An Effective Counterselection System for Listeria monocytogenes and Its Use To Characterize the Monocin Genomic Region of Strain 10403S.

PubMed

Argov, Tal; Rabinovich, Lev; Sigal, Nadejda; Herskovits, Anat A

2017-03-15

Construction of Listeria monocytogenes mutants by allelic exchange has been laborious and time-consuming due to lack of proficient selection markers for the final recombination event, that is, a marker conveying substance sensitivity to the bacteria bearing it, enabling the exclusion of merodiploids and selection for plasmid loss. In order to address this issue, we engineered a counterselection marker based on a mutated phenylalanyl-tRNA synthetase gene ( pheS* ). This mutation renders the phenylalanine-binding site of the enzyme more promiscuous and allows the binding of the toxic p -chloro-phenylalanine analog ( p -Cl-phe) as a substrate. When pheS* is introduced into L. monocytogenes and highly expressed under control of a constitutively active promoter, the bacteria become sensitive to p -Cl-phe supplemented in the medium. This enabled us to utilize pheS* as a negative selection marker and generate a novel, efficient suicide vector for allelic exchange in L. monocytogenes We used this vector to investigate the monocin genomic region in L. monocytogenes strain 10403S by constructing deletion mutants of the region. We have found this region to be active and to cause bacterial lysis upon mitomycin C treatment. The future applications of such an effective counterselection system, which does not require any background genomic alterations, are vast, as it can be modularly used in various selection systems (e.g., genetic screens). We expect this counterselection marker to be a valuable genetic tool in research on L. monocytogenes IMPORTANCE L. monocytogenes is an opportunistic intracellular pathogen and a widely studied model organism. An efficient counterselection marker is a long-standing need in Listeria research for improving the ability to design and perform various genetic manipulations and screening systems for different purposes. We report the construction and utilization of an efficient suicide vector for allelic exchange which can be conjugated, leaves no marker in the bacterial chromosome, and does not require the use of sometimes leaky inducible promoters. This highly efficient genome editing tool for L. monocytogenes will allow for rapid sequential mutagenesis, introduction of point mutations, and design of screening systems. We anticipate that it will be extensively used by the research community and yield novel insights into the diverse fields studied using this model organism. Copyright © 2017 American Society for Microbiology.

The Molecular Basis of the Response to Radiation

DTIC Science & Technology

1999-07-01

S. cerevisiae and S. pombe ). After PCR amplification of human cDNA libraries as described below, PCR products are analyzed on 4% NuSieve agarose...media lacking uracil as well as counterselected against on media containing uracil and 0.1% 5-fluoroorotic acid (5FOA). Induction of the LacZ gene...evolutionarily distant species (S. cerevisiae andS. pombe ) to develop degenerate PCR based primers. For example, a fission yeast homolog of RAD9 named rhp9 was

mazF, a novel counter-selectable marker for unmarked chromosomal manipulation in Bacillus subtilis.

PubMed

Zhang, Xiao-Zhou; Yan, Xin; Cui, Zhong-Li; Hong, Qing; Li, Shun-Peng

2006-05-19

Here, we present a novel method for the directed genetic manipulation of the Bacillus subtilis chromosome free of any selection marker. Our new approach employed the Escherichia coli toxin gene mazF as a counter-selectable marker. The mazF gene was placed under the control of an isopropyl-beta-D-thiogalactopyranoside (IPTG)-inducible expression system and associated with a spectomycin-resistance gene to form the MazF cassette, which was flanked by two directly-repeated (DR) sequences. A double-crossover event between the linearized delivery vector and the chromosome integrated the MazF cassette into a target locus and yielded an IPTG-sensitive strain with spectomycin-resistance, in which the wild-type chromosome copy had been replaced by the modified copy at the targeted locus. Another single-crossover event between the two DR sequences led to the excision of the MazF cassette and generated a strain with IPTG resistance, thereby realizing the desired alteration to the chromosome without introducing any unwanted selection markers. We used this method repeatedly and successfully to inactivate a specific gene, to introduce a gene of interest and to realize the in-frame deletion of a target gene in the same strain. As there is no prerequisite strain for this method, it will be a powerful and universal tool.

SAMe prevents the induction of the immunoproteasome and preserves the 26S proteasome in the DDC-induced MDB mouse model.

PubMed

Bardag-Gorce, Fawzia; Oliva, Joan; Li, Jun; French, Barbara A; French, Samuel W

2010-06-01

Mallory-Denk bodies (MDBs) form in the liver of alcoholic patients. This occurs because of the accumulation and aggregation of ubiquitinated cytokeratins, which hypothetically is due to the ubiquitin-proteasome pathway's (UPP) failure to degrade the cytokeratins. The experimental model of MDB formation was used in which MDBs were induced by refeeding DDC to drug-primed mice. The gene expression and protein levels of LMP2, LMP7 and MECL-1, the catalytic subunits in the immunoproteasome, as well as FAT10, were increased in the liver cells forming MDBs but not in the intervening normal hepatocytes. Chymotrypsin-like activity of the UPP was decreased by DDC refeeding, indicating that a switch from the UPP to the immunoproteasome had occurred at the expense of the 26S proteasome. The failure of the UPP to digest cytokeratins would explain MDB aggregate formation. SAMe prevented the decrease in UPP activity, the increase in LMP2, LMP7, and MECL-1 protein levels and MDB formation induced by DDC. DDC refeeding also induced the TNFalpha and IFNgamma receptors. SAMe prevented the increase in the TNFalpha and IFNgamma receptors, supporting the idea that TNFalpha and IFNgamma were responsible for the up regulation of LMP2, LPM7, and FAT10. These results support the conclusion that MDBs form in FAT10 over-expressing hepatocytes where the up regulation of the immunoproteasome occurs at the expense of the 26S proteasome. Copyright 2010 Elsevier Inc. All rights reserved.

Validation of a short Korean version of the UPPS-P Impulsive Behavior Scale.

PubMed

Lim, Sun Young; Kim, Seog Ju

2018-04-23

The purpose of the present study was to validate a Korean version of the short UPPS-P Impulsive Behavior Scale (UPPS-P). This study included 724 undergraduate students who completed the following questionnaires: the Korean UPPS-P, Beck Depression Inventory, State-Trait Anxiety Inventory, Eating Disorder Inventory-2, Alcohol Use Disorder Identification Test, and Canadian Problem Gambling Index. A confirmatory factor analysis supported a 5-factor interrelated model. The internal consistency coefficients for the 5 factors of the short Korean UPPS-P were acceptable (.65-.78 across the subscales), and the subscales of the short Korean UPPS-P were strongly correlated with the long UPPS-P subscales. External validity was demonstrated by associations between the subfactors of impulsivity and various psychopathologies, including depression, anxiety, binge eating, alcohol abuse, and gambling. The present results indicate that the short Korean version of the UPPS-P may be a useful and reliable alternative to the original long-form UPPS-P. © 2018 John Wiley & Sons Australia, Ltd.

Targeted Curing of All Lysogenic Bacteriophage from Streptococcus pyogenes Using a Novel Counter-selection Technique

PubMed Central

Euler, Chad W.; Juncosa, Barbara; Ryan, Patricia A.; Deutsch, Douglas R.; McShan, W. Michael; Fischetti, Vincent A.

2016-01-01

Streptococcus pyogenes is a human commensal and a bacterial pathogen responsible for a wide variety of human diseases differing in symptoms, severity, and tissue tropism. The completed genome sequences of >37 strains of S. pyogenes, representing diverse disease-causing serotypes, have been published. The greatest genetic variation among these strains is attributed to numerous integrated prophage and prophage-like elements, encoding several virulence factors. A comparison of isogenic strains, differing in prophage content, would reveal the effects of these elements on streptococcal pathogenesis. However, curing strains of prophage is often difficult and sometimes unattainable. We have applied a novel counter-selection approach to identify rare S. pyogenes mutants spontaneously cured of select prophage. To accomplish this, we first inserted a two-gene cassette containing a gene for kanamycin resistance (KanR) and the rpsL wild-type gene, responsible for dominant streptomycin sensitivity (SmS), into a targeted prophage on the chromosome of a streptomycin resistant (SmR) mutant of S. pyogenes strain SF370. We then applied antibiotic counter-selection for the re-establishment of the KanS/SmR phenotype to select for isolates cured of targeted prophage. This methodology allowed for the precise selection of spontaneous phage loss and restoration of the natural phage attB attachment sites for all four prophage-like elements in this S. pyogenes chromosome. Overall, 15 mutants were constructed that encompassed every permutation of phage knockout as well as a mutant strain, named CEM1ΔΦ, completely cured of all bacteriophage elements (a ~10% loss of the genome); the only reported S. pyogenes strain free of prophage-like elements. We compared CEM1ΔΦ to the WT strain by analyzing differences in secreted DNase activity, as well as lytic and lysogenic potential. These mutant strains should allow for the direct examination of bacteriophage relationships within S. pyogenes and further elucidate how the presence of prophage may affect overall streptococcal survival, pathogenicity, and evolution. PMID:26756207

Conditional suicide system of Escherichia coli released into soil that uses the Bacillus subtilis sacB gene.

