and their partners on risk factors for breast cancer and instruction in breast examination techniques. The patients were also helped to make appointments for mammograms. This study derived its sample from the intervention program and used data on adherence recorded by the NMSS. After completion of the intervention, telephone interviews were conducted with women who met the inclusion criteria (N = 11). Descriptive statistics indicate that adherence can be successfully described using variables of the EHBM, including perceived susceptibility, perceived severity, perceived benefits, and self-efficacy. The instruments chosen for the research were well tolerated, useful, and efficient to administer and allowed for immediate assessment.

  17. Changes of Motivational Variables in Patients with Multiple Sclerosis in an Exercise Intervention: Associations between Physical Performance and Motivational Determinants

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    Wiebke Geertz

    2015-01-01

    Full Text Available Objectives. This study examines the effects of a standardized fitness training on motivational factors such as the intention to be physically active, self-efficacy, perceived barriers, counterstrategies, and exercise specific social support in patients with progressive Multiple Sclerosis (MS and the relation of these factors to physical performance. Methods. Moderately disabled patients with secondary or primary progressive MS (Expanded Disability Status Scale of 4–6 were randomized to a training group or a waitlist control group. Patients completed on average 20 sessions of training tailored to their individual fitness at baseline over a course of 8–12 weeks. Motivational variables (stage of change according to the transtheoretical model (TTM, self-efficacy, perceived barriers, counterstrategies, and exercise specific social support were assessed via questionnaires at baseline and follow-up. Results. Forty patients completed the trial. We found significant effects on stages of change p=.016 and self-efficacy p=.014 and a trend in counterstrategies p=.08. Significant correlations between change of physical performance during the exercise training and change in the TTM, perceived barriers, and counterstrategies were detected. Conclusion. This study indicates that tailored individual endurance training could stabilize self-efficacy and increase exercise motivation in patients with progressive MS. Motivational variables were related to the physical performance.

  18. Quantification of peptides from immunoglobulin constant and variable regions by LC-MRM MS for assessment of multiple myeloma patients.

    Science.gov (United States)

    Remily-Wood, Elizabeth R; Benson, Kaaron; Baz, Rachid C; Chen, Y Ann; Hussein, Mohamad; Hartley-Brown, Monique A; Sprung, Robert W; Perez, Brianna; Liu, Richard Z; Yoder, Sean J; Teer, Jamie K; Eschrich, Steven A; Koomen, John M

    2014-10-01

    Quantitative MS assays for Igs are compared with existing clinical methods in samples from patients with plasma cell dyscrasias, for example, multiple myeloma (MM). Using LC-MS/MS data, Ig constant region peptides, and transitions were selected for LC-MRM MS. Quantitative assays were used to assess Igs in serum from 83 patients. RNA sequencing and peptide-based LC-MRM are used to define peptides for quantification of the disease-specific Ig. LC-MRM assays quantify serum levels of Igs and their isoforms (IgG1-4, IgA1-2, IgM, IgD, and IgE, as well as kappa (κ) and lambda (λ) light chains). LC-MRM quantification has been applied to single samples from a patient cohort and a longitudinal study of an IgE patient undergoing treatment, to enable comparison with existing clinical methods. Proof-of-concept data for defining and monitoring variable region peptides are provided using the H929 MM cell line and two MM patients. LC-MRM assays targeting constant region peptides determine the type and isoform of the involved Ig and quantify its expression; the LC-MRM approach has improved sensitivity compared with the current clinical method, but slightly higher inter-assay variability. Detection of variable region peptides is a promising way to improve Ig quantification, which could produce a dramatic increase in sensitivity over existing methods, and could further complement current clinical techniques. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  19. The development and application of a multiple gene co-silencing system using endogenous URA3 as a reporter gene in Ganoderma lucidum.

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    Dashuai Mu

    Full Text Available Ganoderma lucidum is one of the most important medicinal mushrooms; however, molecular genetics research on this species has been limited due to a lack of reliable reverse genetic tools. In this study, the endogenous orotidine 5'-monophosphate decarboxylase gene (URA3 was cloned as a silencing reporter, and four gene-silencing methods using hairpin, sense, antisense, and dual promoter constructs, were introduced into G. lucidum through a simple electroporation procedure. A comparison and evaluation of silencing efficiency demonstrated that all of the four methods differentially suppressed the expression of URA3. Our data unequivocally indicate that the dual promoter silencing vector yields the highest rate of URA3 silencing compared with other vectors (up to 81.9%. To highlight the advantages of the dual promoter system, we constructed a co-silencing system based on the dual promoter method and succeeded in co-silencing URA3 and laccase in G. lucidum. The reduction of the mRNA levels of the two genes were correlated. Thus, the screening efficiency for RNAi knockdown of multiple genes may be improved by the co-silencing of an endogenous reporter gene. The molecular tools developed in this study should facilitate the isolation of genes and the characterization of the functions of multiple genes in this pharmaceutically important species, and these tools should be highly useful for the study of other basidiomycetes.

  20. Multiple, non-allelic, intein-coding sequences in eukaryotic RNA polymerase genes

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    Butler Margaret I

    2006-10-01

    Full Text Available Abstract Background Inteins are self-splicing protein elements. They are translated as inserts within host proteins that excise themselves and ligate the flanking portions of the host protein (exteins with a peptide bond. They are encoded as in-frame insertions within the genes for the host proteins. Inteins are found in all three domains of life and in viruses, but have a very sporadic distribution. Only a small number of intein coding sequences have been identified in eukaryotic nuclear genes, and all of these are from ascomycete or basidiomycete fungi. Results We identified seven intein coding sequences within nuclear genes coding for the second largest subunits of RNA polymerase. These sequences were found in diverse eukaryotes: one is in the second largest subunit of RNA polymerase I (RPA2 from the ascomycete fungus Phaeosphaeria nodorum, one is in the RNA polymerase III (RPC2 of the slime mould Dictyostelium discoideum and four intein coding sequences are in RNA polymerase II genes (RPB2, one each from the green alga Chlamydomonas reinhardtii, the zygomycete fungus Spiromyces aspiralis and the chytrid fungi Batrachochytrium dendrobatidis and Coelomomyces stegomyiae. The remaining intein coding sequence is in a viral relic embedded within the genome of the oomycete Phytophthora ramorum. The Chlamydomonas and Dictyostelium inteins are the first nuclear-encoded inteins found outside of the fungi. These new inteins represent a unique dataset: they are found in homologous proteins that form a paralogous group. Although these paralogues diverged early in eukaryotic evolution, their sequences can be aligned over most of their length. The inteins are inserted at multiple distinct sites, each of which corresponds to a highly conserved region of RNA polymerase. This dataset supports earlier work suggesting that inteins preferentially occur in highly conserved regions of their host proteins. Conclusion The identification of these new inteins

  1. Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma.

    Science.gov (United States)

    Zekri, Abdel-Rahman N; Bahnasy, Abeer A; Shoeab, Fatma Elzahraa M; Mohamed, Waleed S; El-Dahshan, Dina H; Ali, Fahmey T; Sabry, Gilane M; Dasgupta, Nairajana; Daoud, Sayed S

    2014-01-01

    We studied promoter methylation (PM) of 11 genes in Peripheral Blood Lymphocytes (PBLs) and tissues of hepatitis C virus (HCV) associated hepatocellular carcinoma (HCC) and chronic hepatitis (CH) Egyptian patients. The present study included 31 HCC with their ANT, 38 CH and 13 normal hepatic tissue (NHT) samples. In all groups, PM of APC, FHIT, p15, p73, p14, p16, DAPK1, CDH1, RARβ, RASSF1A, O(6)MGMT was assessed by methylation-specific PCR (MSP). APC and O6-MGMT protein expression was assessed by immunohistochemistry (IHC) in the studied HCC and CH (20 samples each) as well as in a different HCC and CH set for confirmation of MSP results. PM was associated with progression from CH to HCC. Most genes showed high methylation frequency (MF) and the methylation index (MI) increased with disease progression. MF of p14, p73, RASSF1A, CDH1 and O(6)MGMT was significantly higher in HCC and their ANT. MF of APC was higher in CH. We reported high concordance between MF in HCC and their ANT, MF in PBL and CH tissues as well as between PM and protein expression of APC and O(6)MGMT. A panel of 4 genes (APC, p73, p14, O(6)MGMT) classifies the cases independently into HCC and CH with high accuracy (89.9%), sensitivity (83.9%) and specificity (94.7%). HCV infection may contribute to hepatocarcinogenesis through enhancing PM of multiple genes. PM of APC occurs early in the cascade while PM of p14, p73, RASSF1A, RARB, CDH1 and O(6)MGMT are late changes. A panel of APC, p73, p14, O6-MGMT could be used in monitoring CH patients for early detection of HCC. Also, we found that, the methylation status is not significantly affected by whether the tissue was from the liver or PBL, indicating the possibility of use PBL as indicator to genetic profile instead of liver tissue regardless the stage of disease.

  2. Methylation of multiple genes in hepatitis C virus associated hepatocellular carcinoma

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    Abdel-Rahman N. Zekri

    2014-01-01

    Full Text Available We studied promoter methylation (PM of 11 genes in Peripheral Blood Lymphocytes (PBLs and tissues of hepatitis C virus (HCV associated hepatocellular carcinoma (HCC and chronic hepatitis (CH Egyptian patients. The present study included 31 HCC with their ANT, 38 CH and 13 normal hepatic tissue (NHT samples. In all groups, PM of APC, FHIT, p15, p73, p14, p16, DAPK1, CDH1, RARβ, RASSF1A, O6MGMT was assessed by methylation-specific PCR (MSP. APC and O6-MGMT protein expression was assessed by immunohistochemistry (IHC in the studied HCC and CH (20 samples each as well as in a different HCC and CH set for confirmation of MSP results. PM was associated with progression from CH to HCC. Most genes showed high methylation frequency (MF and the methylation index (MI increased with disease progression. MF of p14, p73, RASSF1A, CDH1 and O6MGMT was significantly higher in HCC and their ANT. MF of APC was higher in CH. We reported high concordance between MF in HCC and their ANT, MF in PBL and CH tissues as well as between PM and protein expression of APC and O6MGMT. A panel of 4 genes (APC, p73, p14, O6MGMT classifies the cases independently into HCC and CH with high accuracy (89.9%, sensitivity (83.9% and specificity (94.7%. HCV infection may contribute to hepatocarcinogenesis through enhancing PM of multiple genes. PM of APC occurs early in the cascade while PM of p14, p73, RASSF1A, RARB, CDH1 and O6MGMT are late changes. A panel of APC, p73, p14, O6-MGMT could be used in monitoring CH patients for early detection of HCC. Also, we found that, the methylation status is not significantly affected by whether the tissue was from the liver or PBL, indicating the possibility of use PBL as indicator to genetic profile instead of liver tissue regardless the stage of disease.

  3. Expression profiling reveals functionally redundant multiple-copy genes related to zinc, iron and cadmium responses in Brassica rapa.

    Science.gov (United States)

    Li, Jimeng; Liu, Bo; Cheng, Feng; Wang, Xiaowu; Aarts, Mark G M; Wu, Jian

    2014-07-01

    Genes underlying environmental adaptability tend to be over-retained in polyploid plant species. Zinc deficiency (ZnD) and iron deficiency (FeD), excess Zn (ZnE) and cadmium exposure (CdE) are major environmental problems for crop cultivation, but little is known about the differential expression of duplicated genes upon these stress conditions. Applying Tag-Seq technology to leaves of Brassica rapa grown under FeD, ZnD, ZnE or CdE conditions, with normal conditions as a control, we examined global gene expression changes and compared the expression patterns of multiple paralogs. We identified 812, 543, 331 and 447 differentially expressed genes under FeD, ZnD, ZnE and CdE conditions, respectively, in B. rapa leaves. Genes involved in regulatory networks centered on the transcription factors bHLH038 or bHLH100 were differentially expressed under (ZnE-induced) FeD. Further analysis revealed that genes associated with Zn, Fe and Cd responses tended to be over-retained in the B. rapa genome. Most of these multiple-copy genes showed the same direction of expression change under stress conditions. We conclude that the duplicated genes involved in trace element responses in B. rapa are functionally redundant, making the regulatory network more complex in B. rapa than in Arabidopsis thaliana. © 2014 The Authors. New Phytologist © 2014 New Phytologist Trust.

  4. High-speed biosensing strategy for non-invasive profiling of multiple cancer fusion genes in urine.

    Science.gov (United States)

    Koo, Kevin M; Wee, Eugene J H; Trau, Matt

    2017-03-15

    Aberrant chromosal rearrangements, such as the multiple variants of TMPRSS2:ERG fusion gene mutations in prostate cancer (PCa), are promising diagnostic and prognostic biomarkers due to their specific expression in cancerous tissue only. Additionally, TMPRSS2:ERG variants are detectable in urine to provide non-invasive PCa diagnostic sampling as an attractive surrogate for needle biopsies. Therefore, rapid and simplistic assays for identifying multiple urinary TMPRSS2:ERG variants are potentially useful to aid in early cancer detection, immediate patient risk stratification, and prompt personalized treatment. However, current strategies for simultaneous detection of multiple gene fusions are limited by tedious and prolonged experimental protocols, thus limiting their use as rapid clinical screening tools. Herein, we report a simple and rapid gene fusion strategy which expliots the specificity of DNA ligase and the speed of isothermal amplification to simultaneously detect multiple fusion gene RNAs within a short sample-to-answer timeframe of 60min. The method has a low detection limit of 2 amol (1000 copies), and was successfully applied for non-invasive fusion gene profiling in patient urine samples with subsequent validation by a PCR-based gold standard approach. Copyright © 2016 Elsevier B.V. All rights reserved.