PubMed Central

Recorbet, G; Robert, C; Givaudan, A; Kudla, B; Normand, P; Faurie, G

1993-01-01

The sacB gene from Bacillus subtilis confers sucrose sensitivity upon gram-negative bacteria. The gene was investigated for use as a potential conditional suicide system for Escherichia coli released into soil. To ensure against the loss of the cell death function encoded under nonselective conditions, the nptI-sacR-B suicide cassette was inserted into the E. coli chromosome by using a circular nonreplicative integration vector. Stability studies yielded no loss of the suicide cassette in the integrated E. coli EL1026 strain. sacB induction in the absence of a selective pressure resulted in a lysis efficiency of up to 99.9%. The microcosm experiments confirmed the ability of the suicide cassette to limit the growth and reduce the survival of E. coli strains released into soil. Sucrose addition to sterile soil resulted in a 10(-3)-fold reduction of the final E. coli population density. sacB induction prevented the proliferation and triggered the rapid disappearance of E. coli from natural soil. Mutation to sucrose tolerance occurred at a frequency of 10(-5), making E. coli EL1026 a potential counterselectable donor strain for gene transfer studies. Specificity and potential adaptability to a wide range of gram-negative bacteria are additional conveniences of this conditional suicide system for the containment and counterselection of engineered microorganisms. PMID:8517732

Conditional suicide system of Escherichia coli released into soil that uses the Bacillus subtilis sacB gene.

PubMed

Recorbet, G; Robert, C; Givaudan, A; Kudla, B; Normand, P; Faurie, G

1993-05-01

The sacB gene from Bacillus subtilis confers sucrose sensitivity upon gram-negative bacteria. The gene was investigated for use as a potential conditional suicide system for Escherichia coli released into soil. To ensure against the loss of the cell death function encoded under nonselective conditions, the nptI-sacR-B suicide cassette was inserted into the E. coli chromosome by using a circular nonreplicative integration vector. Stability studies yielded no loss of the suicide cassette in the integrated E. coli EL1026 strain. sacB induction in the absence of a selective pressure resulted in a lysis efficiency of up to 99.9%. The microcosm experiments confirmed the ability of the suicide cassette to limit the growth and reduce the survival of E. coli strains released into soil. Sucrose addition to sterile soil resulted in a 10(-3)-fold reduction of the final E. coli population density. sacB induction prevented the proliferation and triggered the rapid disappearance of E. coli from natural soil. Mutation to sucrose tolerance occurred at a frequency of 10(-5), making E. coli EL1026 a potential counterselectable donor strain for gene transfer studies. Specificity and potential adaptability to a wide range of gram-negative bacteria are additional conveniences of this conditional suicide system for the containment and counterselection of engineered microorganisms.

Construction of a self-cloning sake yeast that overexpresses alcohol acetyltransferase gene by a two-step gene replacement protocol.

PubMed

Hirosawa, I; Aritomi, K; Hoshida, H; Kashiwagi, S; Nishizawa, Y; Akada, R

2004-07-01

The commercial application of genetically modified industrial microorganisms has been problematic due to public concerns. We constructed a "self-cloning" sake yeast strain that overexpresses the ATF1 gene encoding alcohol acetyltransferase, to improve the flavor profile of Japanese sake. A constitutive yeast overexpression promoter, TDH3p, derived from the glyceraldehyde-3-phosphate dehydrogenase gene from sake yeast was fused to ATF1; and the 5' upstream non-coding sequence of ATF1 was further fused to TDH3p-ATF1. The fragment was placed on a binary vector, pGG119, containing a drug-resistance marker for transformation and a counter-selection marker for excision of unwanted DNA. The plasmid was integrated into the ATF1 locus of a sake yeast strain. This integration constructed tandem repeats of ATF1 and TDH3p-ATF1 sequences, between which the plasmid was inserted. Loss of the plasmid, which occurs through homologous recombination between either the TDH3p downstream ATF1 repeats or the TDH3p upstream repeat sequences, was selected by growing transformants on counter-selective medium. Recombination between the downstream repeats led to reversion to a wild type strain, but that between the upstream repeats resulted in a strain that possessed TDH3p-ATF1 without the extraneous DNA sequences. The self-cloning TDH3p-ATF1 yeast strain produced a higher amount of isoamyl acetate. This is the first expression-controlled self-cloning industrial yeast.

Cloning-Independent and Counterselectable Markerless Mutagenesis System in Streptococcus mutans▿

PubMed Central

Xie, Zhoujie; Okinaga, Toshinori; Qi, Fengxia; Zhang, Zhijun; Merritt, Justin

2011-01-01

Insertion duplication mutagenesis and allelic replacement mutagenesis are among the most commonly utilized approaches for targeted mutagenesis in bacteria. However, both techniques are limited by a variety of factors that can complicate mutant phenotypic studies. To circumvent these limitations, multiple markerless mutagenesis techniques have been developed that utilize either temperature-sensitive plasmids or counterselectable suicide vectors containing both positive- and negative-selection markers. For many species, these techniques are not especially useful due to difficulties of cloning with Escherichia coli and/or a lack of functional negative-selection markers. In this study, we describe the development of a novel approach for the creation of markerless mutations. This system employs a cloning-independent methodology and should be easily adaptable to a wide array of Gram-positive and Gram-negative bacterial species. The entire process of creating both the counterselection cassette and mutation constructs can be completed using overlapping PCR protocols, which allows extremely quick assembly and eliminates the requirement for either temperature-sensitive replicons or suicide vectors. As a proof of principle, we used Streptococcus mutans reference strain UA159 to create markerless in-frame deletions of 3 separate bacteriocin genes as well as triple mutants containing all 3 deletions. Using a panel of 5 separate wild-type S. mutans strains, we further demonstrated that the procedure is nearly 100% efficient at generating clones with the desired markerless mutation, which is a considerable improvement in yield compared to existing approaches. PMID:21948849

Fate of SDS-insoluble glutenin polymers from semolina to dry pasta.

PubMed

Joubert, Marianne; Lullien-Pellerin, Valérie; Morel, Marie-Hélène

2018-02-01

Pasta cooking quality is well known to be related to semolina protein content and composition, however impact of the unextractable polymeric protein content (%UPP) remains disputed. In this work different semolina samples, of variable protein contents (10.5-14.2%) and %UPP (20.2-46.3%) are studied. The changes in %UPP induced by the successive pasta processing steps (mixing, extrusion, drying) but also those occurring during resting periods at 35°C, applied in-between them, were investigated. Effect of a resting period was moderate after mixing, but pronounced after extrusion. Resting of extruded pasta at 35°C significantly increased %UPP, which can even grow beyond that of the semolina. No relationship was found between pasta viscoelastic index (VI) and semolina %UPP or protein content. However, cooked pasta VI was found related to the calculated %UPP of rested fresh pasta. Copyright © 2017 Elsevier Ltd. All rights reserved.

UPP mediated Diabetic Retinopathy via ROS/PARP and NF-κB inflammatory factor pathways.