  5. Joint analysis of expression profiles from multiple cancers improves the identification of microRNA–gene interactions

    Science.gov (United States)

    Chen, Xiaowei; Slack, Frank J.; Zhao, Hongyu

    2013-01-01

    Motivation: MicroRNAs (miRNAs) play a crucial role in tumorigenesis and development through their effects on target genes. The characterization of miRNA–gene interactions will lead to a better understanding of cancer mechanisms. Many computational methods have been developed to infer miRNA targets with/without expression data. Because expression datasets are in general limited in size, most existing methods concatenate datasets from multiple studies to form one aggregated dataset to increase sample size and power. However, such simple aggregation analysis results in identifying miRNA–gene interactions that are mostly common across datasets, whereas specific interactions may be missed by these methods. Recent releases of The Cancer Genome Atlas data provide paired expression profiling of miRNAs and genes in multiple tumors with sufficiently large sample size. To study both common and cancer-specific interactions, it is desirable to develop a method that can jointly analyze multiple cancers to study miRNA–gene interactions without combining all the data into one single dataset. Results: We developed a novel statistical method to jointly analyze expression profiles from multiple cancers to identify miRNA–gene interactions that are both common across cancers and specific to certain cancers. The benefit of this joint analysis approach is demonstrated by both simulation studies and real data analysis of The Cancer Genome Atlas datasets. Compared with simple aggregate analysis or single sample analysis, our method can effectively use the shared information among different but related cancers to improve the identification of miRNA–gene interactions. Another useful property of our method is that it can estimate similarity among cancers through their shared miRNA–gene interactions. Availability and implementation: The program, MCMG, implemented in R is available at http://bioinformatics.med.yale.edu/group/. Contact: hongyu.zhao@yale.edu PMID:23772050

  6. Role of inflammation gene polymorphisms on pain and response to radiotherapy in multiple myeloma patients with painful bone destructions

    OpenAIRE

    Rudžianskienė, Milda; Inčiūra, Arturas; Gerbutavičius, Rolandas; Dambrauskienė, Rūta; Rudžianskas, Viktoras; Juozaitytė, Elona

    2016-01-01

    Background: Previous researches have demonstrated, that the severity of pain perception and it’s response to analgesia is highly dependent on gene polymorphism encoding for cytokines. We evaluated 12 single nucleotide polymorphisms (SNP) in 6 genes encoding for cytokines in multiple myeloma patients (n = 81) and assessed their influence on pain severity and response to palliative radiotherapy. Methods: Pain intensity was assessed by Visual Analogue Scale. The total dose of opioids was convert...

  7. Variability in Dopamine Genes Dissociates Model-Based and Model-Free Reinforcement Learning.

    Science.gov (United States)

    Doll, Bradley B; Bath, Kevin G; Daw, Nathaniel D; Frank, Michael J

    2016-01-27

    Considerable evidence suggests that multiple learning systems can drive behavior. Choice can proceed reflexively from previous actions and their associated outcomes, as captured by "model-free" learning algorithms, or flexibly from prospective consideration of outcomes that might occur, as captured by "model-based" learning algorithms. However, differential contributions of dopamine to these systems are poorly understood. Dopamine is widely thought to support model-free learning by modulating plasticity in striatum. Model-based learning may also be affected by these striatal effects, or by other dopaminergic effects elsewhere, notably on prefrontal working memory function. Indeed, prominent demonstrations linking striatal dopamine to putatively model-free learning did not rule out model-based effects, whereas other studies have reported dopaminergic modulation of verifiably model-based learning, but without distinguishing a prefrontal versus striatal locus. To clarify the relationships between dopamine, neural systems, and learning strategies, we combine a genetic association approach in humans with two well-studied reinforcement learning tasks: one isolating model-based from model-free behavior and the other sensitive to key aspects of striatal plasticity. Prefrontal function was indexed by a polymorphism in the COMT gene, differences of which reflect dopamine levels in the prefrontal cortex. This polymorphism has been associated with differences in prefrontal activity and working memory. Striatal function was indexed by a gene coding for DARPP-32, which is densely expressed in the striatum where it is necessary for synaptic plasticity. We found evidence for our hypothesis that variations in prefrontal dopamine relate to model-based learning, whereas variations in striatal dopamine function relate to model-free learning. Decisions can stem reflexively from their previously associated outcomes or flexibly from deliberative consideration of potential choice outcomes

  8. Genetic variability in the regulation of the expression cluster of MDR genes in patients with breast cancer.

    Science.gov (United States)

    Tsyganov, Matvey M; Freidin, Maxim B; Ibragimova, Marina K; Deryusheva, Irina V; Kazantseva, Polina V; Slonimskaya, Elena M; Cherdyntseva, Nadezhda V; Litviakov, Nikolai V

    2017-08-01

    We aimed to investigate the association between the polymorphism and expression patterns of multiple drug resistance genes (MDR) in breast cancer (BC). The MDR gene expression levels were measured in tumor tissues of 106 breast cancer patients using quantitative real-time PCR. Affymetrix CytoScan™ HD Array chips were used to assess genotypes. Pairwise correlation analysis for ABCB1, ABCC1, ABCC2 and ABCG2 gene expression levels was carried out to reveal co-expression clusters. Associations between SNPs of MDR genes and their preoperative expression levels were assessed using analysis of covariance adjusting for covariates. The SNPs associated with the expression of the ABCB1, ABCC1, ABCC2 and ABCG2 genes before NAC were detected. In addition, 21 SNPs associated with the expression of four ABC-transporter genes and involved in the expression regulation were identified. Validation in an independent sample confirmed the association between the MDR cluster genes and 11 SNPs. Four MDR genes: ABCB1, ABCC1, ABCC2 and ABCG2 were shown to form the functional expression cluster in breast tumor. Further studies are required to discover precise mechanisms of the cluster regulation, thereby providing new approaches and targets to combat the development of the MDR phenotype during chemotherapy.

  9. Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes.

    Science.gov (United States)

    Vandesompele, Jo; De Preter, Katleen; Pattyn, Filip; Poppe, Bruce; Van Roy, Nadine; De Paepe, Anne; Speleman, Frank

    2002-06-18

    Gene-expression analysis is increasingly important in biological research, with real-time reverse transcription PCR (RT-PCR) becoming the method of choice for high-throughput and accurate expression profiling of selected genes. Given the increased sensitivity, reproducibility and large dynamic range of this methodology, the requirements for a proper internal control gene for normalization have become increasingly stringent. Although housekeeping gene expression has been reported to vary considerably, no systematic survey has properly determined the errors related to the common practice of using only one control gene, nor presented an adequate way of working around this problem. We outline a robust and innovative strategy to identify the most stably expressed control genes in a given set of tissues, and to determine the minimum number of genes required to calculate a reliable normalization factor. We have evaluated ten housekeeping genes from different abundance and functional classes in various human tissues, and demonstrated that the conventional use of a single gene for normalization leads to relatively large errors in a significant proportion of samples tested. The geometric mean of multiple carefully selected housekeeping genes was validated as an accurate normalization factor by analyzing publicly available microarray data. The normalization strategy presented here is a prerequisite for accurate RT-PCR expression profiling, which, among other things, opens up the possibility of studying the biological relevance of small expression differences.

  10. Genetic variability in ESAG6 genes among Trypanosoma evansi isolates and in comparison to other Trypanozoon members.

    Science.gov (United States)

    Witola, William H; Sarataphan, Nopporn; Inoue, Noboru; Ohashi, Kazuhiko; Onuma, Misao

    2005-01-01

    Bloodstream trypanosomes take up iron needed for their propagation through the transferrin receptor that, in Trypanosoma brucei, is encoded by expression-site-associated genes (ESAGs), ESAG6 and 7 genes located in variant surface glycoprotein expression sites. ESAG6 and 7 genes in different expression sites have been shown to encode transferrin receptors with varying affinities for polymorphic transferrins. T. brucei could cope with the different host transferrins by switching between expression sites. ESAG6- and 7-encoded transferrin receptor appear to be present in Trypanosoma evansi but the genes have not yet been characterized. In this study, we cloned and sequenced different members of ESAG6 genes in seven isolates of T. evansi from geographically distinct localities in Thailand. We assessed the intra- and inter-species genetic variability in the transferrin receptor gene regions involved in transferrin binding and established that T. evansi, like T. brucei, has widely diverse ESAG6 genes. In addition, T. evansi possess a clade of ESAG6 variants not observed in T. brucei and different T. evansi strains share at least two conserved variants. We further noted that T. evansi possesses all the reported T. equiperdum ESAG6 variants as a subset. Our findings depict a correlation between the genetic diversity in the transferrin-binding regions of ESAG6 genes with the broad host range of T. evansi and T. brucei compared to the narrow host range of Trypanosoma equiperdum.

  11. Multiple interkingdom horizontal gene transfers in Pyrenophora and closely related species and their contributions to phytopathogenic lifestyles.

    Directory of Open Access Journals (Sweden)

    Bao-Fa Sun

    Full Text Available Many studies have reported horizontal gene transfer (HGT events from eukaryotes, especially fungi. However, only a few investigations summarized multiple interkingdom HGTs involving important phytopathogenic species of Pyrenophora and few have investigated the genetic contributions of HGTs to fungi. We investigated HGT events in P. teres and P. tritici-repentis and discovered that both species harbored 14 HGT genes derived from bacteria and plants, including 12 HGT genes that occurred in both species. One gene coding a leucine-rich repeat protein was present in both species of Pyrenophora and it may have been transferred from a host plant. The transfer of genes from a host plant to pathogenic fungi has been reported rarely and we discovered the first evidence for this transfer in phytopathogenic Pyrenophora. Two HGTs in Pyrenophora underwent subsequent duplications. Some HGT genes had homologs in a few other fungi, indicating relatively ancient transfer events. Functional analyses indicated that half of the HGT genes encoded extracellular proteins and these may have facilitated the infection of plants by Pyrenophora via interference with plant defense-response and the degradation of plant cell walls. Some other HGT genes appeared to participate in carbohydrate metabolism. Together, these functions implied that HGTs may have led to highly efficient mechanisms of infection as well as the utilization of host carbohydrates. Evolutionary analyses indicated that HGT genes experienced amelioration, purifying selection, and accelerated evolution. These appeared to constitute adaptations to the background genome of the recipient. The discovery of multiple interkingdom HGTs in Pyrenophora, their significance to infection, and their adaptive evolution, provided valuable insights into the evolutionary significance of interkingdom HGTs from multiple donors.

  12. Multiple interkingdom horizontal gene transfers in Pyrenophora and closely related species and their contributions to phytopathogenic lifestyles.

    Science.gov (United States)

    Sun, Bao-Fa; Xiao, Jin-Hua; He, Shunmin; Liu, Li; Murphy, Robert W; Huang, Da-Wei

    2013-01-01

    Many studies have reported horizontal gene transfer (HGT) events from eukaryotes, especially fungi. However, only a few investigations summarized multiple interkingdom HGTs involving important phytopathogenic species of Pyrenophora and few have investigated the genetic contributions of HGTs to fungi. We investigated HGT events in P. teres and P. tritici-repentis and discovered that both species harbored 14 HGT genes derived from bacteria and plants, including 12 HGT genes that occurred in both species. One gene coding a leucine-rich repeat protein was present in both species of Pyrenophora and it may have been transferred from a host plant. The transfer of genes from a host plant to pathogenic fungi has been reported rarely and we discovered the first evidence for this transfer in phytopathogenic Pyrenophora. Two HGTs in Pyrenophora underwent subsequent duplications. Some HGT genes had homologs in a few other fungi, indicating relatively ancient transfer events. Functional analyses indicated that half of the HGT genes encoded extracellular proteins and these may have facilitated the infection of plants by Pyrenophora via interference with plant defense-response and the degradation of plant cell walls. Some other HGT genes appeared to participate in carbohydrate metabolism. Together, these functions implied that HGTs may have led to highly efficient mechanisms of infection as well as the utilization of host carbohydrates. Evolutionary analyses indicated that HGT genes experienced amelioration, purifying selection, and accelerated evolution. These appeared to constitute adaptations to the background genome of the recipient. The discovery of multiple interkingdom HGTs in Pyrenophora, their significance to infection, and their adaptive evolution, provided valuable insights into the evolutionary significance of interkingdom HGTs from multiple donors.

  13. Multiple sclerosis susceptibility in a Brazilian sample, HLA and CIITA genes

    Directory of Open Access Journals (Sweden)

    Eduardo Ribeiro Paradela

    2014-06-01

    Full Text Available Introduction: The multiple sclerosis (MS is a chronic disease of the central nervous system that affects mainly young adults. This disease is characterized by the spread of demyelinating lesions in time and space. This condition may be influenced by genetic factors as heterogeneity, incomplete penetrance, polygenic inheritance and epigenetic factors, which makes this complex disease a challenge for geneticists. Objectives: The aim of this study was to investigate the association between HLA alleles from DQA1, DQB1 and DRB1 loci (6p21.3, genetic polymorphisms -168A/G (rs3087456 and +1614 G/C (rs4774 in the CIITA gene (16p13 and susceptibility to MS in a miscegenated sample from Rio de Janeiro state, RJ, Brazil. Method: DNA samples from 52 patients with relapsing remitting multiple sclerosis (MSRR [21 males (40.38% and 31 females (59.62%] and 116 healthy controls [46 males (39.65% and 70 females (60.35%] matched by race, sex and age were analyzed by techniques of PCR, SSP-PCR, electrophoresis and DNA sequencing. Results: A significant association between MS and HLA-DRB1*15:01 allele was observed [p value=.002; Odds Ratio (OR=3.2], especially in women (p=.001; OR=4.9, which remained statistically significant after Bonferroni correction. Furthermore, it was observed that the polymorphism +1614 G/C, “C/C” profile, in association with the allele DRB1*15:01 influences the increased susceptibility to MS in women (p=.029; OR=5.6. In addition, it was observed that the "G/G" profile in CIITA polymorphism +1614G/C may be associated with the resistance to MS (p=.02; OR=0.23, as well as HLA-DRB1*11:02 (p=.02, OR=0.5. The HLA-DQB1*06:02 allele also has been implicated as a possible susceptibility factor for MS (p=.02; OR=1.8, data not confirmed after Bonferronís correction. Conclusion: Together, these results reinforce the polygenic nature of MS, and proposed that the CIITA gene, which is the regulator of the expression of HLA-D, is an additive factor to

  14. Multiple Genes Cause Postmating Prezygotic Reproductive Isolation in the Drosophila virilis Group.

    Science.gov (United States)

    Ahmed-Braimah, Yasir H

    2016-12-07

    Understanding the genetic basis of speciation is a central problem in evolutionary biology. Studies of reproductive isolation have provided several insights into the genetic causes of speciation, especially in taxa that lend themselves to detailed genetic scrutiny. Reproductive barriers have usually been divided into those that occur before zygote formation (prezygotic) and after (postzygotic), with the latter receiving a great deal of attention over several decades. Reproductive barriers that occur after mating but before zygote formation [postmating prezygotic (PMPZ)] are especially understudied at the genetic level. Here, I present a phenotypic and genetic analysis of a PMPZ reproductive barrier between two species of the Drosophila virilis group: D. americana and D. virilis This species pair shows strong PMPZ isolation, especially when D. americana males mate with D. virilis females: ∼99% of eggs laid after these heterospecific copulations are not fertilized. Previous work has shown that the paternal loci contributing to this incompatibility reside on two chromosomes, one of which (chromosome 5) likely carries multiple factors. The other (chromosome 2) is fixed for a paracentric inversion that encompasses nearly half the chromosome. Here, I present two results. First, I show that PMPZ in this species cross is largely due to defective sperm storage in heterospecific copulations. Second, using advanced intercross and backcross mapping approaches, I identify genomic regions that carry genes capable of rescuing heterospecific fertilization. I conclude that paternal incompatibility between D. americana males and D. virilis females is underlain by four or more genes on chromosomes 2 and 5. Copyright © 2016 Ahmed-Braimah.