PubMed

Luo, D-W; Zheng, Z; Wang, H; Fan, Y; Chen, F; Sun, Y; Wang, W-J; Sun, T; Xu, X

2015-01-01

Diabetic retinopathy (DR) is a leading cause of blindness in adults at working age. Human diabetic retinopathy is characterized by the basement membrane thick, pericytes loss, microaneurysms formation, retina neovascularization and vitreous hemorrhage. To investigate whether UPP activated ROS/PARP and NF-κB inflammatory factor pathways in Diabetic Retinopathy, human retinal endothelial cells (HRECs) and rats with streptozotocin-induced diabetes were used to determine the effect of UPP on ROS generation, cell apoptosis, mitochondrial membrane potential (ΔΨm) and inflammatory factor protein expression, through flow cytometry assay, immunohistochemistry, Real-time PCR, Western blot analysis and ELISA. The levels of ROS and apoptosis and the expressions of UPP (Ub and E3) and inflammatory factor protein were increased in high glucose-induced HRECs and retina of diabetic rats, while ΔΨm was decreased. The UPP inhibitor and UbshRNA could attenuate these effects through inhibiting the pathway of ROS/PARP and the expression of NF-κB inflammatory factors, and the increased UPP was a result of high glucose-induced increase of ROS generation and NF-κBp65 expression, accompanied with the decrease of ΔΨm. Clinical study showed the overexpression of UPP and detachment of epiretinal membranes in proliferative DR (PDR) patients. It has been indicated that the pathogenic effect of UPP on DR was involved in the increase of ROS generation and NF-κB expression, which associated with the ROS/PARP and NF-κB inflammatory factor pathways. Our study supports a new insight for further application of UPP inhibitor in DR treatment.

Comparative studies on exenatide-loaded poly (D,L-lactic-co-glycolic acid) microparticles prepared by a novel ultra-fine particle processing system and spray drying.

PubMed

Zhu, Chune; Huang, Ying; Zhang, Xiaoying; Mei, Liling; Pan, Xin; Li, Ge; Wu, Chuanbin

2015-08-01

The purpose of this study was to compare the properties of exenatide-loaded poly (D,L-lactic-co-glycolic acid) microparticles (Ex-PLGA-MPs) prepared by a novel ultra-fine particle processing system (UPPS) and spray drying. UPPS is a proprietary technology developed by our group based on the disk rotation principle. Characteristics of the MPs including morphology, particle size distribution, drug content, encapsulation efficiency and in vitro release were comparatively studied. Cytotoxicity of the MPs was examined on A549 cells and the pharmacodynamics was investigated in vivo in type 2 diabetes Sprague-Dawley (SD) rats. Ex-PLGA-MPs prepared by UPPS showed larger particle size, denser surface, greater encapsulation efficiency, less initial burst release, and stable sustained release for more than one month in vitro as compared with the spray drying MPs. Meanwhile, the UPPS MPs effectively controlled the body growth rate and blood glucose in diabetes rats for at least three weeks after a single injection, while the spray drying MPs showed effective control period of about two weeks. UPPS technology was demonstrated to manufacture Ex-PLGA-MPs as a potential sustained release protein/polypeptide delivery system, which is an alternative method for the most commonly used spray drying. This comparative research provides a new guidance for microparticle preparation technology. Copyright © 2015 Elsevier B.V. All rights reserved.

Factor Analysis of the Brazilian Version of UPPS Impulsive Behavior Scale.

PubMed

Sediyama, Cristina Y N; Moura, Ricardo; Garcia, Marina S; da Silva, Antonio G; Soraggi, Carolina; Neves, Fernando S; Albuquerque, Maicon R; Whiteside, Setephen P; Malloy-Diniz, Leandro F

2017-01-01

Objective: To examine the internal consistency and factor structure of the Brazilian adaptation of the UPPS Impulsive Behavior Scale. Methods: UPPS is a self-report scale composed by 40 items assessing four factors of impulsivity: (a) urgency, (b) lack of premeditation; (c) lack of perseverance; (d) sensation seeking. In the present study 384 participants (278 women and 106 men), who were recruited from schools, universities, leisure centers and workplaces fulfilled the UPPS scale. An exploratory factor analysis was performed by using Varimax factor rotation and Kaiser Normalization, and we also conducted two confirmatory analyses to test the independency of the UPPS components found in previous analysis. Results: Results showed a decrease in mean UPPS total scores with age and this analysis showed that the youngest participants (below 30 years) scored significantly higher than the other groups over 30 years. No difference in gender was found. Cronbach's alpha, results indicated satisfactory values for all subscales, with similar high values for the subscales and confirmatory factor analysis indexes also indicated a poor model fit. The results of two exploratory factor analysis were satisfactory. Conclusion: Our results showed that the Portuguese version has the same four-factor structure of the original and previous translations of the UPPS.

The Atacama Cosmology Telescope: The Two-season ACTPol Sunyaev–Zel’dovich Effect Selected Cluster Catalog

NASA Astrophysics Data System (ADS)

Hilton, Matt; Hasselfield, Matthew; Sifón, Cristóbal; Battaglia, Nicholas; Aiola, Simone; Bharadwaj, V.; Bond, J. Richard; Choi, Steve K.; Crichton, Devin; Datta, Rahul; Devlin, Mark J.; Dunkley, Joanna; Dünner, Rolando; Gallardo, Patricio A.; Gralla, Megan; Hincks, Adam D.; Ho, Shuay-Pwu P.; Hubmayr, Johannes; Huffenberger, Kevin M.; Hughes, John P.; Koopman, Brian J.; Kosowsky, Arthur; Louis, Thibaut; Madhavacheril, Mathew S.; Marriage, Tobias A.; Maurin, Loïc; McMahon, Jeff; Miyatake, Hironao; Moodley, Kavilan; Næss, Sigurd; Nati, Federico; Newburgh, Laura; Niemack, Michael D.; Oguri, Masamune; Page, Lyman A.; Partridge, Bruce; Schmitt, Benjamin L.; Sievers, Jon; Spergel, David N.; Staggs, Suzanne T.; Trac, Hy; van Engelen, Alexander; Vavagiakis, Eve M.; Wollack, Edward J.

2018-03-01

We present a catalog of 182 galaxy clusters detected through the Sunyaev–Zel’dovich (SZ) effect by the Atacama Cosmology Telescope in a contiguous 987.5 deg2 field. The clusters were detected as SZ decrements by applying a matched filter to 148 GHz maps that combine the original ACT equatorial survey with data from the first two observing seasons using the ACTPol receiver. Optical/IR confirmation and redshift measurements come from a combination of large public surveys and our own follow-up observations. Where necessary, we measured photometric redshifts for clusters using a pipeline that achieves accuracy Δz/(1 + z) = 0.015 when tested on Sloan Digital Sky Survey data. Under the assumption that clusters can be described by the so-called universal pressure profile (UPP) and its associated mass scaling law, the full signal-to-noise ratio > 4 sample spans the mass range 1.6< {M}500{{c}}UPP}/{10}14 {M}ȯ < 9.1, with median {M}500{{c}}UPP}=3.1× {10}14 {M}ȯ . The sample covers the redshift range 0.1 < z < 1.4 (median z = 0.49), and 28 clusters are new discoveries (median z = 0.80). We compare our catalog with other overlapping cluster samples selected using the SZ, optical, and X-ray wavelengths. We find that the ratio of the UPP-based SZ mass to richness-based weak-lensing mass is < {M}500{{c}}UPP}> /< {M}500{{c}}λ {WL}> =0.68+/- 0.11. After applying this calibration, the mass distribution for clusters with M 500c > 4 × 1014 M ⊙ is consistent with the number of such clusters found in the South Pole Telescope SZ survey.

Ubiquitin-proteasome pathway and cellular responses to oxidative stress

USDA-ARS?s Scientific Manuscript database

The ubiquitin-proteasome pathway (UPP) is the primary cytosolic proteolytic machinery for the selective degradation of various forms of damaged proteins. Thus, the UPP is an important protein quality control mechanism. In the canonical UPP, both ubiquitin and the 26S proteasome are involved. Subs...

Gene doctoring: a method for recombineering in laboratory and pathogenic Escherichia coli strains.