  15. Deleting multiple lytic genes enhances biomass yield and production of recombinant proteins by Bacillus subtilis.

    Science.gov (United States)

    Wang, Yi; Chen, Zhenmin; Zhao, Ruili; Jin, Tingting; Zhang, Xiaoming; Chen, Xiangdong

    2014-08-31

    Bacillus subtilis is widely used in agriculture and industrial biotechnology; however, cell autolysis significantly decreases its yield in liquid cultures. Numerous factors mediate the lysis of B. subtilis, such as cannibalism factors, prophages, and peptidoglycan (PG) hydrolases. The aim of this work was to use molecular genetic techniques to develop a new strategy to prevent cell lysis and enhance biomass as well as the production of recombinant proteins. Five genes or genetic elements representing three different functional categories were studied as follows: lytC encoding PG hydrolases, the prophage genes xpf and yqxG-yqxH-cwlA (yGlA), and skfA and sdpC that encode cannibalism factors. Cell lysis was reduced and biomass was enhanced by deleting individually skfA, sdpC, xpf, and lytC. We constructed the multiple deletion mutant LM2531 (skfA sdpC lytC xpf) and found that after 4 h of culture, its biomass yield was significantly increased compared with that of prototypical B. subtilis 168 (wild-type) strain and that 15% and 92% of the cells were lysed in cultures of LM2531 and wild-type, respectively. Moreover, two expression vectors were constructed for producing recombinant proteins (β-galactosidase and nattokinase) under the control of the P43 promoter. Cultures of LM2531 and wild-type transformants produced 13741 U/ml and 7991 U/ml of intracellular β-galactosidase, respectively (1.72-fold increase). Further, the level of secreted nattokinase produced by strain LM2531 increased by 2.6-fold compared with wild-type (5226 IU/ml vs. 2028 IU/ml, respectively). Our novel, systematic multigene deletion approach designed to inhibit cell lysis significantly increased the biomass yield and the production of recombinant proteins by B. subtilis. These findings show promise for guiding efforts to manipulate the genomes of other B. subtilis strains that are used for industrial purposes.

  16. Fine Mapping and Functional Analysis of the Multiple Sclerosis Risk Gene CD6

    Science.gov (United States)

    Swaminathan, Bhairavi; Cuapio, Angélica; Alloza, Iraide; Matesanz, Fuencisla; Alcina, Antonio; García-Barcina, Maria; Fedetz, Maria; Fernández, Óscar; Lucas, Miguel; Órpez, Teresa; Pinto-Medel, Mª Jesus; Otaegui, David; Olascoaga, Javier; Urcelay, Elena; Ortiz, Miguel A.; Arroyo, Rafael; Oksenberg, Jorge R.; Antigüedad, Alfredo; Tolosa, Eva; Vandenbroeck, Koen

    2013-01-01

    CD6 has recently been identified and validated as risk gene for multiple sclerosis (MS), based on the association of a single nucleotide polymorphism (SNP), rs17824933, located in intron 1. CD6 is a cell surface scavenger receptor involved in T-cell activation and proliferation, as well as in thymocyte differentiation. In this study, we performed a haptag SNP screen of the CD6 gene locus using a total of thirteen tagging SNPs, of which three were non-synonymous SNPs, and replicated the recently reported GWAS SNP rs650258 in a Spanish-Basque collection of 814 controls and 823 cases. Validation of the six most strongly associated SNPs was performed in an independent collection of 2265 MS patients and 2600 healthy controls. We identified association of haplotypes composed of two non-synonymous SNPs [rs11230563 (R225W) and rs2074225 (A257V)] in the 2nd SRCR domain with susceptibility to MS (Pmax(T) permutation = 1×10−4). The effect of these haplotypes on CD6 surface expression and cytokine secretion was also tested. The analysis showed significantly different CD6 expression patterns in the distinct cell subsets, i.e. – CD4+ naïve cells, P = 0.0001; CD8+ naïve cells, P<0.0001; CD4+ and CD8+ central memory cells, P = 0.01 and 0.05, respectively; and natural killer T (NKT) cells, P = 0.02; with the protective haplotype (RA) showing higher expression of CD6. However, no significant changes were observed in natural killer (NK) cells, effector memory and terminally differentiated effector memory T cells. Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4+ and CD8+ T cells. PMID:23638056

  17. Modulation of brain activity by multiple lexical and word form variables in visual word recognition: A parametric fMRI study.

    Science.gov (United States)

    Hauk, Olaf; Davis, Matthew H; Pulvermüller, Friedemann

    2008-09-01

    Psycholinguistic research has documented a range of variables that influence visual word recognition performance. Many of these variables are highly intercorrelated. Most previous studies have used factorial designs, which do not exploit the full range of values available for continuous variables, and are prone to skewed stimulus selection as well as to effects of the baseline (e.g. when contrasting words with pseudowords). In our study, we used a parametric approach to study the effects of several psycholinguistic variables on brain activation. We focussed on the variable word frequency, which has been used in numerous previous behavioural, electrophysiological and neuroimaging studies, in order to investigate the neuronal network underlying visual word processing. Furthermore, we investigated the variable orthographic typicality as well as a combined variable for word length and orthographic neighbourhood size (N), for which neuroimaging results are still either scarce or inconsistent. Data were analysed using multiple linear regression analysis of event-related fMRI data acquired from 21 subjects in a silent reading paradigm. The frequency variable correlated negatively with activation in left fusiform gyrus, bilateral inferior frontal gyri and bilateral insulae, indicating that word frequency can affect multiple aspects of word processing. N correlated positively with brain activity in left and right middle temporal gyri as well as right inferior frontal gyrus. Thus, our analysis revealed multiple distinct brain areas involved in visual word processing within one data set.

  18. Usefulness of Housekeeping Genes for the Diagnosis of Helicobacter pylori Infection, Strain Discrimination and Detection of Multiple Infection.

    Science.gov (United States)

    Palau, Montserrat; Kulmann, Marcos; Ramírez-Lázaro, María José; Lario, Sergio; Quilez, María Elisa; Campo, Rafael; Piqué, Núria; Calvet, Xavier; Miñana-Galbis, David

    2016-12-01

    Helicobacter pylori infects human stomachs of over half the world's population, evades the immune response and establishes a chronic infection. Although most people remains asymptomatic, duodenal and gastric ulcers, MALT lymphoma and progression to gastric cancer could be developed. Several virulence factors such as flagella, lipopolysaccharide, adhesins and especially the vacuolating cytotoxin VacA and the oncoprotein CagA have been described for H. pylori. Despite the extensive published data on H. pylori, more research is needed to determine new virulence markers, the exact mode of transmission or the role of multiple infection. Amplification and sequencing of six housekeeping genes (amiA, cgt, cpn60, cpn70, dnaJ, and luxS) related to H. pylori pathogenesis have been performed in order to evaluate their usefulness for the specific detection of H. pylori, the genetic discrimination at strain level and the detection of multiple infection. A total of 52 H. pylori clones, isolated from 14 gastric biopsies from 11 patients, were analyzed for this purpose. All genes were specifically amplified for H. pylori and all clones isolated from different patients were discriminated, with gene distances ranged from 0.9 to 7.8%. Although most clones isolated from the same patient showed identical gene sequences, an event of multiple infection was detected in all the genes and microevolution events were showed for amiA and cpn60 genes. These results suggested that housekeeping genes could be useful for H. pylori detection and to elucidate the mode of transmission and the relevance of the multiple infection. © 2016 John Wiley & Sons Ltd.

  19. Multiple mechanisms promote the retained expression of gene duplicates in the tetraploid frog Xenopus laevis.

    Directory of Open Access Journals (Sweden)

    2006-04-01

    Full Text Available Gene duplication provides a window of opportunity for biological variants to persist under the protection of a co-expressed copy with similar or redundant function. Duplication catalyzes innovation (neofunctionalization, subfunction degeneration (subfunctionalization, and genetic buffering (redundancy, and the genetic survival of each paralog is triggered by mechanisms that add, compromise, or do not alter protein function. We tested the applicability of three types of mechanisms for promoting the retained expression of duplicated genes in 290 expressed paralogs of the tetraploid clawed frog, Xenopus laevis. Tests were based on explicit expectations concerning the ka/ks ratio, and the number and location of nonsynonymous substitutions after duplication. Functional constraints on the majority of paralogs are not significantly different from a singleton ortholog. However, we recover strong support that some of them have an asymmetric rate of nonsynonymous substitution: 6% match predictions of the neofunctionalization hypothesis in that (1 each paralog accumulated nonsynonymous substitutions at a significantly different rate and (2 the one that evolves faster has a higher ka/ks ratio than the other paralog and than a singleton ortholog. Fewer paralogs (3% exhibit a complementary pattern of substitution at the protein level that is predicted by enhancement or degradation of different functional domains, and the remaining 13% have a higher average ka/ks ratio in both paralogs that is consistent with altered functional constraints, diversifying selection, or activity-reducing mutations after duplication. We estimate that these paralogs have been retained since they originated by genome duplication between 21 and 41 million years ago. Multiple mechanisms operate to promote the retained expression of duplicates in the same genome, in genes in the same functional class, over the same period of time following duplication, and sometimes in the same pair of

  20. Multiple signaling pathways direct the initiation of tyrosine hydroxylase gene expression in cultured brain neurons.

    Science.gov (United States)

    Du, X; Iacovitti, L

    1997-10-15

    cultures were treated with aFGF and all co-activator molecules simultaneously. Our results suggest that there are multiple ways to signal the initiation of the TH gene, each of which requires the synergy of specific growth factors and either DA, PKA or PKC pathway activators. Since only the combination of growth factor and all co-activators together produces maximum TH induction, each molecule may signal a unique intracellular pathway which converges at targets on the TH gene.

  1. Multiple Renal Cyst Development but Not Situs Abnormalities in Transgenic RNAi Mice against Inv::GFP Rescue Gene

    Science.gov (United States)

    Kamijho, Yuki; Shiozaki, Yayoi; Sakurai, Eiki; Hanaoka, Kazunori; Watanabe, Daisuke

    2014-01-01

    In this study we generated RNA interference (RNAi)-mediated gene knockdown transgenic mice (transgenic RNAi mice) against the functional Inv gene. Inv mutant mice show consistently reversed internal organs (situs inversus), multiple renal cysts and neonatal lethality. The Inv::GFP-rescue mice, which introduced the Inv::GFP fusion gene, can rescue inv mutant mice phenotypes. This indicates that the Inv::GFP gene is functional in vivo. To analyze the physiological functions of the Inv gene, and to demonstrate the availability of transgenic RNAi mice, we introduced a short hairpin RNA expression vector against GFP mRNA into Inv::GFP-rescue mice and analyzed the gene silencing effects and Inv functions by examining phenotypes. Transgenic RNAi mice with the Inv::GFP-rescue gene (Inv-KD mice) down-regulated Inv::GFP fusion protein and showed hypomorphic phenotypes of inv mutant mice, such as renal cyst development, but not situs abnormalities or postnatal lethality. This indicates that shRNAi-mediated gene silencing systems that target the tag sequence of the fusion gene work properly in vivo, and suggests that a relatively high level of Inv protein is required for kidney development in contrast to left/right axis determination. Inv::GFP protein was significantly down-regulated in the germ cells of Inv-KD mice testis compared with somatic cells, suggesting the existence of a testicular germ cell-specific enhanced RNAi system that regulates germ cell development. The Inv-KD mouse is useful for studying Inv gene functions in adult tissue that are unable to be analyzed in inv mutant mice showing postnatal lethality. In addition, the shRNA-based gene silencing system against the tag sequence of the fusion gene can be utilized as a new technique to regulate gene expression in either in vitro or in vivo experiments. PMID:24586938

  2. Rapid genome reshaping by multiple-gene loss after whole-genome duplication in teleost fish suggested by mathematical modeling.

    Science.gov (United States)

    Inoue, Jun; Sato, Yukuto; Sinclair, Robert; Tsukamoto, Katsumi; Nishida, Mutsumi

    2015-12-01

    Whole-genome duplication (WGD) is believed to be a significant source of major evolutionary innovation. Redundant genes resulting from WGD are thought to be lost or acquire new functions. However, the rates of gene loss and thus temporal process of genome reshaping after WGD remain unclear. The WGD shared by all teleost fish, one-half of all jawed vertebrates, was more recent than the two ancient WGDs that occurred before the origin of jawed vertebrates, and thus lends itself to analysis of gene loss and genome reshaping. Using a newly developed orthology identification pipeline, we inferred the post-teleost-specific WGD evolutionary histories of 6,892 protein-coding genes from nine phylogenetically representative teleost genomes on a time-calibrated tree. We found that rapid gene loss did occur in the first 60 My, with a loss of more than 70-80% of duplicated genes, and produced similar genomic gene arrangements within teleosts in that relatively short time. Mathematical modeling suggests that rapid gene loss occurred mainly by events involving simultaneous loss of multiple genes. We found that the subsequent 250 My were characterized by slow and steady loss of individual genes. Our pipeline also identified about 1,100 shared single-copy genes that are inferred to have become singletons before the divergence of clupeocephalan teleosts. Therefore, our comparative genome analysis suggests that rapid gene loss just after the WGD reshaped teleost genomes before the major divergence, and provides a useful set of marker genes for future phylogenetic analysis.

  3. No evidence that polymorphisms of the vanishing white matter disease genes are risk factors in multiple sclerosis

    NARCIS (Netherlands)

    Pronk, J.C.; Scheper, G.C.; Andel, R.J.; van Berkel, C.G.M.; Polman, C.H.; Uitdehaag, B.M.J.; van der Knaap, M.S.

    2008-01-01

    Febrile infections are known to cause exacerbations in the white matter disorders 'vanishing white matter' (VWM) and multiple sclerosis (MS). We hypothesized that polymorphisms in EIF2B1-5, the genes involved in VWM, might be risk factors for the development of MS or temperature sensitivity in

  4. AS3MT-mediated tolerance to arsenic evolved by multiple independent horizontal gene transfers from bacteria to eukaryotes

    DEFF Research Database (Denmark)

    Palmgren, Michael Broberg; Engström, Karin; Hallström, Björn M

    2017-01-01

    the evolutionary origin of AS3MT and assessed the ability of different genotypes to produce methylated arsenic metabolites. Phylogenetic analysis suggests that multiple, independent horizontal gene transfers between different bacteria, and from bacteria to eukaryotes, increased tolerance to environmental arsenic...

  5. Mycobacterium malmesburyense sp. nov., a non-tuberculous species of the genus Mycobacterium revealed by multiple gene sequence characterization

    CSIR Research Space (South Africa)

    Gcebe, N

    2017-04-01

    Full Text Available Journal of Systematic and Evolutionary Microbiology: DOI 10.1099/ijsem.0.001678 Mycobacterium malmesburyense sp. nov., a non-tuberculous species of the genus Mycobacterium revealed by multiple gene sequence characterization Gcebe N Rutten V Gey...