PubMed

Lee, David J; Bingle, Lewis E H; Heurlier, Karin; Pallen, Mark J; Penn, Charles W; Busby, Stephen J W; Hobman, Jon L

2009-12-09

Homologous recombination mediated by the lambda-Red genes is a common method for making chromosomal modifications in Escherichia coli. Several protocols have been developed that differ in the mechanisms by which DNA, carrying regions homologous to the chromosome, are delivered into the cell. A common technique is to electroporate linear DNA fragments into cells. Alternatively, DNA fragments are generated in vivo by digestion of a donor plasmid with a nuclease that does not cleave the host genome. In both cases the lambda-Red gene products recombine homologous regions carried on the linear DNA fragments with the chromosome. We have successfully used both techniques to generate chromosomal mutations in E. coli K-12 strains. However, we have had limited success with these lambda-Red based recombination techniques in pathogenic E. coli strains, which has led us to develop an enhanced protocol for recombineering in such strains. Our goal was to develop a high-throughput recombineering system, primarily for the coupling of genes to epitope tags, which could also be used for deletion of genes in both pathogenic and K-12 E. coli strains. To that end we have designed a series of donor plasmids for use with the lambda-Red recombination system, which when cleaved in vivo by the I-SceI meganuclease generate a discrete linear DNA fragment, allowing for C-terminal tagging of chromosomal genes with a 6xHis, 3xFLAG, 4xProteinA or GFP tag or for the deletion of chromosomal regions. We have enhanced existing protocols and technologies by inclusion of a cassette conferring kanamycin resistance and, crucially, by including the sacB gene on the donor plasmid, so that all but true recombinants are counter-selected on kanamycin and sucrose containing media, thus eliminating the need for extensive screening. This method has the added advantage of limiting the exposure of cells to the potential damaging effects of the lambda-Red system, which can lead to unwanted secondary alterations to the chromosome. We have developed a counter-selective recombineering technique for epitope tagging or for deleting genes in E. coli. We have demonstrated the versatility of the technique by modifying the chromosome of the enterohaemorrhagic O157:H7 (EHEC), uropathogenic CFT073 (UPEC), enteroaggregative O42 (EAEC) and enterotoxigenic H10407 (ETEC) E. coli strains as well as in K-12 laboratory strains.

No Pain, No Gain: The Learning Curve in Assessing Collaboratives.

ERIC Educational Resources Information Center

Rendon, Laura I.; Gans, Wendy L.; Calleroz, Mistalene D.

1998-01-01

Presents a case study of an assessment project designed to evaluate the Ford Foundation's Urban Partnership Program (UPP). Discusses UPP's assessment model and theory, and documents the project's yearly progress since its inception in 1992. Details UPP's goals and outcomes in assisting at-risk students. (EMH)

Factor Analysis of the Brazilian Version of UPPS Impulsive Behavior Scale

PubMed Central

Sediyama, Cristina Y. N.; Moura, Ricardo; Garcia, Marina S.; da Silva, Antonio G.; Soraggi, Carolina; Neves, Fernando S.; Albuquerque, Maicon R.; Whiteside, Setephen P.; Malloy-Diniz, Leandro F.

2017-01-01

Objective: To examine the internal consistency and factor structure of the Brazilian adaptation of the UPPS Impulsive Behavior Scale. Methods: UPPS is a self-report scale composed by 40 items assessing four factors of impulsivity: (a) urgency, (b) lack of premeditation; (c) lack of perseverance; (d) sensation seeking. In the present study 384 participants (278 women and 106 men), who were recruited from schools, universities, leisure centers and workplaces fulfilled the UPPS scale. An exploratory factor analysis was performed by using Varimax factor rotation and Kaiser Normalization, and we also conducted two confirmatory analyses to test the independency of the UPPS components found in previous analysis. Results: Results showed a decrease in mean UPPS total scores with age and this analysis showed that the youngest participants (below 30 years) scored significantly higher than the other groups over 30 years. No difference in gender was found. Cronbach’s alpha, results indicated satisfactory values for all subscales, with similar high values for the subscales and confirmatory factor analysis indexes also indicated a poor model fit. The results of two exploratory factor analysis were satisfactory. Conclusion: Our results showed that the Portuguese version has the same four-factor structure of the original and previous translations of the UPPS. PMID:28484414

Concordance between the original and short version of the Impulsive Behaviour Scale UPPS-P using an IRT model

PubMed Central

2018-01-01

The UPPS Impulsive Behaviour Scale (with five dimensions of impulsive behaviour) is being widely used. One of the handicaps of this instrument is its relatively long administration time. This has led to the development of a short version: SUPPS-P. There are no studies comparing the relationship between the SUPPS-P scores and the original UPPS-P scores. The objectives of this study, therefore, were to analyse the psychometric properties, concordance of person measures, and efficiency of the SUPPS-P compared to those on UPPS-P, applying an Item Response Theory Model. The UPPS-P and SUPPS-P were administered to 455 undergraduate students. Confirmatory factorial analysis replicated structures reported in previous studies: the five correlated factors structure and the model with two second-order factors (Urgency and Lack of Awareness) with Sensation Seeking dimension as a different factor. Rasch analysis show that both of the instruments presented adequate model-data fit. The results show the measurement for each dimension of UPPS-P offered more precision than SUPPS-P. The structure of items location was maintained in each dimension of SUPPS-P compared to the UPPS-P, but with better person and item separation indices of the UPPS-P dimensions. The concordance analysis reveals high correlations values between scores on both versions. From the standpoint of reducing items, it can be considered that the reduced version is more efficient. This study does not support the equivalence of items on the dimensions of Sensation Seeking and Lack of perseverance. PMID:29561902

Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia.

PubMed

Graham, Steven H; Liu, Hao

2017-03-01

The ubiquitin proteasome pathway (UPP) is essential for removing abnormal proteins and preventing accumulation of potentially toxic proteins within the neuron. UPP dysfunction occurs with normal aging and is associated with abnormal accumulation of protein aggregates within neurons in neurodegenerative diseases. Ischemia disrupts UPP function and thus may contribute to UPP dysfunction seen in the aging brain and in neurodegenerative diseases. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), an important component of the UPP in the neuron, is covalently modified and its activity inhibited by reactive lipids produced after ischemia. As a result, degradation of toxic proteins is impaired which may exacerbate neuronal function and cell death in stroke and neurodegenerative diseases. Preserving or restoring UCHL1 activity may be an effective therapeutic strategy in stroke and neurodegenerative diseases. Published by Elsevier B.V.

Cloning-independent markerless gene editing in Streptococcus sanguinis: novel insights in type IV pilus biology.

PubMed

Gurung, Ishwori; Berry, Jamie-Lee; Hall, Alexander M J; Pelicic, Vladimir

2017-04-07

Streptococcus sanguinis, a naturally competent opportunistic human pathogen, is a Gram-positive workhorse for genomics. It has recently emerged as a model for the study of type IV pili (Tfp)-exceptionally widespread and important prokaryotic filaments. To enhance genetic manipulation of Streptococcus sanguinis, we have developed a cloning-independent methodology, which uses a counterselectable marker and allows sophisticated markerless gene editing in situ. We illustrate the utility of this methodology by answering several questions regarding Tfp biology by (i) deleting single or mutiple genes, (ii) altering specific bases in genes of interest, and (iii) engineering genes to encode proteins with appended affinity tags. We show that (i) the last six genes in the pil locus harbouring all the genes dedicated to Tfp biology play no role in piliation or Tfp-mediated motility, (ii) two highly conserved Asp residues are crucial for enzymatic activity of the prepilin peptidase PilD and (iii) that pilin subunits with a C-terminally appended hexa-histidine (6His) tag are still assembled into functional Tfp. The methodology for genetic manipulation we describe here should be broadly applicable. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Cloning-independent markerless gene editing in Streptococcus sanguinis: novel insights in type IV pilus biology

PubMed Central

Gurung, Ishwori; Berry, Jamie-Lee; Hall, Alexander M. J.

2017-01-01

Abstract Streptococcus sanguinis, a naturally competent opportunistic human pathogen, is a Gram-positive workhorse for genomics. It has recently emerged as a model for the study of type IV pili (Tfp)—exceptionally widespread and important prokaryotic filaments. To enhance genetic manipulation of Streptococcus sanguinis, we have developed a cloning-independent methodology, which uses a counterselectable marker and allows sophisticated markerless gene editing in situ. We illustrate the utility of this methodology by answering several questions regarding Tfp biology by (i) deleting single or mutiple genes, (ii) altering specific bases in genes of interest, and (iii) engineering genes to encode proteins with appended affinity tags. We show that (i) the last six genes in the pil locus harbouring all the genes dedicated to Tfp biology play no role in piliation or Tfp-mediated motility, (ii) two highly conserved Asp residues are crucial for enzymatic activity of the prepilin peptidase PilD and (iii) that pilin subunits with a C-terminally appended hexa-histidine (6His) tag are still assembled into functional Tfp. The methodology for genetic manipulation we describe here should be broadly applicable. PMID:27903891

Coregulation of terpenoid pathway genes and prediction of isoprene production in Bacillus subtilis using transcriptomics

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hess, Becky M.; Xue, Junfeng; Markillie, Lye Meng

2013-06-19

The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding the system level regulation and control of the pathway. To address this limitation, we examined Bacillus subtilis grown under multiple conditions and then determined the relationship between altered isoprene production and the pattern of gene expression. Wemore » found that terpenoid genes appeared to fall into two distinct subsets with opposing correlations with respect to the amount of isoprene produced. The group whose expression levels positively correlated with isoprene production included dxs, the gene responsible for the commitment step in the pathway, as well as ispD, and two genes that participate in the mevalonate pathway, yhfS and pksG. The subset of terpenoid genes that inversely correlated with isoprene production included ispH, ispF, hepS, uppS, ispE, and dxr. A genome wide partial least squares regression model was created to identify other genes or pathways that contribute to isoprene production. This analysis showed that a subset of 213 regulated genes was sufficient to create a predictive model of isoprene production under different conditions and showed correlations at the transcriptional level. We conclude that gene expression levels alone are sufficiently informative about the metabolic state of a cell that produces increased isoprene and can be used to build a model which accurately predicts production of this secondary metabolite across many simulated environmental conditions.« less

A dual selection based, targeted gene replacement tool for Magnaporthe grisea and Fusarium oxysporum.

PubMed

Khang, Chang Hyun; Park, Sook-Young; Lee, Yong-Hwan; Kang, Seogchan

2005-06-01

Rapid progress in fungal genome sequencing presents many new opportunities for functional genomic analysis of fungal biology through the systematic mutagenesis of the genes identified through sequencing. However, the lack of efficient tools for targeted gene replacement is a limiting factor for fungal functional genomics, as it often necessitates the screening of a large number of transformants to identify the desired mutant. We developed an efficient method of gene replacement and evaluated factors affecting the efficiency of this method using two plant pathogenic fungi, Magnaporthe grisea and Fusarium oxysporum. This method is based on Agrobacterium tumefaciens-mediated transformation with a mutant allele of the target gene flanked by the herpes simplex virus thymidine kinase (HSVtk) gene as a conditional negative selection marker against ectopic transformants. The HSVtk gene product converts 5-fluoro-2'-deoxyuridine to a compound toxic to diverse fungi. Because ectopic transformants express HSVtk, while gene replacement mutants lack HSVtk, growing transformants on a medium amended with 5-fluoro-2'-deoxyuridine facilitates the identification of targeted mutants by counter-selecting against ectopic transformants. In addition to M. grisea and F. oxysporum, the method and associated vectors are likely to be applicable to manipulating genes in a broad spectrum of fungi, thus potentially serving as an efficient, universal functional genomic tool for harnessing the growing body of fungal genome sequence data to study fungal biology.

Cloning of ubiquitin-activating enzyme and ubiquitin-conjugating enzyme genes from Gracilaria lemaneiformis and their activity under heat shock.

PubMed

Li, Guang-Qi; Zang, Xiao-Nan; Zhang, Xue-Cheng; Lu, Ning; Ding, Yan; Gong, Le; Chen, Wen-Chao

2014-03-15

To study the response of Gracilaria lemaneiformis to heat stress, two key enzymes - ubiquitin-activating enzyme (E1) and ubiquitin-conjugating enzyme (E2) - of the Ubiquitin/26S proteasome pathway (UPP) were studied in three strains of G. lemaneiformis-wild type, heat-tolerant cultivar 981 and heat-tolerant cultivar 07-2. The full length DNA sequence of E1 contained only one exon. The open reading frame (ORF) sequence was 981 nucleotides encoding 326 amino acids, which contained conserved ATP binding sites (LYDRQIRLWGLE, ELAKNVLLAGV, LKEMN, VVCAI) and the ubiquitin-activating domains (VVCAI…LMTEAC, VFLDLGDEYSYQ, AIVGGMWGRE). The gene sequence of E2 contained four exons and three introns. The sum of the four exons gave an open reading frame sequence of 444 nucleotides encoding 147 amino acids, which contained a conserved ubiquitin-activating domain (GSICLDIL), ubiquitin-conjugating domains (RIYHPNIN, KVLLSICSLL, DDPLV) and ubiquitin-ligase (E3) recognition sites (KRI, YPF, WSP). Real-time-PCR analysis of transcription levels of E1 and E2 under heat shock conditions (28°C and 32°C) showed that in wild type, transcriptions of E1 and E2 were up-regulated at 28°C, while at 32°C, transcriptions of the two enzymes were below the normal level. In cultivar 981 and cultivar 07-2 of G. lemaneiformis, the transcription levels of the two enzymes were up-regulated at 32°C, and transcription level of cultivar 07-2 was even higher than that of cultivar 981. These results suggest that the UPP plays an important role in high temperature resistance of G. lemaneiformis and the bioactivity of UPP is directly related to the heat-resistant ability of G. lemaneiformis. Copyright © 2013 Elsevier B.V. All rights reserved.

Coregulation of Terpenoid Pathway Genes and Prediction of Isoprene Production in Bacillus subtilis Using Transcriptomics.

PubMed

Hess, Becky M; Xue, Junfeng; Markillie, Lye Meng; Taylor, Ronald C; Wiley, H Steven; Ahring, Birgitte K; Linggi, Bryan

2013-01-01

The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes, as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding system level regulation and control of the pathway. To address these limitations, we examined Bacillus subtilis grown under multiple conditions and determined the relationship between altered isoprene production and gene expression patterns. We found that with respect to the amount of isoprene produced, terpenoid genes fall into two distinct subsets with opposing correlations. The group whose expression levels positively correlated with isoprene production included dxs, which is responsible for the commitment step in the pathway, ispD, and two genes that participate in the mevalonate pathway, yhfS and pksG. The subset of terpenoid genes that inversely correlated with isoprene production included ispH, ispF, hepS, uppS, ispE, and dxr. A genome-wide partial least squares regression model was created to identify other genes or pathways that contribute to isoprene production. These analyses showed that a subset of 213 regulated genes was sufficient to create a predictive model of isoprene production under different conditions and showed correlations at the transcriptional level. We conclude that gene expression levels alone are sufficiently informative about the metabolic state of a cell that produces increased isoprene and can be used to build a model that accurately predicts production of this secondary metabolite across many simulated environmental conditions.

Coregulation of Terpenoid Pathway Genes and Prediction of Isoprene Production in Bacillus subtilis Using Transcriptomics

PubMed Central

Hess, Becky M.; Xue, Junfeng; Markillie, Lye Meng; Taylor, Ronald C.; Wiley, H. Steven; Ahring, Birgitte K.; Linggi, Bryan

2013-01-01

The isoprenoid pathway converts pyruvate to isoprene and related isoprenoid compounds in plants and some bacteria. Currently, this pathway is of great interest because of the critical role that isoprenoids play in basic cellular processes, as well as the industrial value of metabolites such as isoprene. Although the regulation of several pathway genes has been described, there is a paucity of information regarding system level regulation and control of the pathway. To address these limitations, we examined Bacillus subtilis grown under multiple conditions and determined the relationship between altered isoprene production and gene expression patterns. We found that with respect to the amount of isoprene produced, terpenoid genes fall into two distinct subsets with opposing correlations. The group whose expression levels positively correlated with isoprene production included dxs, which is responsible for the commitment step in the pathway, ispD, and two genes that participate in the mevalonate pathway, yhfS and pksG. The subset of terpenoid genes that inversely correlated with isoprene production included ispH, ispF, hepS, uppS, ispE, and dxr. A genome-wide partial least squares regression model was created to identify other genes or pathways that contribute to isoprene production. These analyses showed that a subset of 213 regulated genes was sufficient to create a predictive model of isoprene production under different conditions and showed correlations at the transcriptional level. We conclude that gene expression levels alone are sufficiently informative about the metabolic state of a cell that produces increased isoprene and can be used to build a model that accurately predicts production of this secondary metabolite across many simulated environmental conditions. PMID:23840410

Impulsivity and the sexes: measurement and structural invariance of the UPPS-P Impulsive Behavior Scale.