  6. Polyuridylylation and processing of transcripts from multiple gene minicircles in chloroplasts of the dinoflagellate Amphidinium carterae

    KAUST Repository

    Barbrook, Adrian C.

    2012-05-05

    Although transcription and transcript processing in the chloroplasts of plants have been extensively characterised, the RNA metabolism of other chloroplast lineages across the eukaryotes remains poorly understood. In this paper, we use RT-PCR to study transcription and transcript processing in the chloroplasts of Amphidinium carterae, a model peridinin-containing dinoflagellate. These organisms have a highly unusual chloroplast genome, with genes located on multiple small \\'minicircle\\' elements, and a number of idiosyncratic features of RNA metabolism including transcription via a rolling circle mechanism, and 3′ terminal polyuridylylation of transcripts. We demonstrate that transcription occurs in A. carterae via a rolling circle mechanism, as previously shown in the dinoflagellate Heterocapsa, and present evidence for the production of both polycistronic and monocistronic transcripts from A. carterae minicircles, including several regions containing ORFs previously not known to be expressed. We demonstrate the presence of both polyuridylylated and non-polyuridylylated transcripts in A. carterae, and show that polycistronic transcripts can be terminally polyuridylylated. We present a model for RNA metabolism in dinoflagellate chloroplasts where long polycistronic precursors are processed to form mature transcripts. Terminal polyuridylylation may mark transcripts with the correct 3′ end. © 2012 Springer Science+Business Media B.V.

  7. Vitamin D receptor gene is epigenetically altered and transcriptionally up-regulated in multiple sclerosis.

    Science.gov (United States)

    Ayuso, Teresa; Aznar, Patricia; Soriano, Luis; Olaskoaga, Ander; Roldán, Miren; Otano, María; Ajuria, Iratxe; Soriano, Gerardo; Lacruz, Francisco; Mendioroz, Maite

    2017-01-01

    Vitamin D deficiency has been linked to increased risk of multiple sclerosis (MS) and poor outcome. However, the specific role that vitamin D plays in MS still remains unknown. In order to identify potential mechanisms underlying vitamin D effects in MS, we profiled epigenetic changes in vitamin D receptor (VDR) gene to identify genomic regulatory elements relevant to MS pathogenesis. Human T cells derived from whole blood by negative selection were isolated in a set of 23 relapsing-remitting MS (RRMS) patients and 12 controls matched by age and gender. DNA methylation levels were assessed by bisulfite cloning sequencing in two regulatory elements of VDR. mRNA levels were measured by RT-qPCR to assess changes in VDR expression between patients and controls. An alternative VDR promoter placed at exon 1c showed increased DNA methylation levels in RRMS patients (median 30.08%, interquartile range 19.2%) compared to controls (18.75%, 9.5%), p-valuemultiple sclerosis, and it is associated with VDR mRNA upregulation. This locus may represent a candidate regulatory element in the genome relevant to MS pathogenesis.

  8. Inhibition of activated Ras suppresses multiple oncogenic Hub genes in human epithelial tumors.

    Science.gov (United States)

    Cao, Lei; Wang, Ping; Luo, Hui; Wang, Xi-Rui; Wang, Xie-Feng; Zhang, Jun-Xia; Wang, Ying-Yi; Yao, Lei; Liu, Ning; You, Yong-Ping

    2014-10-01

    Cancer cells may involve diverse mutations, but they often rely on continued expression of a single oncoprotein for survival, as a response to targeting this protein. Generally, Ras is overexpressed in human epithelial tumors and cancellation of activated Ras inhibits carcinoma cell proliferation and differentiation ability, and induces apoptotosis of tumor cells. However, the mechanisms of inhibition of activated Ras that suppress the malignancy activity of human epithelial tumors remain to be illuminated. We utilized text-mining of MEDLINE abstracts with natural language processing to establish the Ras biologic association network, and identified several interactions of this network with the Ras pathway. Our investigation not only examined the expression of Ras and Hub genes (PIK3CA, MDM2, CCND1, EGFR, JUN, MYC, VEGFA, ERK1 and ERK2) but also confirmed inhibition of activated Ras reduced expression of multiple oncogene in vitro studies. Our studies provide strong support for the conclusion that cancellation of activated Ras specifically regulates defective Ras pathways in human tumor cells.

  9. Time course analysis of gene expression identifies multiple genes with differential expression in patients with in-stent restenosis

    Directory of Open Access Journals (Sweden)

    Gudnason Thorarinn

    2011-02-01

    Full Text Available Abstract Background The vascular disease in-stent restenosis (ISR is characterized by formation of neointima and adverse inward remodeling of the artery after injury by coronary stent implantation. We hypothesized that the analysis of gene expression in peripheral blood mononuclear cells (PBMCs would demonstrate differences in transcript expression between individuals who develop ISR and those who do not. Methods and Results We determined and investigated PBMC gene expression of 358 patients undergoing an index procedure to treat in de novo coronary artery lesions with bare metallic stents, using a novel time-varying intercept model to optimally assess the time course of gene expression across a time course of blood samples. Validation analyses were conducted in an independent sample of 97 patients with similar time-course blood sampling and gene expression data. We identified 47 probesets with differential expression, of which 36 were validated upon independent replication testing. The genes identified have varied functions, including some related to cellular growth and metabolism, such as the NAB2 and LAMP genes. Conclusions In a study of patients undergoing bare metallic stent implantation, we have identified and replicated differential gene expression in peripheral blood mononuclear cells, studied across a time series of blood samples. The genes identified suggest alterations in cellular growth and metabolism pathways, and these results provide the basis for further specific functional hypothesis generation and testing of the mechanisms of ISR.

  10. Novel mutations including deletions of the entire OFD1 gene in 30 families with type I orofaciodigital syndrome: a study of the extensive clinical variability

    Science.gov (United States)

    Bisschoff, Izak J; Zeschnigk, Christine; Horn, Denise; Wellek, Brigitte; Rieß, Angelika; Wessels, Maja; Willems, Patrick; Jensen, Peter; Busche, Andreas; Bekkebraten, Jens; Chopra, Maya; Hove, Hanne Dahlgaard; Evers, Christina; Heimdal, Ketil; Kaiser, Ann-Sophie; Kunstmann, Erdmut; Robinson, Kristina Lagerstedt; Linné, Maja; Martin, Patricia; McGrath, James; Pradel, Winnie; Prescott, Trine E; Roesler, Bernd; Rudolf, Gorazd; Siebers-Renelt, Ulrike; Tyshchenko, Nataliya; Wieczorek, Dagmar; Wolff, Gerhard; Dobyns, William B.; Morris-Rosendahl, Deborah J

    2017-01-01

    OFD1, now recognized as a ciliopathy, is characterized by malformations of the face, oral cavity and digits, and is transmitted as an X-linked condition with lethality in males. Mutations in OFD1 also cause X-linked Joubert syndrome (JBTS10) and Simpson–Golabi–Behmel syndrome type 2 (SGBS2). We have studied 55 sporadic and six familial cases of suspected OFD1. Comprehensive mutation analysis in OFD1 revealed mutations in 37 female patients from 30 families; 22 mutations have not been previously described including two heterozygous deletions spanning OFD1 and neighbouring genes. Analysis of clinical findings in patients with mutations revealed that oral features are the most reliable diagnostic criteria. A first, detailed evaluation of brain MRIs from seven patients with cognitive defects illustrated extensive variability with the complete brain phenotype consisting of complete agenesis of the corpus callosum, large single or multiple interhemispheric cysts, striking cortical infolding of gyri, ventriculomegaly, mild molar tooth malformation and moderate to severe cerebellar vermis hypoplasia. Although the OFD1 gene apparently escapes X-inactivation, skewed inactivation was observed in seven of 14 patients. The direction of skewing did not correlate with disease severity, reinforcing the hypothesis that additional factors contribute to the extensive intrafamilial variability. PMID:23033313

  11. The interaction between smoking and HLA genes in multiple sclerosis: replication and refinement.

    Science.gov (United States)

    Hedström, Anna Karin; Katsoulis, Michail; Hössjer, Ola; Bomfim, Izaura L; Oturai, Annette; Sondergaard, Helle Bach; Sellebjerg, Finn; Ullum, Henrik; Thørner, Lise Wegner; Gustavsen, Marte Wendel; Harbo, Hanne F; Obradovic, Dragana; Gianfrancesco, Milena A; Barcellos, Lisa F; Schaefer, Catherine A; Hillert, Jan; Kockum, Ingrid; Olsson, Tomas; Alfredsson, Lars

    2017-10-01

    Interactions between environment and genetics may contribute to multiple sclerosis (MS) development. We investigated whether the previously observed interaction between smoking and HLA genotype in the Swedish population could be replicated, refined and extended to include other populations. We used six independent case-control studies from five different countries (Sweden, Denmark, Norway, Serbia, United States). A pooled analysis was performed for replication of previous observations (7190 cases, 8876 controls). Refined detailed analyses were carried out by combining the genetically similar populations from the Nordic studies (6265 cases, 8401 controls). In both the pooled analyses and in the combined Nordic material, interactions were observed between HLA-DRB*15 and absence of HLA-A*02 and between smoking and each of the genetic risk factors. Two way interactions were observed between each combination of the three variables, invariant over categories of the third. Further, there was also a three way interaction between the risk factors. The difference in MS risk between the extremes was considerable; smokers carrying HLA-DRB1*15 and lacking HLA-A*02 had a 13-fold increased risk compared with never smokers without these genetic risk factors (OR 12.7, 95% CI 10.8-14.9). The risk of MS associated with HLA genotypes is strongly influenced by smoking status and vice versa. Since the function of HLA molecules is to present peptide antigens to T cells, the demonstrated interactions strongly suggest that smoking alters MS risk through actions on adaptive immunity.

  12. A comparison on parameter-estimation methods in multiple regression analysis with existence of multicollinearity among independent variables

    Directory of Open Access Journals (Sweden)

    Hukharnsusatrue, A.

    2005-11-01

    Full Text Available The objective of this research is to compare multiple regression coefficients estimating methods with existence of multicollinearity among independent variables. The estimation methods are Ordinary Least Squares method (OLS, Restricted Least Squares method (RLS, Restricted Ridge Regression method (RRR and Restricted Liu method (RL when restrictions are true and restrictions are not true. The study used the Monte Carlo Simulation method. The experiment was repeated 1,000 times under each situation. The analyzed results of the data are demonstrated as follows. CASE 1: The restrictions are true. In all cases, RRR and RL methods have a smaller Average Mean Square Error (AMSE than OLS and RLS method, respectively. RRR method provides the smallest AMSE when the level of correlations is high and also provides the smallest AMSE for all level of correlations and all sample sizes when standard deviation is equal to 5. However, RL method provides the smallest AMSE when the level of correlations is low and middle, except in the case of standard deviation equal to 3, small sample sizes, RRR method provides the smallest AMSE.The AMSE varies with, most to least, respectively, level of correlations, standard deviation and number of independent variables but inversely with to sample size.CASE 2: The restrictions are not true.In all cases, RRR method provides the smallest AMSE, except in the case of standard deviation equal to 1 and error of restrictions equal to 5%, OLS method provides the smallest AMSE when the level of correlations is low or median and there is a large sample size, but the small sample sizes, RL method provides the smallest AMSE. In addition, when error of restrictions is increased, OLS method provides the smallest AMSE for all level, of correlations and all sample sizes, except when the level of correlations is high and sample sizes small. Moreover, the case OLS method provides the smallest AMSE, the most RLS method has a smaller AMSE than

  13. DNA replication of histone gene repeats in Drosophila melanogaster tissue culture cells: multiple initiation sites and replication pause sites.

    Science.gov (United States)

    Shinomiya, T; Ina, S

    1993-01-01

    We showed previously that DNA replication initiates at multiple sites in the 5-kb histone gene repeating unit in early embryos of Drosophila melanogaster. The present report shows evidence that replication in the same chromosomal region initiates at multiple sites in tissue culture cells as well. First, we analyzed replication intermediates by the two-dimensional gel electrophoretic replicon mapping method and detected bubble-form replication intermediates for all fragments restricted at different sites in the repeating unit. Second, we analyzed bromodeoxyuridine-labeled nascent strands amplified by the polymerase chain reaction method and detected little differences in the size distribution of nascent strands specific to six short segments located at different sites in the repeating unit. These results strongly suggest that DNA replication initiates at multiple sites located within the repeating unit. We also found several replication pause sites located at 5' upstream regions of some histone genes. Images PMID:8321216

  14. Non-classical HLA-E gene variability in Brazilians: a nearly invariable locus surrounded by the most variable genes in the human genome.

    Science.gov (United States)

    Veiga-Castelli, L C; Castelli, E C; Mendes, C T; da Silva, W A; Faucher, M-C; Beauchemin, K; Roger, M; Moreau, P; Donadi, E A

    2012-01-01

    The non-classical human leukocyte antigen (HLA) class I genes present a very low rate of variation. So far, only 10 HLA-E alleles encoding three proteins have been described, but only two are frequently found in worldwide populations. Because of its historical background, Brazilians are very suitable for population genetic studies. Therefore, 104 bone marrow donors from Brazil were evaluated for HLA-E exons 1-4. Seven variation sites were found, including two known single nucleotide polymorphisms (SNPs) at positions +424 and +756 and five new SNPs at positions +170 (intron 1), +1294 (intron 3), +1625, +1645 and +1857 (exon 4). Haplotyping analysis did show eight haplotypes, three of them known as E*01:01:01, E*01:03:01 and E*01:03:02:01 and five HLA-E new alleles that carry the new variation sites. The HLA-E*01:01:01 allele was the predominant haplotype (62.50%), followed by E*01:03:02:01 (24.52%). Selective neutrality tests have disclosed an interesting pattern of selective pressures in which balancing selection is probably shaping allele frequency distributions at an SNP at exon 3 (codon 107), sequence diversity at exon 4 and the non-coding regions is facing significant purifying pressure. Even in an admixed population such as the Brazilian one, the HLA-E locus is very conserved, presenting few polymorphic SNPs in the coding region. © 2011 John Wiley & Sons A/S.