PubMed

Cyders, Melissa A

2013-02-01

Before it is possible to test whether men and women differ in impulsivity, it is necessary to evaluate whether impulsivity measures are invariant across sex. The UPPS-P Impulsive Behavior Scale (negative urgency, lack of premeditation, lack of perseverance, and sensation seeking, with added subscale of positive urgency) is one measure of five dispositions toward rash action that has shown to have robust and clinically useful relationships among risk-taking outcomes. In the current research, the author examined (a) the psychometric measurement invariance of the UPPS-P across sex, (b) the scale's structural invariance across sex, and (c) whether the five impulsivity traits differentially relate to risk outcomes as a function of sex. In a sample of 1,372 undergraduates, the author found evidence for measurement and invariance across sex: Thus, comparisons of men and women on the UPPS-P can be considered valid. Additionally, although males tend to report higher levels of sensation seeking and positive urgency (and possibly lack of perseverance), the relationships between the UPPS-P traits and risk outcomes were generally invariant across sex. The UPPS-P appears to function comparably across males and females, and mean differences on this scale between the sexes can be thought to reflect trait-level differences.

The structure of the UPPS-R-Child impulsivity scale and its relations with substance use outcomes among treatment-seeking adolescents.

PubMed

Tomko, Rachel L; Prisciandaro, James J; Falls, Sandhya Kutty; Magid, Viktoriya

2016-04-01

A youth version of the UPPS Impulsivity Scale (UPPS-R-C) was previously shown to predict drinking initiation among pre-adolescents. The goals of the current study were to confirm the structure of the UPPS-R-C using a sample of treatment-seeking adolescents and to examine the scales' relations with alcohol use, marijuana use, and problems related to substance use. Participants (N=120; ages 12-18; M=15.7) completed questionnaires at treatment intake. Confirmatory factor analysis (CFA) of the UPPS-R-C was conducted using a 5-factor model with factors corresponding to negative urgency, positive urgency, lack of perseverance, lack of premeditation, and sensation seeking. Relations between UPPS-R-C factors and binge drinking, marijuana use, and problems resulting from substance use were examined using path analysis. CFA suggested the 5-factor model provided adequate fit to the data. The hypothesized path model was partially supported, positive urgency was associated with frequency of binge drinking, and both negative urgency and frequency of binge drinking was associated with problems due to substance use. Other hypothesized paths were not significant. Although not hypothesized, negative urgency was associated with frequency of marijuana use and lack of perseverance was associated with problems due to use. Results suggest that the UPPS-R-C can be used with a treatment-seeking sample of adolescents. Furthermore, negative urgency, positive urgency, and lack of perseverance may be indicative of more severe substance use problems in a treatment setting. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The Structure of the UPPS-R-Child Impulsivity Scale and its Relations with Substance Use Outcomes Among Treatment-Seeking Adolescents

PubMed Central

Prisciandaro, James J.; Kutty Falls, Sandhya; Magid, Viktoriya

2016-01-01

Background A youth version of the UPPS Impulsivity Scale (UPPS-R-C) was previously shown to predict drinking initiation among pre-adolescents. The goals of the current study were to confirm the structure of the UPPS-R-C using a sample of treatment-seeking adolescents and to examine the scales’ relations with alcohol use, marijuana use, and problems related to substance use. Method Participants (N = 120; ages 12–18; M = 15.7) completed questionnaires at treatment intake. Confirmatory factor analysis (CFA) of the UPPS-R-C was conducted using a 5-factor model with factors corresponding to negative urgency, positive urgency, lack of perseverance, lack of premeditation, and sensation seeking. Relations between UPPS-R-C factors and binge drinking, marijuana use, and problems resulting from substance use were examined using path analysis. Results CFA suggested the 5-factor model provided adequate fit to the data. The hypothesized path model was partially supported, positive urgency was associated with frequency of binge drinking, and both negative urgency and frequency of binge drinking was associated with problems due to substance use. Other hypothesized paths were not significant. Although not hypothesized, negative urgency was associated with frequency of marijuana use and lack of perseverance was associated with problems due to use. Conclusions Results suggest that the UPPS-R-C can be used with a treatment-seeking sample of adolescents. Furthermore, negative urgency, positive urgency, and lack of perseverance may be indicative of more severe substance use problems in a treatment setting. PMID:26905208

Differential Gene Expression in Explanted Human Retinal Pigment Epithelial Cells 12-Hours Post-Exposure to 532 nm, 120 ps Pulsed Laser Light

DTIC Science & Technology

2004-04-01

cycling, anaerobic enzymes and kinase enzymes as well as specific cellular channel or receptor components. However, the most striking revelation of the...degradation. Most notably up-regulated were the genes for the enzymes essential in the ubiquitin-proteoasome pathway (UPP) shown to be up-regulated in response...to oxidative stress in eye tissue (1). These were ubiquitin [2.0], 3 ubiquitin-conjugating enzyme genes E2 [2.3], E2D2 [2.3] and E2D3 [2.8]. Also up

Formation of distinct inclusion bodies by inhibition of ubiquitin-proteasome and autophagy-lysosome pathways.

PubMed

Lee, Junho; Yang, Kyu-Hwan; Joe, Cheol O; Kang, Seok-Seong

2011-01-14

Accumulation of misfolded proteins is caused by the impairment of protein quality control systems, such as ubiquitin-proteasome pathway (UPP) and autophagy-lysosome pathway (ALP). In this study, the formation of inclusion bodies was examined after the blockade of UPP and/or ALP in A549 cells. UPP inhibition induced a single and large inclusion body localized in microtubule-organizing center. Interestingly, however, ALP inhibition generated dispersed small inclusion bodies in the cytoplasm. Tuberous sclerosis complex 2 was selectively accumulated in the inclusion bodies of UPP-inhibited cells, but not those of ALP-inhibited cells. Blockade of transcription and translation entirely inhibited the formation of inclusion body induced by UPP inhibition, but partially by ALP inhibition. Moreover, the simultaneous inhibition of two protein catabolic pathways independently developed two distinct inclusion bodies within a single cell. These findings clearly demonstrated that dysfunction of each catabolic pathway induced formation and accumulation of unique inclusion bodies on the basis of morphology, localization and formation process in A549 cells. Copyright © 2010 Elsevier Inc. All rights reserved.

Psychometric properties of the Spanish version of the UPPS-P Impulsive Behavior Scale: A Rasch rating scale analysis and confirmatory factor analysis.

PubMed

Pilatti, Angelina; Lozano, Oscar M; Cyders, Melissa A

2015-12-01

The present study was aimed at determining the psychometric properties of the Spanish version of the UPPS-P Impulsive Behavior Scale in a sample of college students. Participants were 318 college students (36.2% men; mean age = 20.9 years, SD = 6.4 years). The psychometric properties of this Spanish version were analyzed using the Rasch model, and the factor structure was examined using confirmatory factor analysis. The verification of the global fit of the data showed adequate indexes for persons and items. The reliability estimates were high for both items and persons. Differential item functioning across gender was found for 23 items, which likely reflects known differences in impulsivity levels between men and women. The factor structure of the Spanish version of the UPPS-P replicates previous work with the original UPPS-P Scale. Overall, results suggest that test scores from the Spanish version of the UPPS-P show adequate psychometric properties to accurately assess the multidimensional model of impulsivity, which represents the most exhaustive measure of this construct. (c) 2015 APA, all rights reserved).

The Universal Plausibility Metric (UPM) & Principle (UPP).

PubMed

Abel, David L

2009-12-03

Mere possibility is not an adequate basis for asserting scientific plausibility. A precisely defined universal bound is needed beyond which the assertion of plausibility, particularly in life-origin models, can be considered operationally falsified. But can something so seemingly relative and subjective as plausibility ever be quantified? Amazingly, the answer is, "Yes." A method of objectively measuring the plausibility of any chance hypothesis (The Universal Plausibility Metric [UPM]) is presented. A numerical inequality is also provided whereby any chance hypothesis can be definitively falsified when its UPM metric of xi is < 1 (The Universal Plausibility Principle [UPP]). Both UPM and UPP pre-exist and are independent of any experimental design and data set. No low-probability hypothetical plausibility assertion should survive peer-review without subjection to the UPP inequality standard of formal falsification (xi < 1).

FAA/NASA UAS Traffic Management Pilot Program (UPP)

NASA Technical Reports Server (NTRS)

Johnson, Ronald D.; Kopardekar, Parimal H.; Rios, Joseph L.

2018-01-01

NASA Ames is leading ATM R&D organization. NASA started working on UTM in 2012, it's come a long way primarily due to close relationship with FAA and industry. We have a research transition team between FAA and NASA for UTM. We have a few other RTTs as well. UTM is a great example of collaborative innovation, and now it's reaching very exciting stage of UTM Pilot Project (UPP). NASA is supporting FAA and industry to make the UPP most productive and successful.

The Universal Plausibility Metric (UPM) & Principle (UPP)

PubMed Central

2009-01-01

Background Mere possibility is not an adequate basis for asserting scientific plausibility. A precisely defined universal bound is needed beyond which the assertion of plausibility, particularly in life-origin models, can be considered operationally falsified. But can something so seemingly relative and subjective as plausibility ever be quantified? Amazingly, the answer is, "Yes." A method of objectively measuring the plausibility of any chance hypothesis (The Universal Plausibility Metric [UPM]) is presented. A numerical inequality is also provided whereby any chance hypothesis can be definitively falsified when its UPM metric of ξ is < 1 (The Universal Plausibility Principle [UPP]). Both UPM and UPP pre-exist and are independent of any experimental design and data set. Conclusion No low-probability hypothetical plausibility assertion should survive peer-review without subjection to the UPP inequality standard of formal falsification (ξ < 1). PMID:19958539

Inhibition of the ubiquitin-proteasome pathway does not protect against ventilator-induced accelerated proteolysis or atrophy in the diaphragm.

PubMed

Smuder, Ashley J; Nelson, W Bradley; Hudson, Matthew B; Kavazis, Andreas N; Powers, Scott K

2014-07-01

Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin-proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group). The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx. Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.

Improving the selection efficiency of the counter-selection marker pheS* for the genetic engineering of Bacillus amyloliquefaciens.

PubMed

Kharchenko, Maria S; Teslya, Petr N; Babaeva, Maria N; Zakataeva, Natalia P

2018-05-01

Bacillus subtilis pheS was genetically modified to obtain a counter-selection marker with high selection efficiency in Bacillus amyloliquefaciens. The application of the new replication-thermosensitive integrative vector pNZTM1, containing this marker, pheS BsT255S/A309G , with a two-step replacement recombination procedure provides an effective tool for the genetic engineering of industrially important Bacillus species. Copyright © 2018. Published by Elsevier B.V.

Signal processing in urodynamics: towards high definition urethral pressure profilometry.

PubMed

Klünder, Mario; Sawodny, Oliver; Amend, Bastian; Ederer, Michael; Kelp, Alexandra; Sievert, Karl-Dietrich; Stenzl, Arnulf; Feuer, Ronny

2016-03-22

Urethral pressure profilometry (UPP) is used in the diagnosis of stress urinary incontinence (SUI) which is a significant medical, social, and economic problem. Low spatial pressure resolution, common occurrence of artifacts, and uncertainties in data location limit the diagnostic value of UPP. To overcome these limitations, high definition urethral pressure profilometry (HD-UPP) combining enhanced UPP hardware and signal processing algorithms has been developed. In this work, we present the different signal processing steps in HD-UPP and show experimental results from female minipigs. We use a special microtip catheter with high angular pressure resolution and an integrated inclination sensor. Signals from the catheter are filtered and time-correlated artifacts removed. A signal reconstruction algorithm processes pressure data into a detailed pressure image on the urethra's inside. Finally, the pressure distribution on the urethra's outside is calculated through deconvolution. A mathematical model of the urethra is contained in a point-spread-function (PSF) which is identified depending on geometric and material properties of the urethra. We additionally investigate the PSF's frequency response to determine the relevant frequency band for pressure information on the urinary sphincter. Experimental pressure data are spatially located and processed into high resolution pressure images. Artifacts are successfully removed from data without blurring other details. The pressure distribution on the urethra's outside is reconstructed and compared to the one on the inside. Finally, the pressure images are mapped onto the urethral geometry calculated from inclination and position data to provide an integrated image of pressure distribution, anatomical shape, and location. With its advanced sensing capabilities, the novel microtip catheter collects an unprecedented amount of urethral pressure data. Through sequential signal processing steps, physicians are provided with detailed information on the pressure distribution in and around the urethra. Therefore, HD-UPP overcomes many current limitations of conventional UPP and offers the opportunity to evaluate urethral structures, especially the sphincter, in context of the correct anatomical location. This could enable the development of focal therapy approaches in the treatment of SUI.

Do Different Facets of Impulsivity Predict Different Types of Aggression?

PubMed Central

Derefinko, Karen; DeWall, C. Nathan; Metze, Amanda V.; Walsh, Erin C.; Lynam, Donald R.

2011-01-01

The current study examined the relations between impulsivity-related traits (as assessed by the UPPS-P Impulsive Behavior Scale) and aggressive behaviors. Results indicated that UPPS-P Lack of Premeditation and Sensation Seeking were important in predicting general violence. In contrast, UPPS-P Urgency was most useful in predicting intimate partner violence. To further explore relations between intimate partner violence and Urgency, a measure of autonomic response to pleasant and aversive stimuli and facets of Neuroticism from the NEO PI-R were used as control variables. Autonomic responsivity was correlated with intimate partner violence at the zero-order level, and predicted significant variance in intimate partner violence in regression equations. However, UPPS-P Urgency was able to account for unique variance in intimate partner violence above and beyond measures of Neuroticism and arousal. Implications regarding the use of a multifaceted conceptualization of impulsivity in the prediction of different types of violent behavior are discussed. PMID:21259270

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP.

PubMed

Bickford, Justin S; Nick, Harry S

2013-12-01

Isoprenoid lipid carriers are essential in protein glycosylation and bacterial cell envelope biosynthesis. The enzymes involved in their metabolism (synthases, kinases and phosphatases) are therefore critical to cell viability. In this review, we focus on two broad groups of isoprenoid pyrophosphate phosphatases. One group, containing phosphatidic acid phosphatase motifs, includes the eukaryotic dolichyl pyrophosphate phosphatases and proposed recycling bacterial undecaprenol pyrophosphate phosphatases, PgpB, YbjB and YeiU/LpxT. The second group comprises the bacterial undecaprenol pyrophosphate phosphatase, BacA/UppP, responsible for initial formation of undecaprenyl phosphate, which we predict contains a tyrosine phosphate phosphatase motif resembling that of the tumour suppressor, phosphatase and tensin homologue (PTEN). Based on protein sequence alignments across species and 2D structure predictions, we propose catalytic and lipid recognition motifs unique to BacA/UppP enzymes. The verification of our proposed active-site residues would provide new strategies for the development of substrate-specific inhibitors which mimic both the lipid and pyrophosphate moieties, leading to the development of novel antimicrobial agents.

A Highly Thermostable Kanamycin Resistance Marker Expands the Tool Kit for Genetic Manipulation of Caldicellulosiruptor bescii

PubMed Central

Lipscomb, Gina L.; Conway, Jonathan M.; Blumer-Schuette, Sara E.; Kelly, Robert M.

2016-01-01

ABSTRACT Caldicellulosiruptor bescii, an anaerobic Gram-positive bacterium with an optimal growth temperature of 78°C, is the most thermophilic cellulose degrader known. It is of great biotechnological interest, as it efficiently deconstructs nonpretreated lignocellulosic plant biomass. Currently, its genetic manipulation relies on a mutant uracil auxotrophic background strain that contains a random deletion in the pyrF genome region. The pyrF gene serves as a genetic marker to select for uracil prototrophy, and it can also be counterselected for loss via resistance to the compound 5-fluoroorotic acid (5-FOA). To expand the C. bescii genetic tool kit, kanamycin resistance was developed as a selection for genetic manipulation. A codon-optimized version of the highly thermostable kanamycin resistance gene (named Cbhtk) allowed the use of kanamycin selection to obtain transformants of either replicating or integrating vector constructs in C. bescii. These strains showed resistance to kanamycin at concentrations >50 μg · ml−1, whereas wild-type C. bescii was sensitive to kanamycin at 10 μg · ml−1. In addition, placement of the Cbhtk marker between homologous recombination regions in an integrating vector allowed direct selection of a chromosomal mutation using both kanamycin and 5-FOA. Furthermore, the use of kanamycin selection enabled the targeted deletion of the pyrE gene in wild-type C. bescii, generating a uracil auxotrophic genetic background strain resistant to 5-FOA. The pyrE gene functioned as a counterselectable marker, like pyrF, and was used together with Cbhtk in the ΔpyrE background strain to delete genes encoding lactate dehydrogenase and the CbeI restriction enzyme. IMPORTANCE Caldicellulosiruptor bescii is a thermophilic anaerobic bacterium with an optimal growth temperature of 78°C, and it has the ability to efficiently deconstruct nonpretreated lignocellulosic plant biomass. It is, therefore, of biotechnological interest for genetic engineering applications geared toward biofuel production. The current genetic system used with C. bescii is based upon only a single selection strategy, and this uses the gene involved in a primary biosynthetic pathway. There are many advantages with an additional genetic selection using an antibiotic. This presents a challenge for thermophilic microorganisms, as only a limited number of antibiotics are stable above 50°C, and a thermostable version of the enzyme conferring antibiotic resistance must be obtained. In this work, we have developed a selection system for C. bescii using the antibiotic kanamycin and have shown that, in combination with the biosynthetic gene marker, it can be used to efficiently delete genes in this organism. PMID:27208106