  15. Multiple-locus variable-number tandem-repeat analysis genotyping of human Brucella isolates from Turkey.

    Science.gov (United States)

    Kiliç, Selçuk; Ivanov, Ivan N; Durmaz, Riza; Bayraktar, Mehmet Refik; Ayaslioglu, Ergin; Uyanik, M Hamidullah; Aliskan, Hikmet; Yasar, Ekrem; Bayramoglu, Gülçin; Arslantürk, Ahmet; Vergnaud, Gilles; Kantardjiev, Todor V

    2011-09-01

    A multiple-locus variable-number tandem-repeat analysis (MLVA) was applied to investigate the epidemiological relationship and genetic diversity among 162 human Brucella isolates collected from all geographic regions of Turkey in an 8-year period (2001 to 2008). The isolates were genotyped by using an MLVA assay developed in Orsay, France (MLVA-16(Orsay)) including eight minisatellite (panel 1) and eight microsatellite (panel 2, subdivided into 2A and 2B) markers. Panels 1 and 2A distinguish 14 genotypes; two of these represented 85% of the strains. Panel 2B displayed a very high discriminatory power. Three loci from panel 2B had diversity index values higher than 0.74. MLVA-16(Orsay) yielded 105 genotypes; 73 were represented by a unique isolate, and 32 included two to eight isolates. The isolates from different patients within the same outbreak or from the same patient before first-line therapy and after relapse showed identical genotypes. A number of MLVA genotypes appeared to be partially restricted to some geographic areas and displayed no annual variation, possibly reflecting persistence of genotypes in certain areas for a time span of at least a decade. This study, representing the first molecular typing results of human Brucella isolates from Turkey, indicated that Turkish human Brucella melitensis isolates were most closely related to the neighboring countries' isolates included in the East Mediterranean group.

  16. Multiple-Locus Variable-Number Tandem-Repeat Analysis Genotyping of Human Brucella Isolates from Turkey▿†

    Science.gov (United States)

    Kılıç, Selçuk; Ivanov, Ivan N.; Durmaz, Rıza; Bayraktar, Mehmet Refik; Ayaşlıoğlu, Ergin; Uyanık, M. Hamidullah; Alışkan, Hikmet; Yaşar, Ekrem; Bayramoğlu, Gülçin; Arslantürk, Ahmet; Vergnaud, Gilles; Kantardjiev, Todor V.

    2011-01-01

    A multiple-locus variable-number tandem-repeat analysis (MLVA) was applied to investigate the epidemiological relationship and genetic diversity among 162 human Brucella isolates collected from all geographic regions of Turkey in an 8-year period (2001 to 2008). The isolates were genotyped by using an MLVA assay developed in Orsay, France (MLVA-16Orsay) including eight minisatellite (panel 1) and eight microsatellite (panel 2, subdivided into 2A and 2B) markers. Panels 1 and 2A distinguish 14 genotypes; two of these represented 85% of the strains. Panel 2B displayed a very high discriminatory power. Three loci from panel 2B had diversity index values higher than 0.74. MLVA-16Orsay yielded 105 genotypes; 73 were represented by a unique isolate, and 32 included two to eight isolates. The isolates from different patients within the same outbreak or from the same patient before first-line therapy and after relapse showed identical genotypes. A number of MLVA genotypes appeared to be partially restricted to some geographic areas and displayed no annual variation, possibly reflecting persistence of genotypes in certain areas for a time span of at least a decade. This study, representing the first molecular typing results of human Brucella isolates from Turkey, indicated that Turkish human Brucella melitensis isolates were most closely related to the neighboring countries' isolates included in the East Mediterranean group. PMID:21795514

  17. Multiple-locus variable-number tandem-repeat analysis as a tool for subtyping Listeria monocytogenes strains.

    Science.gov (United States)

    Sperry, Katharine E Volpe; Kathariou, Sophia; Edwards, Justin S; Wolf, Leslie A

    2008-04-01

    Listeria monocytogenes, like many other food-borne bacteria, has certain strains that are commonly linked to outbreaks. Due to the relatively low numbers of affected individuals, outbreaks of L. monocytogenes can be difficult to detect. The current technique of molecular subtyping in PulseNet laboratories to identify genetically similar strains is pulsed-field gel electrophoresis (PFGE). While PFGE is state-of-the-art, interlaboratory comparisons are difficult because the results are highly susceptible to discrepancies due to even minor variations in experimental conditions and the subjectivity of band marking. This research was aimed at the development of a multiple-locus variable-number tandem-repeat analysis (MLVA) that can be implemented in PulseNet laboratories to replace or complement existing protocols. MLVA has proven to be a rapid and highly discriminatory tool for subtyping many bacteria. In this study, a novel MLVA method for L. monocytogenes strains was developed utilizing eight loci multiplexed into two PCRs. The PCR products were separated by capillary gel electrophoresis for high throughput and accurate sizing, and the fragment sizes were analyzed and clustered based on the number of repeats. When tested against a panel of 193 epidemiologically linked and nonlinked isolates, this MLVA for L. monocytogenes strains demonstrates strong epidemiological concordance. Since MLVA is a high-throughput screening method that is fairly inexpensive, easy to perform, rapid, and reliable, it is well suited to interlaboratory comparisons during epidemiological investigations of food-borne illness.

  18. Diversity of Acinetobacter baumannii in four French military hospitals, as assessed by multiple locus variable number of tandem repeats analysis.

    Directory of Open Access Journals (Sweden)

    Yolande Hauck

    Full Text Available BACKGROUND: Infections by A. calcoaceticus-A. baumannii (ACB complex isolates represent a serious threat for wounded and burn patients. Three international multidrug-resistant (MDR clones (EU clone I-III are responsible for a large proportion of nosocomial infections with A. baumannii but other emerging strains with high epidemic potential also occur. METHODOLOGY/PRINCIPAL FINDINGS: We automatized a Multiple locus variable number of tandem repeats (VNTR analysis (MLVA protocol and used it to investigate the genetic diversity of 136 ACB isolates from four military hospitals and one childrens hospital. Acinetobacter sp other than baumannii isolates represented 22.6% (31/137 with a majority being A. pittii. The genotyping protocol designed for A.baumannii was also efficient to cluster A. pittii isolates. Fifty-five percent of A. baumannii isolates belonged to the two international clones I and II, and we identified new clones which members were found in the different hospitals. Analysis of two CRISPR-cas systems helped define two clonal complexes and provided phylogenetic information to help trace back their emergence. CONCLUSIONS/SIGNIFICANCE: The increasing occurrence of A. baumannii infections in the hospital calls for measures to rapidly characterize the isolates and identify emerging clones. The automatized MLVA protocol can be the instrument for such surveys. In addition, the investigation of CRISPR/cas systems may give important keys to understand the evolution of some highly successful clonal complexes.

  19. Disability, quality of life, personality, cognitive and psychological variables associated with fatigue in patients with multiple sclerosis.

    Science.gov (United States)

    Fernández-Muñoz, J J; Morón-Verdasco, A; Cigarán-Méndez, M; Muñoz-Hellín, E; Pérez-de-Heredia-Torres, M; Fernández-de-las-Peñas, C

    2015-08-01

    To examine the associations between function, quality of life, personality, cognitive and psychological outcomes with fatigue in patients with MS. One hundred and eight patients (54% women) with definite MS participated. MS-related fatigue was assessed with the Fatigue Impact Scale (FIS). Demographic and clinical data (weight, height, medication and history of pain), specific disease outcomes (Functional Assessment of Multiple Sclerosis/FAMS), general disease outcomes (Beck Depression Inventory/BDI-II, and Short-Form Health Survey 36/SF-36) and personality (NEO Five-Factor Inventory/NEOFFI) were assessed. Correlation and regression analyses were performed to determine associations between variables. A significant positive correlation existed between the FIS and EDSS (r=0.190; Ppersonality (NEOFFI neuroticism: r=-0.39, P<0.01; agreeableness: r=-0.206, P<0.05; conscientiousness: r=-0.279, P<0.01) were also observed. Stepwise regression analyses revealed that FAMS thinking/fatigue, physical function (SF-36) and FAMS emotional well-being explained 62.5% of the variance in fatigue (r2=0.652; r2 adjusted=0.625; F=23.774; P<0.001). This study indicates that MS-related fatigue shows an impact on physical, cognitive and emotional aspects in this population. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  20. Molecular typing of Argentinian Mycobacterium avium subsp. paratuberculosis isolates by multiple-locus variable number-tandem repeat analysis

    Directory of Open Access Journals (Sweden)

    Andrea Gioffré

    2015-06-01

    Full Text Available Multiple-locus variable number-tandem repeat analysis (MLVA of Mycobacterium avium subspecies paratuberculosis (MAP isolates may contribute to the knowledge of strain diversity in Argentina. Although the diversity of MAP has been previously investigated in Argentina using IS900-RFLP, a small number of isolates were employed, and a low discriminative power was reached. The aim of the present study was to test the genetic diversity among MAP isolates using an MLVA approach based on 8 repetitive loci. We studied 97 isolates from cattle, goat and sheep and could describe 7 different patterns: INMV1, INMV2, INMV11, INMV13, INMV16, INMV33 and one incomplete pattern. INMV1 and INMV2 were the most frequent patterns, grouping 76.3% of the isolates. We were also able to demonstrate the coexistence of genotypes in herds and co-infection at the organism level. This study shows that all the patterns described are common to those described in Europe, suggesting an epidemiological link between the continents.

  1. Molecular typing of Argentinian Mycobacterium avium subsp. paratuberculosis isolates by multiple-locus variable number-tandem repeat analysis.

    Science.gov (United States)

    Gioffré, Andrea; Correa Muñoz, Magnolia; Alvarado Pinedo, María F; Vaca, Roberto; Morsella, Claudia; Fiorentino, María Andrea; Paolicchi, Fernando; Ruybal, Paula; Zumárraga, Martín; Travería, Gabriel E; Romano, María Isabel

    2015-06-01

    Multiple-locus variable number-tandem repeat analysis (MLVA) of Mycobacterium avium subspecies paratuberculosis (MAP) isolates may contribute to the knowledge of strain diversity in Argentina. Although the diversity of MAP has been previously investigated in Argentina using IS900-RFLP, a small number of isolates were employed, and a low discriminative power was reached. The aim of the present study was to test the genetic diversity among MAP isolates using an MLVA approach based on 8 repetitive loci. We studied 97 isolates from cattle, goat and sheep and could describe 7 different patterns: INMV1, INMV2, INMV11, INMV13, INMV16, INMV33 and one incomplete pattern. INMV1 and INMV2 were the most frequent patterns, grouping 76.3% of the isolates. We were also able to demonstrate the coexistence of genotypes in herds and co-infection at the organism level. This study shows that all the patterns described are common to those described in Europe, suggesting an epidemiological link between the continents.

  2. Microbiome characterization using SMRT sequencing on 16S rRNA genes across a range of amplicon sizes and variable region content

    Science.gov (United States)

    The sequence of variable regions along the 16S ribosomal RNA gene is often used to conduct metagenomic surveys of bacterial populations in specific habitats, because of the inter-species variability in these regions and because it is possible to design amplification primers in sections of the gene t...

  3. A novel mutation in the tRNAIle gene (MTTI) affecting the variable loop in a patient with chronic progressive external ophthalmoplegia (CPEO).

    Science.gov (United States)

    Berardo, Andres; Coku, Jorida; Kurt, Bulent; DiMauro, Salvatore; Hirano, Michio

    2010-03-01

    We describe a 62-year-old woman with chronic progressive external ophthalmoplegia (CPEO), multiple lipomas, diabetes mellitus, and a novel mitochondrial DNA (mtDNA) mutation at nucleotide 4302 (4302A>G) of the tRNA(Ile) gene (MTTI). This is the first mutation at position 44 in the variable loop (V loop) of any mitochondrial tRNA. The muscle biopsy revealed 10% ragged-red/ragged-blue fibers and 25% cytochrome c oxidase (COX)-deficient fibers. No deletions or duplications were detected by Southern blot analysis. The 4302A>G transition was present only in the patient's muscle and single-fiber analysis revealed significantly higher levels of the mutation in COX-deficient than in normal fibers. Like tRNA(Leu(UUR)), tRNA(Ile) appears to be a "hot spot" for mtDNA mutations causing CPEO. Copyright 2010 Elsevier B.V. All rights reserved.

  4. Three subfamilies of pheromone and receptor genes generate multiple B mating specificities in the mushroom Coprinus cinereus.

    Science.gov (United States)

    Halsall, J R; Milner, M J; Casselton, L A

    2000-01-01

    The B mating type locus of the basidiomycete Coprinus cinereus encodes a large family of lipopeptide pheromones and their seven transmembrane domain receptors. Here we show that the B42 locus, like the previously described B6 locus, derives its unique specificity from nine multiallelic genes that are organized into three subgroups each comprising a receptor and two pheromone genes. We show that the three genes within each group are kept together as a functional unit by being embedded in an allele-specific DNA sequence. Using a combination of sequence analysis, Southern blotting, and DNA-mediated transformation with cloned genes, we demonstrate that different B loci may share alleles of one or two groups of genes. This is consistent with the prediction that the three subgroups of genes are functionally redundant and that it is the different combinations of their alleles that generate the multiple B mating specificities found in nature. The B42 locus was found to contain an additional gene, mfs1, that encodes a putative multidrug transporter belonging to the major facilitator family. In strains with other B mating specificities, this gene, whose functional significance was not established, lies in a region of shared homology flanking the B locus. PMID:10757757

  5. Variable expressivity and genetic heterogeneity involving DPT and SEMA3D genes in autosomal dominant familial Meniere's disease.

    Science.gov (United States)

    Martín-Sierra, Carmen; Gallego-Martinez, Alvaro; Requena, Teresa; Frejo, Lidia; Batuecas-Caletrío, Angel; Lopez-Escamez, Jose A

    2017-02-01

    Autosomal dominant (AD) familial Meniere's disease (FMD) is a rare disorder involving the inner ear defined by sensorineural hearing loss, tinnitus and episodic vertigo. Here, we have identified two novel and rare heterozygous variants in the SEMA3D and DPT genes segregating with the complete phenotype that have variable expressivity in two pedigrees with AD-FMD. A detailed characterization of the phenotype within each family illustrates the clinical heterogeneity in the onset and progression of the disease. We also showed the expression of both genes in the human cochlea and performed in silico analyses of these variants. Three-dimensional protein modelling showed changes in the structure of the protein indicating potential physical interactions. These results confirm a genetic heterogeneity in FMD with incomplete penetrance and variable expressivity.

  6. Multiple Regression and Mediator Variables can be used to Avoid Double Counting when Economic Values are Derived using Stochastic Herd Simulation

    DEFF Research Database (Denmark)

    Østergaard, Søren; Ettema, Jehan Frans; Hjortø, Line

    variable, while using the traits representing the direct effects of metritis on yield, fertility and occurrence of other diseases as mediator variables. The economic value of metritis was estimated to be €78 per 100 cow-years for each 1% increase of metritis in the period of 1-100 days in milk...... in multiparous cows. The merit of using this approach was demonstrated since the economic value of metritis was estimated to be 81% higher when no mediator variables were included in the multiple regression analysis......Multiple regression and model building with mediator variables was addressed to avoid double counting when economic values are estimated from data simulated with herd simulation modeling (using the SimHerd model). The simulated incidence of metritis was analyzed statistically as the independent...

  7. Identification of Gene Markers Associated with Aggressive Meningioma by Filtering across Multiple Sets of Gene Expression Arrays

    OpenAIRE

    Stuart, Jourdan E.; Lusis, Eriks A.; Scheck, Adrienne C; Coons, Stephen W; Lal, Anita; Perry, Arie; Gutmann, David H.

    2011-01-01

    Meningiomasare common intracranial tumors but relatively little is known about the genetic events responsible for their clinical diversity. While recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of mening...

  8. A Hybrid One-Way ANOVA Approach for the Robust and Efficient Estimation of Differential Gene Expression with Multiple Patterns.

    Science.gov (United States)

    Mollah, Mohammad Manir Hossain; Jamal, Rahman; Mokhtar, Norfilza Mohd; Harun, Roslan; Mollah, Md Nurul Haque

    2015-01-01

    Identifying genes that are differentially expressed (DE) between two or more conditions with multiple patterns of expression is one of the primary objectives of gene expression data analysis. Several statistical approaches, including one-way analysis of variance (ANOVA), are used to identify DE genes. However, most of these methods provide misleading results for two or more conditions with multiple patterns of expression in the presence of outlying genes. In this paper, an attempt is made to develop a hybrid one-way ANOVA approach that unifies the robustness and efficiency of estimation using the minimum β-divergence method to overcome some problems that arise in the existing robust methods for both small- and large-sample cases with multiple patterns of expression. The proposed method relies on a β-weight function, which produces values between 0 and 1. The β-weight function with β = 0.2 is used as a measure of outlier detection. It assigns smaller weights (≥ 0) to outlying expressions and larger weights (≤ 1) to typical expressions. The distribution of the β-weights is used to calculate the cut-off point, which is compared to the observed β-weight of an expression to determine whether that gene expression is an outlier. This weight function plays a key role in unifying the robustness and efficiency of estimation in one-way ANOVA. Analyses of simulated gene expression profiles revealed that all eight methods (ANOVA, SAM, LIMMA, EBarrays, eLNN, KW, robust BetaEB and proposed) perform almost identically for m = 2 conditions in the absence of outliers. However, the robust BetaEB method and the proposed method exhibited considerably better performance than the other six methods in the presence of outliers. In this case, the BetaEB method exhibited slightly better performance than the proposed method for the small-sample cases, but the the proposed method exhibited much better performance than the BetaEB method for both the small- and large-sample cases in

  9. A Hybrid One-Way ANOVA Approach for the Robust and Efficient Estimation of Differential Gene Expression with Multiple Patterns.

    Directory of Open Access Journals (Sweden)

    Mohammad Manir Hossain Mollah

    Full Text Available Identifying genes that are differentially expressed (DE between two or more conditions with multiple patterns of expression is one of the primary objectives of gene expression data analysis. Several statistical approaches, including one-way analysis of variance (ANOVA, are used to identify DE genes. However, most of these methods provide misleading results for two or more conditions with multiple patterns of expression in the presence of outlying genes. In this paper, an attempt is made to develop a hybrid one-way ANOVA approach that unifies the robustness and efficiency of estimation using the minimum β-divergence method to overcome some problems that arise in the existing robust methods for both small- and large-sample cases with multiple patterns of expression.The proposed method relies on a β-weight function, which produces values between 0 and 1. The β-weight function with β = 0.2 is used as a measure of outlier detection. It assigns smaller weights (≥ 0 to outlying expressions and larger weights (≤ 1 to typical expressions. The distribution of the β-weights is used to calculate the cut-off point, which is compared to the observed β-weight of an expression to determine whether that gene expression is an outlier. This weight function plays a key role in unifying the robustness and efficiency of estimation in one-way ANOVA.Analyses of simulated gene expression profiles revealed that all eight methods (ANOVA, SAM, LIMMA, EBarrays, eLNN, KW, robust BetaEB and proposed perform almost identically for m = 2 conditions in the absence of outliers. However, the robust BetaEB method and the proposed method exhibited considerably better performance than the other six methods in the presence of outliers. In this case, the BetaEB method exhibited slightly better performance than the proposed method for the small-sample cases, but the the proposed method exhibited much better performance than the BetaEB method for both the small- and large

  10. Identification of gene markers associated with aggressive meningioma by filtering across multiple sets of gene expression arrays.

    Science.gov (United States)

    Stuart, Jourdan E; Lusis, Eriks A; Scheck, Adrienne C; Coons, Stephen W; Lal, Anita; Perry, Arie; Gutmann, David H

    2011-01-01

    Meningiomas are common intracranial tumors, but relatively little is known about the genetic events responsible for their clinical diversity. Although recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of meningiomas and then verified the remaining genes by quantitative polymerase chain reaction followed by examination using a third microarray expression cohort. Using this approach, we identified 9 overexpressed (TPX2, RRM2, TOP2A, PI3, BIRC5, CDC2, NUSAP1, DLG7, SOX11) and 2 underexpressed (TIMP3, KCNMA1) genes in grade III versus grade I meningiomas. As a further validation step, we analyzed these genes in a fourth cohort and found that patients with grade II meningiomas with high topoisomerase 2-α protein expressions (>5% labeling index) had shorter times to death than patients with low expressions. We believe that this multistep multi-cohort approach provides a robust method for reducing false-positives while generating a list of reproducible candidate genes that are associated with clinically aggressive meningiomas and are suitable for analysis for their potential prognostic value.

  11. Multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP and lung resistance protein (LRP gene expression in childhood acute lymphoblastic leukemia

    Directory of Open Access Journals (Sweden)

    Elvis Terci Valera

    Full Text Available CONTEXT: Despite the advances in the cure rate for acute lymphoblastic leukemia, approximately 25% of affected children suffer relapses. Expression of genes for the multiple drug resistance protein (MDR-1, multidrug resistance-related protein (MRP, and lung resistance protein (LRP may confer the phenotype of resistance to the treatment of neoplasias. OBJECTIVE: To analyze the expression of the MDR-1, MRP and LRP genes in children with a diagnosis of acute lymphoblastic leukemia via the semiquantitative reverse transcription polymerase chain reaction (RT-PCR, and to determine the correlation between expression and event-free survival and clinical and laboratory variables. DESIGN: A retrospective clinical study. SETTING: Laboratory of Pediatric Oncology, Department of Pediatrics, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Brazil. METHODS: Bone marrow aspirates from 30 children with a diagnosis of acute lymphoblastic leukemia were assessed for the expression of messenger RNA for the MDR-1, MRP and LRP genes by semi-quantitative RT-PCR. RESULTS: In the three groups studied, only the increased expression of LRP was related to worsened event-free survival (p = 0.005. The presence of the common acute lymphoblastic leukemia antigen (CALLA was correlated with increased LRP expression (p = 0.009 and increased risk of relapse or death (p = 0.05. The relative risk of relapse or death was six times higher among children with high LRP expression upon diagnosis (p = 0.05, as confirmed by multivariate analysis of the three genes studied (p = 0.035. DISCUSSION: Cell resistance to drugs is a determinant of the response to chemotherapy and its detection via RT-PCR may be of clinical importance. CONCLUSIONS: Evaluation of the expression of genes for resistance to antineoplastic drugs in childhood acute lymphoblastic leukemia upon diagnosis, and particularly the expression of the LRP gene, may be of clinical relevance, and should be the

  12. Variable penetrance of hypogonadism in a sibship with Kallmann syndrome due to a deletion of the KAL gene

    Energy Technology Data Exchange (ETDEWEB)

    Parenti, G.; Rizzolo, M.G.; Ghezzi, M. [Federico II University, Naples (Italy)] [and others

    1995-07-03

    We report on the clinical and molecular characterization of 3 sibs with X-linked ichthyosis and variable expression of Kallmann syndrome. One of the affected brothers had mild hyposmia and showed normal pubertal progression. However, we demonstrated the same partial deletion of the X-linked Kallmann gene, sparing the first exon in the mildly affected patient as well as in one of his severely affected brothers. 13 refs., 1 fig., 1 tab.

  13. Sertoli-cell-specific knockout of connexin 43 leads to multiple alterations in testicular gene expression in prepubertal mice

    Directory of Open Access Journals (Sweden)

    Sarah Giese

    2012-11-01

    A significant decline in human male reproductive function has been reported for the past 20 years but the molecular mechanisms remain poorly understood. However, recent studies showed that the gap junction protein connexin-43 (CX43; also known as GJA1 might be involved. CX43 is the predominant testicular connexin (CX in most species, including in humans. Alterations of its expression are associated with different forms of spermatogenic disorders and infertility. Men with impaired spermatogenesis often exhibit a reduction or loss of CX43 expression in germ cells (GCs and Sertoli cells (SCs. Adult male transgenic mice with a conditional knockout (KO of the Gja1 gene [referred to here as connexin-43 (Cx43] in SCs (SCCx43KO show a comparable testicular phenotype to humans and are infertile. To detect possible signaling pathways and molecular mechanisms leading to the testicular phenotype in adult SCCx43KO mice and to their failure to initiate spermatogenesis, the testicular gene expression of 8-day-old SCCx43KO and wild-type (WT mice was compared. Microarray analysis revealed that 658 genes were significantly regulated in testes of SCCx43KO mice. Of these genes, 135 were upregulated, whereas 523 genes were downregulated. For selected genes the results of the microarray analysis were confirmed using quantitative real-time PCR and immunostaining. The majority of the downregulated genes are GC-specific and are essential for mitotic and meiotic progression of spermatogenesis, including Stra8, Dazl and members of the DM (dsx and map-3 gene family. Other altered genes can be associated with transcription, metabolism, cell migration and cytoskeleton organization. Our data show that deletion of Cx43 in SCs leads to multiple alterations of gene expression in prepubertal mice and primarily affects GCs. The candidate genes could represent helpful markers for investigators exploring human testicular biopsies from patients showing corresponding spermatogenic deficiencies and for

  14. Understanding Autoimmune Mechanisms in Multiple Sclerosis Using Gene Expression Microarrays: Treatment Effect and Cytokine-related Pathways

    Directory of Open Access Journals (Sweden)

    A. Achiron

    2004-01-01

    Full Text Available Multiple sclerosis (MS is a central nervous system disease in which activated autoreactive T-cells invade the blood brain barrier and initiate an inflammatory response that leads to myelin destruction and axonal loss. The etiology of MS, as well as the mechanisms associated with its unexpected onset, the unpredictable clinical course spanning decades, and the different rates of progression leading to disability over time, remains an enigma. We have applied gene expression microarrays technology in peripheral blood mononuclear cells (PBMC to better understand MS pathogenesis and better target treatment approaches. A signature of 535 genes were found to distinguish immunomodulatory treatment effects between 13 treated and 13 untreated MS patients. In addition, the expression pattern of 1109 gene transcripts that were previously reported to significantly differentiate between MS patients and healthy subjects were further analyzed to study the effect of cytokine-related pathways on disease pathogenesis. When relative gene expression for 26 MS patients was compared to 18 healthy controls, 30 genes related to various cytokine-associated pathways were identified. These genes belong to a variety of families such as interleukins, small inducible cytokine subfamily and tumor necrosis factor ligand and receptor. Further analysis disclosed seven cytokine-associated genes within the immunomodulatory treatment signature, and two cytokine-associated genes SCYA4 (small inducible cytokine A4 and FCAR (Fc fragment of IgA, CD89 that were common to both the MS gene expression signature and the immunomodulatory treatment gene expression signature. Our results indicate that cytokine-associated genes are involved in various pathogenic pathways in MS and also related to immunomodulatory treatment effects.

  15. The orthologs of HLA-DQ and -DP genes display abundant levels of variability in macaque species.

    Science.gov (United States)

    Otting, Nel; van der Wiel, Marit K H; de Groot, Nanine; de Vos-Rouweler, Annemiek J M; de Groot, Natasja G; Doxiadis, Gaby G M; Wiseman, Roger W; O'Connor, David H; Bontrop, Ronald E

    2017-02-01

    The human major histocompatibility complex (MHC) region encodes three types of class II molecules designated HLA-DR, -DQ, and -DP. Both the HLA-DQ and -DP gene region comprise a duplicated tandem of A and B genes, whereas in macaques, only one set of genes is present per region. A substantial sequencing project on the DQ and DP genes in various macaque populations resulted in the detection of previously 304 unreported full-length alleles. Phylogenetic studies showed that humans and macaques share trans-species lineages for the DQA1 and DQB1 genes, whereas the DPA1 and DPB1 lineages in macaques appear to be species-specific. Amino acid variability plot analyses revealed that each of the four genes displays more allelic variation in macaques than is encountered in humans. Moreover, the numbers of different amino acids at certain positions in the encoded proteins are higher than in humans. This phenomenon is remarkably prominent at the contact positions of the peptide-binding sites of the deduced macaque DPβ-chains. These differences in the MHC class II DP regions of macaques and humans suggest separate evolutionary mechanisms in the generation of diversity.

  16. Biological characterization and variability of the nucleocapsid protein gene of Groundnut bud necrosis virus isolates infecting pea from India

    Directory of Open Access Journals (Sweden)

    Mohammad AKRAM

    2012-09-01

    Full Text Available A disease of pea characterized by browning in veins, leaves and stems, mostly in growing tips, and brown circular spots on pods, was recorded in four districts of Uttar Pradesh, India. The causal agent of this disease was detected by reverse transcription-polymerase chain reaction (RT-PCR using primers pair HRP 26/HRP 28 and identified as Groundnut bud necrosis virus (GBNV on the basis of nucleocapsid protein (NP gene sequence. Virus isolates from Bareilly (BRY, Kanpur (KNP, Udham Singh Nagar (USN and Shahjahanpur (SJP were designated as GBNV-[Pea_BRY], GBNV-[Pea_KNP], GBNV-[Pea_USN] and GBNV-[Pea_SJP] and their NP genes sequenced. The sequence data of each isolate were deposited at NCBI database (JF281101-JF281104. The complete nucleotide sequence of the NP genes of all the GBNV isolates had a single open reading frame of 831 nucleotides and 276 amino acids. The isolates had among them 2% variability at amino acid level and 2‒3 variability at nucleotide level, but had variability with other GBNV isolates of fabaceous hosts in the range of 0‒6% at amino acid level and 1‒8% at nucleotide level. Though this variation in nucleotide sequences of GBNV isolates from fabaceous hosts is within the limits of species demarcation for tospoviruses, formation of a separate cluster within the GBNV isolates indicates the possibility of distinct variants in GBNV.

  17. Multi-Modal Multi-Task Learning for Joint Prediction of Multiple Regression and Classification Variables in Alzheimer’s Disease

    Science.gov (United States)

    Zhang, Daoqiang; Shen, Dinggang

    2011-01-01

    Many machine learning and pattern classification methods have been applied to the diagnosis of Alzheimer’s disease (AD) and its prodromal stage, i.e., mild cognitive impairment (MCI). Recently, rather than predicting categorical variables as in classification, several pattern regression methods have also been used to estimate continuous clinical variables from brain images. However, most existing regression methods focus on estimating multiple clinical variables separately and thus cannot utilize the intrinsic useful correlation information among different clinical variables. On the other hand, in those regression methods, only a single modality of data (usually only the structural MRI) is often used, without considering the complementary information that can be provided by different modalities. In this paper, we propose a general methodology, namely Multi-Modal Multi-Task (M3T) learning, to jointly predict multiple variables from multi-modal data. Here, the variables include not only the clinical variables used for regression but also the categorical variable used for classification, with different tasks corresponding to prediction of different variables. Specifically, our method contains two key components, i.e., (1) a multi-task feature selection which selects the common subset of relevant features for multiple variables from each modality, and (2) a multi-modal support vector machine which fuses the above-selected features from all modalities to predict multiple (regression and classification) variables. To validate our method, we perform two sets of experiments on ADNI baseline MRI, FDG-PET, and cerebrospinal fluid (CSF) data from 45 AD patients, 91 MCI patients, and 50 healthy controls (HC). In the first set of experiments, we estimate two clinical variables such as Mini Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale - Cognitive Subscale (ADAS-Cog), as well as one categorical variable (with value of ‘AD’, ‘MCI’ or

  18. The multiple sclerosis susceptibility genes TAGAP and IL2RA are regulated by vitamin D in CD4+ T cells.

    Science.gov (United States)

    Berge, T; Leikfoss, I S; Brorson, I S; Bos, S D; Page, C M; Gustavsen, M W; Bjølgerud, A; Holmøy, T; Celius, E G; Damoiseaux, J; Smolders, J; Harbo, H F; Spurkland, A

    2016-03-01

    Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals. The majority of the MS-associated gene variants are located in genetic regions with importance for T-cell differentiation. Vitamin D is a potent immunomodulator, and vitamin D deficiency has been suggested to be associated with increased MS disease susceptibility and activity. In CD4+ T cells, we have analyzed in vitro vitamin D responsiveness of genes that contain an MS-associated single-nucleotide polymorphism (SNP) and with one or more vitamin D response elements in their regulatory regions. We identify IL2RA and TAGAP as novel vitamin D target genes. The vitamin D response is observed in samples from both MS patients and controls, and is not dependent on the genotype of MS-associated SNPs in the respective genes.

  19. Vitamin D supplementation up-regulates IL-6 and IL-17A gene expression in multiple sclerosis patients.

    Science.gov (United States)

    Naghavi Gargari, Bahar; Behmanesh, Mehrdad; Shirvani Farsani, Zeinab; Pahlevan Kakhki, Majid; Azimi, Amir Reza

    2015-09-01

    Vitamin D regulates gene expression and affects target cell functions. IL-6 and IL-17A are pro-inflammatory cytokines associated with MS pathogenesis. The aim of this study was to investigate the vitamin D effects on the expression level of IL-6 and IL-17A in peripheral blood mononuclear cells (PBMCs) of multiple sclerosis (MS) patients. Also, we performed a correlation analysis between the gene expression and some clinical features such as serum level of vitamin D and the expanded disability status scale (EDSS). Significant up-regulation of IL-6 and IL-17A gene expression was shown under vitamin D treatment. Also, some gender specific correlations between the gene expression with vitamin D levels were detected in female RR-MS patients. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Multiple translocation of the AVR-Pita effector gene among chromosomes of the rice blast fungus Magnaporthe oryzae and related species.

    Directory of Open Access Journals (Sweden)

    Izumi Chuma

    2011-07-01

    Full Text Available Magnaporthe oryzae is the causal agent of rice blast disease, a devastating problem worldwide. This fungus has caused breakdown of resistance conferred by newly developed commercial cultivars. To address how the rice blast fungus adapts itself to new resistance genes so quickly, we examined chromosomal locations of AVR-Pita, a subtelomeric gene family corresponding to the Pita resistance gene, in various isolates of M. oryzae (including wheat and millet pathogens and its related species. We found that AVR-Pita (AVR-Pita1 and AVR-Pita2 is highly variable in its genome location, occurring in chromosomes 1, 3, 4, 5, 6, 7, and supernumerary chromosomes, particularly in rice-infecting isolates. When expressed in M. oryzae, most of the AVR-Pita homologs could elicit Pita-mediated resistance, even those from non-rice isolates. AVR-Pita was flanked by a retrotransposon, which presumably contributed to its multiple translocation across the genome. On the other hand, family member AVR-Pita3, which lacks avirulence activity, was stably located on chromosome 7 in a vast majority of isolates. These results suggest that the diversification in genome location of AVR-Pita in the rice isolates is a consequence of recognition by Pita in rice. We propose a model that the multiple translocation of AVR-Pita may be associated with its frequent loss and recovery mediated by its transfer among individuals in asexual populations. This model implies that the high mobility of AVR-Pita is a key mechanism accounting for the rapid adaptation toward Pita. Dynamic adaptation of some fungal plant pathogens may be achieved by deletion and recovery of avirulence genes using a population as a unit of adaptation.

  1. Gene-Environment Interplay and Psychopathology: Multiple Varieties but Real Effects

    Science.gov (United States)

    Rutter, Michael; Moffitt, Terrie E.; Caspi, Avshalom

    2006-01-01

    Gene-environment interplay is a general term that covers several divergent concepts with different meanings and different implications. In this review, we evaluate research evidence on four varieties of gene-environment interplay. First, we consider epigenetic mechanisms by which environmental influences alter the effects of genes. Second, we…

  2. Graphene Quantum Dots Downregulate Multiple Multidrug-Resistant Genes via Interacting with Their C-Rich Promoters.

    Science.gov (United States)

    Luo, Chao; Li, Yanfang; Guo, Lijuan; Zhang, Fangwei; Liu, Hui; Zhang, Jiali; Zheng, Jing; Zhang, Jingyan; Guo, Shouwu

    2017-11-01

    Multidrug resistance (MDR) is the major factor in the failure of many forms of chemotherapy, mostly due to the increased efflux of anticancer drugs that mediated by ATP-binding cassette (ABC) transporters. Therefore, inhibiting ABC transporters is one of effective methods of overcoming MDR. However, high enrichment of ABC transporters in cells and their broad substrate spectra made to circumvent MDR are almost insurmountable by a single specific ABC transporter inhibitor. Here, this study demonstrates that graphene quantum dots (GQDs) could downregulate the expressions of P-glycoprotein, multidrug resistance protein MRP1, and breast cancer resistance protein genes via interacting with C-rich regions of their promoters. This is the first example that a single reagent could suppress multiple MDR genes, suggesting that it will be possible to target multiple ABC transporters simultaneously with a single reagent. The inhibitory ability of the GQDs to these drug-resistant genes is validated further by reversing the doxorubicin resistance of MCF-7/ADR cells. Notably, GQDs have superb chemical and physical properties, unique structure, low toxicity, and high biocompatibility; hence, their capability of inhibiting multiple drug-resistant genes holds great potential in cancer therapy. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Blueprint for a minimal photoautotrophic cell: conserved and variable genes in Synechococcus elongatus PCC 7942

    Directory of Open Access Journals (Sweden)

    Peretó Juli

    2011-01-01

    Full Text Available Abstract Background Simpler biological systems should be easier to understand and to engineer towards pre-defined goals. One way to achieve biological simplicity is through genome minimization. Here we looked for genomic islands in the fresh water cyanobacteria Synechococcus elongatus PCC 7942 (genome size 2.7 Mb that could be used as targets for deletion. We also looked for conserved genes that might be essential for cell survival. Results By using a combination of methods we identified 170 xenologs, 136 ORFans and 1401 core genes in the genome of S. elongatus PCC 7942. These represent 6.5%, 5.2% and 53.6% of the annotated genes respectively. We considered that genes in genomic islands could be found if they showed a combination of: a unusual G+C content; b unusual phylogenetic similarity; and/or c a small number of the highly iterated palindrome 1 (HIP1 motif plus an unusual codon usage. The origin of the largest genomic island by horizontal gene transfer (HGT could be corroborated by lack of coverage among metagenomic sequences from a fresh water microbialite. Evidence is also presented that xenologous genes tend to cluster in operons. Interestingly, most genes coding for proteins with a diguanylate cyclase domain are predicted to be xenologs, suggesting a role for horizontal gene transfer in the evolution of Synechococcus sensory systems. Conclusions Our estimates of genomic islands in PCC 7942 are larger than those predicted by other published methods like SIGI-HMM. Our results set a guide to non-essential genes in S. elongatus PCC 7942 indicating a path towards the engineering of a model photoautotrophic bacterial cell.

  4. Logic Learning Machine and standard supervised methods for Hodgkin's lymphoma prognosis using gene expression data and clinical variables.

    Science.gov (United States)

    Parodi, Stefano; Manneschi, Chiara; Verda, Damiano; Ferrari, Enrico; Muselli, Marco

    2018-03-01

    This study evaluates the performance of a set of machine learning techniques in predicting the prognosis of Hodgkin's lymphoma using clinical factors and gene expression data. Analysed samples from 130 Hodgkin's lymphoma patients included a small set of clinical variables and more than 54,000 gene features. Machine learning classifiers included three black-box algorithms ( k-nearest neighbour, Artificial Neural Network, and Support Vector Machine) and two methods based on intelligible rules (Decision Tree and the innovative Logic Learning Machine method). Support Vector Machine clearly outperformed any of the other methods. Among the two rule-based algorithms, Logic Learning Machine performed better and identified a set of simple intelligible rules based on a combination of clinical variables and gene expressions. Decision Tree identified a non-coding gene ( XIST) involved in the early phases of X chromosome inactivation that was overexpressed in females and in non-relapsed patients. XIST expression might be responsible for the better prognosis of female Hodgkin's lymphoma patients.

  5. Regulating Multiple Variables To Understand the Nucleation and Growth and Transformation of PbS Nanocrystal Superlattices.

    Science.gov (United States)

    Wang, Zhongwu; Bian, Kaifu; Nagaoka, Yasutaka; Fan, Hongyou; Cao, Y Charles

    2017-10-18

    Nanocrystals (NCs) can self-assemble into ordered superlattices with collective properties, but the ability for controlling NC assembly remains poorly understandable toward achievement of desired superlattice. This work regulates several key variables of PbS NC assembly (e.g., NC concentration and solubility, solvent type, evaporation rate, seed mediation and thermal treatment), and thoroughly exploits the nucleation and growth as well as subsequent superlattice transformation of NC assembles and underneath mechanisms. PbS NCs in toluene self-assemble into a single face-centered-cubic (fcc) and body-centered-cubic (bcc) superlattice, respectively, at concentrations ≤17.5 and ≥70 mg/mL, but an intermediate concentration between them causes the coexistence of the two superlattices. Differently, NCs in hexane or chloroform self-assemble into only a single bcc superlattice. Distinct controls of NC assembly in solvent with variable concentrations confirm the NC concentration/solubility mediated nucleation and growth of superlattice, in which an evaporation-induced local gradient of NC concentration causes simultaneous nucleation of the two superlattices. The observation for the dense packing planes of NCs in fast growing fcc rather than bcc reveals the difference of entropic driving forces responsible for the two distinct superlattices. Decelerating the solvent evaporation does not amend the superlattice symmetry, but improves the superlattice crystallinity. In addition to shrinking the superlattice volume, thermal treatment also transforms the bcc to an fcc superlattice at 175 °C. Through a seed-meditated growth, the concentration-dependent superlattice does not change lattice symmetry over the course of continuous growth, whereas the newly nucleated secondary small nuclei through a concentration change have relatively higher surface energy and quickly dissolve in solution, providing additional NC sources for the ripening of the primarily nucleated larger and

  6. A large pheromone and receptor gene complex determines multiple B mating type specificities in Coprinus cinereus.

    Science.gov (United States)

    O'Shea, S F; Chaure, P T; Halsall, J R; Olesnicky, N S; Leibbrandt, A; Connerton, I F; Casselton, L A

    1998-01-01

    Pheromone signaling plays an essential role in the mating and sexual development of mushroom fungi. Multiallelic genes encoding the peptide pheromones and their cognate 7-transmembrane helix (7-TM) receptors are sequestered in the B mating type locus. Here we describe the isolation of the B6 mating type locus of Coprinus cinereus. DNA sequencing and transformation analysis identified nine genes encoding three 7-TM receptors and six peptide pheromone precursors embedded within 17 kb of mating type-specific sequence. The arrangement of the nine genes suggests that there may be three functionally independent subfamilies of genes each comprising two pheromone genes and one receptor gene. None of the nine B6 genes showed detectable homology to corresponding B gene sequences in the genomic DNA from a B3 strain, and each of the B6 genes independently alter B mating specificity when introduced into a B3 host strain. However, only genes in two of the B6 groups were able to activate B-regulated development in a B42 host. Southern blot analysis showed that these genes failed to cross-hybridize to corresponding genes in the B42 host, whereas the three genes of the third subfamily, which could not activate development in the B42 host, did cross-hybridize. We conclude that cross-hybridization identifies the same alleles of a particular subfamily of genes in different B loci and that B6 and B42 share alleles of one subfamily. There are an estimated 79 B mating specificities: we suggest that it is the different allele combinations of gene subfamilies that generate these large numbers. PMID:9539426

  7. The DUB/USP17 deubiquitinating enzymes: A gene family within a tandemly repeated sequence, is also embedded within the copy number variable Beta-defensin cluster

    Directory of Open Access Journals (Sweden)

    Scott Christopher J

    2010-04-01

    Full Text Available Abstract Background The DUB/USP17 subfamily of deubiquitinating enzymes were originally identified as immediate early genes induced in response to cytokine stimulation in mice (DUB-1, DUB-1A, DUB-2, DUB-2A. Subsequently we have identified a number of human family members and shown that one of these (DUB-3 is also cytokine inducible. We originally showed that constitutive expression of DUB-3 can block cell proliferation and more recently we have demonstrated that this is due to its regulation of the ubiquitination and activity of the 'CAAX' box protease RCE1. Results Here we demonstrate that the human DUB/USP17 family members are found on both chromosome 4p16.1, within a block of tandem repeats, and on chromosome 8p23.1, embedded within the copy number variable beta-defensin cluster. In addition, we show that the multiple genes observed in humans and other distantly related mammals have arisen due to the independent expansion of an ancestral sequence within each species. However, it is also apparent when sequences from humans and the more closely related chimpanzee are compared, that duplication events have taken place prior to these species separating. Conclusions The observation that the DUB/USP17 genes, which can influence cell growth and survival, have evolved from an unstable ancestral sequence which has undergone multiple and varied duplications in the species examined marks this as a unique family. In addition, their presence within the beta-defensin repeat raises the question whether they may contribute to the influence of this repeat on immune related conditions.

  8. Phage exposure causes dynamic shifts in the expression states of specific phase-variable genes of Campylobacter jejuni

    DEFF Research Database (Denmark)

    Aidley, Jack; Holst Sørensen, Martine C.; Bayliss, Christopher D.

    2017-01-01

    Phase variation (PV) creates phenotypic heterogeneity at high frequencies and in a reversible manner. This phenomenon allows bacteria to adapt to a variety of different environments and selective pressures. In Campylobacter jejuni this reversible adaptive process is mediated by mutations...... in homopolymeric G/C tracts. Many C. jejuni-specific phages are dependent on phase-variable surface structures for successful infection. We previously identified the capsular polysaccharide (CPS) moiety, MeOPN-GalfNAc, as a receptor for phage F336 and showed that phase-variable expression of the transferase...... for this CPS modification, cj1421, and two other phase-variable CPS genes generated phage resistance in C. jejuni. Here we investigate the population dynamics of C. jejuni NCTC11168 when exposed to phage F336 in vitro using a newly described method - the 28-locus-CJ11168 PV analysis. Dynamic switching...

  9. Substrain Differences Reveal Novel Disease-Modifying Gene Candidates That Alter the Clinical Course of a Rodent Model of Multiple Sclerosis

    Science.gov (United States)

    Summers deLuca, Leslie E.; Pikor, Natalia B.; O’Leary, Jennifer; Galicia-Rosas, Georgina; Ward, Lesley A.; Defreitas, Dustin; Finlay, Trisha M.; Ousman, Shalina S.; Osborne, Lucy R.; Gommerman, Jennifer L.

    2011-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a rodent model of multiple sclerosis that is executed in animals by immunization with myelin Ag in adjuvant. The SJL/J autoimmuneprone strain of mouse has been used to model relapsing–remitting multiple sclerosis. However, significant variations in peak scores, timing of onset, and incidence are observed among laboratories, with the postacute (relapse) phase of the disease exhibiting significant inconsistency. We characterized two substrains of SJL/J mice that exhibit profoundly different EAE disease parameters. Induction of EAE in the first SJL/J substrain resulted in many cases of chronic EAE that was dominated by an aggressive B cell response to the immunizing Ag and to endogenous CNS Ags. In contrast, the other SJL/J substrain exhibited a relapsing–remitting form of EAE concomitant with an elevated number of cytokine-producing CD4+ T cells in the CNS. Exploiting these interstrain differences, we performed a genome-wide copy number analysis on the two disparate SJL/J substrains and discovered numerous gene-dosage differences. In particular, one inflammation-associated gene, Naip1, was present at a higher copy number in the SJL/J substrain that exhibited relapsing–remitting EAE. These results demonstrate that substrain differences, perhaps at the level of genomic copy number, can account for variability in the postacute phase of EAE and may drive chronic versus relapsing disease. PMID:20173032

  10. Quantitative transfer of Salmonella Typhimurium LT2 during mechanical slicing of tomatoes as impacted by multiple processing variables.

    Science.gov (United States)

    Wang, Haiqiang; Ryser, Elliot T

    2016-10-03

    Slicing of fresh produce can readily lead to pathogen cross-contamination with pre-sliced tomatoes having been linked to multistate outbreaks of salmonellosis in the United States. This study aimed to assess the impact of multiple processing variables on quantitative transfer of Salmonella during simulated commercial slicing of tomatoes. One red round tomato was inoculated with Salmonella Typhimurium LT2 at ~5logCFU/g and sliced using a manual or electric slicer, followed by 20 uninoculated tomatoes. Thereafter, the distribution of Salmonella on inoculated and uninoculated tomato slices was evaluated along with the transfer of Salmonella from different parts of the slicer. The impact of multiple processing variables including post-contamination hold time (0 and 30min), tomato wetness (dry and wet), processing room temperature (23, 10 and 4°C), slice thickness (0.48, 0.64, and 0.95cm), tomato variety (Torero, Rebelski, and Bigdena) and pre-wash treatment (no wash, tap water, and chlorine) was also investigated. The data were fitted to a two-parameter exponential decay model (Y=A⋅exp(BX)) with the percentage of Salmonella transferred to 20 uninoculated tomatoes then calculated. Salmonella populations on nine inoculated tomato slices ranged from 4.6±0.2 to 5.5±0.3logCFU/g, with higher populations on slices from the blossom and stem scar ends. However, Salmonella transfer to the previously uninoculated slices was similar (P>0.05), ranging from 2.1±0.2 to 3.4±0.2logCFU/g. Significantly fewer salmonellae transferred from the blade (3.4±0.4 log CFU, P≤0.05) than from the back and bottom plates (4.7±0.3 log CFU) or the whole manual slicer (5.2±0.2 log CFU) to the 20 uninoculated tomatoes. However, the blade was the primary contributor to Salmonella transfer for the electric slicer. Post-contamination hold time, processing temperature and tomato slice thickness did not significantly impact (P>0.05) the Salmonella transfer rate (parameter B) or the overall

  11. Malignant effects of multiple rare variants in sarcomere genes on the prognosis of patients with hypertrophic cardiomyopathy.

    Science.gov (United States)

    Wang, Jizheng; Wang, Yilu; Zou, Yubao; Sun, Kai; Wang, Zhimin; Ding, Hu; Yuan, Jinqing; Wei, Wei; Hou, Qing; Wang, Hu; Liu, Xuan; Zhang, Hongju; Ji, Yun; Zhou, Xianliang; Sharma, Ravi K; Wang, Daowen; Ahmad, Ferhaan; Hui, Rutai; Song, Lei

    2014-09-01

    Although genetic testing has been recommended in patients with hypertrophic cardiomyopathy (HCM) in current clinical practice, its utility in prognostic prediction remains to be ascertained. We assessed the dosage effect of rare variants in sarcomere genes on the long-term outcomes of HCM. A total of 529 unrelated HCM patients were prospectively recruited and followed for 4.7 ± 3.2 years. Eight sarcomere genes were screened with targeted resequencing and identified variants were validated through Sanger sequencing. After polymorphisms and likely neutral rare variants were excluded, the patients were segregated into three groups based on the dosage of rare variants: no rare variant, a single rare variant, and multiple rare variants. Multiple rare variants were identified in 7.2% (38/529) of the study patients. Patients with multiple rare variants were younger at diagnosis, and had greater maximum LV wall thicknesses and larger left atria. The risk for cardiovascular death in patients with multiple rare variants was higher than in those without rare variants (P =10⁻⁵) or in those with a single rare variant (P = 2 × 10⁻⁵). Multivariable analysis revealed that multiple rare variants were a risk factor for cardiovascular death [hazard ratio (HR) 3.74, 95% confidence interval (CI) 1.84-7.58, P = 0.0003], as well as sudden cardiac death (HR 3.57, 95% CI 1.23-10.35, P = 0.019) and heart failure-related death (HR 4.62, 95% CI 1.67-12.76, P = 0.003). The presence of multiple rare variants in sarcomere genes is a risk factor for malignant outcomes in HCM, and may be appropriate to consider as a criterion in the risk stratification of HCM patients. © 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.

  12. Multiple-locus variable-number tandem-repeat analysis (MLVA) genotyping of human Brucella isolates in Malaysia.

    Science.gov (United States)

    Tay, Bee Yong; Ahmad, Norazah; Hashim, Rohaidah; Mohamed Zahidi, Jama'ayah; Thong, Kwai Lin; Koh, Xiu Pei; Mohd Noor, Azura

    2015-06-02

    Brucellosis is one of the most common zoonotic diseases worldwide. It can cause acute febrile illness in human and is a major health problem. Studies in human brucellosis in Malaysia is limited and so far no genotyping studies has been done on Brucella isolates. The aim of the study was to determine the genetic diversity among Brucella species isolated from human brucellosis, obtained over a 6-year period (2009-2014). In this study, the genotypic characteristics of 43 human Brucella melitensis isolates were analysed using multiple-locus variable-number tandem-repeat analysis (MLVA) which consisted of eight minisatellite loci (panel 1) and eight microsatellite loci; panels 2A (3 microsatellite loci) and panel 2B (5 microsatellite loci). Two human Brucella suis isolates were also investigated using the MLVA assay. Using panel 1 (MLVA8), two genotypes namely genotype 43 and 44 were obtained from the 43 B. melitensis isolates. Using the combination of panels 1 and 2A loci (MLVA11), two genotypes were obtained while using the complete panels 1, 2A and 2B, nine genotypes were obtained. The polymorphisms in using the complete panels (MLVA16) were observed in three loci from panel 2B, which showed a diversity index higher than 0.17. All B. melitensis isolates were closely related to the East Mediterranean group. For B. suis isolates, only genotype 6 and genotype 33 were obtained using panel 1 and MLVA11 respectively. In conclusion, the results of the present study showed a low genetic diversity among B. melitensis and B. suis isolates from human patients. Based on the MLVA16 assay, B. melitensis belonging to the East Mediterranean group is responsible for the vast majority of Brucella infections in our Malaysian patients. To our knowledge, this is the first genotyping study of human Brucella isolates in Malaysia.

  13. A new typing technique for the Rickettsiales Ehrlichia ruminantium: multiple-locus variable number tandem repeat analysis.

    Science.gov (United States)

    Pilet, Héloïse; Vachiéry, Nathalie; Berrich, Moez; Bouchouicha, Rim; Durand, Benoît; Pruneau, Ludovic; Pinarello, Valérie; Saldana, Angélique; Carasco-Lacombe, Catherine; Lefrançois, Thierry; Meyer, Damien F; Martinez, Dominique; Boulouis, Henri-Jean; Haddad, Nadia

    2012-02-01

    Ehrlichia ruminantium (ER) is a member of the order Rickettsiales transmitted by Amblyomma ticks. This obligatory intracellular bacterium is the causative agent of a fatal disease in ruminants, named heartwater. It represents a constraint on breeding development in sub-Saharan Africa and in the Caribbean. The genetic diversity of the strains of ER, which could be a limiting factor to obtain effective vaccines, needs to be better characterized. For this purpose, we developed a molecular typing technique based on the polymorphism of variable number tandem repeat (VNTR) sequences, MLVA (multiple locus VNTR analysis). Eight (out of 21) VNTR candidates were validated using 17 samples representing a panel of ER strains from different geographical origins from West, South Africa, and Caribbean areas and in ER infected ticks and goat tissues. This result demonstrated the ability of these VNTRs to type a wide range of strains. The stability of the selected VNTR markers was very good, at the time scale needed for epidemiological purposes: in particular, no difference in the VNTR profiles was observed between virulent and attenuated strains (for Gardel and Senegal strains) and between strains (Gardel and Blonde strains) isolated in the same area 19years apart. We validated the strong discriminatory power of MLVA for ER and found a high level of polymorphism between the available strains, with 10 different profiles out of 13 ER strains. The MLVA scheme described in this study is a rapid and efficient molecular typing tool for ER, which allows rapid and direct typing of this intracellular pathogen without preliminary culture and gives reliable results that can be used for further epidemiological studies. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Spatial variability and changes of metabolite concentrations in the cortico-spinal tract in multiple sclerosis using coronal CSI.

    Science.gov (United States)

    Tur, Carmen; Wheeler-Kingshott, Claudia A M; Altmann, Daniel R; Miller, David H; Thompson, Alan J; Ciccarelli, Olga

    2014-03-01

    We characterized metabolic changes along the cortico-spinal tract (CST) in multiple sclerosis (MS) patients using a novel application of chemical shift imaging (CSI) and considering the spatial variation of metabolite levels. Thirteen relapsing-remitting (RR) and 13 primary-progressive (PP) MS patients and 16 controls underwent (1)H-MR CSI, which was applied to coronal-oblique scans to sample the entire CST. The concentrations of the main metabolites, i.e., N-acetyl-aspartate, myo-Inositol (Ins), choline containing compounds (Cho) and creatine and phosphocreatine (Cr), were calculated within voxels placed in regions where the CST is located, from cerebral peduncle to corona radiata. Differences in metabolite concentrations between groups and associations between metabolite concentrations and disability were investigated, allowing for the spatial variability of metabolite concentrations in the statistical model. RRMS patients showed higher CST Cho concentration than controls, and higher CST Ins concentration than PPMS, suggesting greater inflammation and glial proliferation in the RR than in the PP course. In RRMS, a significant, albeit modest, association between greater Ins concentration and greater disability suggested that gliosis may be relevant to disability. In PPMS, lower CST Cho and Cr concentrations correlated with greater disability, suggesting that in the progressive stage of the disease, inflammation declines and energy metabolism reduces. Attention to the spatial variation of metabolite concentrations made it possible to detect in patients a greater increase in Cr concentration towards the superior voxels as compared to controls and a stronger association between Cho and disability, suggesting that this step improves our ability to identify clinically relevant metabolic changes. Copyright © 2012 Wiley Periodicals, Inc.

  15. Identification of genes that regulate multiple cellular processes/responses in the context of lipotoxicity to hepatoma cells

    Directory of Open Access Journals (Sweden)

    Yedwabnick Matthew

    2007-10-01

    Full Text Available Abstract Background In order to devise efficient treatments for complex, multi-factorial diseases, it is important to identify the genes which regulate multiple cellular processes. Exposure to elevated levels of free fatty acids (FFAs and tumor necrosis factor alpha (TNF-α alters multiple cellular processes, causing lipotoxicity. Intracellular lipid accumulation has been shown to reduce the lipotoxicity of saturated FFA. We hypothesized that the genes which simultaneously regulate lipid accumulation as well as cytotoxicity may provide better targets to counter lipotoxicity of saturated FFA. Results As a model system to test this hypothesis, human hepatoblastoma cells (HepG2 were exposed to elevated physiological levels of FFAs and TNF-α. Triglyceride (TG accumulation, toxicity and the genomic responses to the treatments were measured. Here, we present a framework to identify such genes in the context of lipotoxicity. The aim of the current study is to identify the genes that could be altered to treat or ameliorate the cellular responses affected by a complex disease rather than to identify the causal genes. Genes that regulate the TG accumulation, cytotoxicity or both were identified by a modified genetic algorithm partial least squares (GA/PLS analysis. The analyses identified NADH dehydrogenase and mitogen activated protein kinases (MAPKs as important regulators of both cytotoxicity and lipid accumulation in response to FFA and TNF-α exposure. In agreement with the predictions, inhibiting NADH dehydrogenase and c-Jun N-terminal kinase (JNK reduced cytotoxicity significantly and increased intracellular TG accumulation. Inhibiting another MAPK pathway, the extracellular signal regulated kinase (ERK, on the other hand, improved the cytotoxicity without changing TG accumulation. Much greater reduction in the toxicity was observed upon inhibiting the NADH dehydrogenase and MAPK (which were identified by the dual-response analysis, than for the

  16. Baseline Chromatin Modification Levels May Predict Interindividual Variability in Ozone-Induced Gene Expression

    Science.gov (United States)

    Traditional toxicological paradigms have relied on factors such as age, genotype, and disease status to explain variability in responsiveness to toxicant exposure; however, these are neither sufficient to faithfully identify differentially responsive individuals nor are they modi...

  17. The population structure of Staphylococcus aureus in China and Europe assessed by