Active Site Conformational Dynamics in Human Uridine Phosphorylase 1

PubMed Central

Roosild, Tarmo P.; Castronovo, Samantha

2010-01-01

Uridine phosphorylase (UPP) is a central enzyme in the pyrimidine salvage pathway, catalyzing the reversible phosphorolysis of uridine to uracil and ribose-1-phosphate. Human UPP activity has been a focus of cancer research due to its role in activating fluoropyrimidine nucleoside chemotherapeutic agents such as 5-fluorouracil (5-FU) and capecitabine. Additionally, specific molecular inhibitors of this enzyme have been found to raise endogenous uridine concentrations, which can produce a cytoprotective effect on normal tissues exposed to these drugs. Here we report the structure of hUPP1 bound to 5-FU at 2.3 Å resolution. Analysis of this structure reveals new insights as to the conformational motions the enzyme undergoes in the course of substrate binding and catalysis. The dimeric enzyme is capable of a large hinge motion between its two domains, facilitating ligand exchange and explaining observed cooperativity between the two active sites in binding phosphate-bearing substrates. Further, a loop toward the back end of the uracil binding pocket is shown to flexibly adjust to the varying chemistry of different compounds through an “induced-fit” association mechanism that was not observed in earlier hUPP1 structures. The details surrounding these dynamic aspects of hUPP1 structure and function provide unexplored avenues to develop novel inhibitors of this protein with improved specificity and increased affinity. Given the recent emergence of new roles for uridine as a neuron protective compound in ischemia and degenerative diseases, such as Alzheimer's and Parkinson's, inhibitors of hUPP1 with greater efficacy, which are able to boost cellular uridine levels without adverse side-effects, may have a wide range of therapeutic applications. PMID:20856879

Impulsivity traits and addiction-related behaviors in youth.

PubMed

Rømer Thomsen, Kristine; Callesen, Mette Buhl; Hesse, Morten; Kvamme, Timo Lehmann; Pedersen, Michael Mulbjerg; Pedersen, Mads Uffe; Voon, Valerie

2018-04-12

Background and aims Impulsivity is a risk factor for addictive behaviors. The UPPS-P impulsivity model has been associated with substance addiction and gambling disorder, but its role in other non-substance addiction-related behaviors is less understood. We sought to examine associations between UPPS-P impulsivity traits and indicators of multiple substance and non-substance addiction-related behaviors in youth with varying involvement in these behaviors. Methods Participants (N = 109, aged 16-26 years, 69% males) were selected from a national survey based on their level of externalizing problems to achieve a broad distribution of involvement in addiction-related behaviors. Participants completed the UPPS-P Questionnaire and standardized questionnaires assessing problematic use of substances (alcohol, cannabis, and other drugs) and non-substances (Internet gaming, pornography, and food). Regression analyses were used to assess associations between impulsivity traits and indicators of addiction-related behaviors. Results The UPPS-P model was positively associated with indicators of all addiction-related behaviors except problematic Internet gaming. In the fully adjusted models, sensation seeking and lack of perseverance were associated with problematic use of alcohol, urgency was associated with problematic use of cannabis, and lack of perseverance was associated with problematic use of other drugs than cannabis. Furthermore, urgency and lack of perseverance were associated with binge eating and lack of perseverance was associated with problematic use of pornography. Discussion and conclusions We emphasize the role of trait impulsivity across multiple addiction-related behaviors. Our findings in at-risk youth highlight urgency and lack of perseverance as potential predictors for the development of addictions and as potential preventative therapeutic targets.

U.S. EPA, Pesticide Product Label, , 05/26/1993

EPA Pesticide Factsheets

2011-04-14

... 01 'harm •• appllc.tor toward th. upp.r corn,.". ... 1 5 II. (1.5m) • II h-om o.~~c.c'-ilr.ct ~t: •• flnl .,ray mf.t tow.rd the upp.r cor",,, of the room or ar ••. Fill ...

The Ubiquitin-Proteasome Pathway and Synaptic Plasticity

ERIC Educational Resources Information Center

Hegde, Ashok N.

2010-01-01

Proteolysis by the ubiquitin-proteasome pathway (UPP) has emerged as a new molecular mechanism that controls wide-ranging functions in the nervous system, including fine-tuning of synaptic connections during development and synaptic plasticity in the adult organism. In the UPP, attachment of a small protein, ubiquitin, tags the substrates for…

Genetic Tools for the Industrially Promising Methanotroph Methylomicrobium buryatense

DOE Office of Scientific and Technical Information (OSTI.GOV)

Puri, AW; Owen, S; Chu, F

2015-02-10

Aerobic methanotrophs oxidize methane at ambient temperatures and pressures and are therefore attractive systems for methane-based bioconversions. In this work, we developed and validated genetic tools for Methylomicrobium buryatense, a haloalkaliphilic gammaproteobacterial (type I) methanotroph. M. buryatense was isolated directly on natural gas and grows robustly in pure culture with a 3-h doubling time, enabling rapid genetic manipulation compared to many other methanotrophic species. As a proof of concept, we used a sucrose counterselection system to eliminate glycogen production in M. buryatense by constructing unmarked deletions in two redundant glycogen synthase genes. We also selected for a more genetically tractablemore » variant strain that can be conjugated with small incompatibility group P (IncP)-based broad-host-range vectors and determined that this capability is due to loss of the native plasmid. These tools make M. buryatense a promising model system for studying aerobic methanotroph physiology and enable metabolic engineering in this bacterium for industrial biocatalysis of methane.« less

Clinical Importance of Angiogenic Cytokines, Fibrinolytic Activity and Effusion Size in Parapneumonic Effusions

PubMed Central

Chung, Chi-Li; Hsiao, Shih-Hsin; Hsiao, George; Sheu, Joen-Rong; Chen, Wei-Lin; Chang, Shi-Chuan

2013-01-01

Objective To investigate the relationship among angiogenic cytokines, fibrinolytic activity and effusion size in parapneumonic effusion (PPE) and their clinical importance. Methods From January 2008 through December 2010, 26 uncomplicated (UPPE) and 38 complicated (CPPE) PPE were studied. Based on chest ultrasonography, there were non-loculated in 30, uni-loculated in 12, and multi-loculated effusions in 22 patients. The effusion size radiological scores, and effusion vascular endothelial growth factor (VEGF), interleukin (IL)-8, plasminogen activator inhibitor type-1 (PAI-1) and tissue type plasminogen activator (tPA) were measured on admission. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up. Results The effusion size and effusion VEGF, IL-8 and PAI-1/tPA ratio were significantly higher in CPPE than in UPPE, and significantly higher in multi-loculated PPE than in non-locualted and uni-loculated PPE, respectively. VEGF (cutoff value 1975 pg/ml) and IL-8 (cutoff value 1937 pg/ml) seemed best to discriminate between UPPE and CPPE. VEGF, IL-8 and effusion size correlated positively with PAI-1/tPA ratio in both UPPE and CPPE. Moreover, the level of VEGF, but not IL-8, correlated positively with effusion size in all patients (r = 0.79, p<0.001) and in UPPE (r = 0.64, p<0.001) and CPPE (r = 0.71, p<0.001) groups. The patients with higher VEGF or greater effusion were prone to have medical treatment failure (n = 10; VEGF, odds ratio 1.01, p = 0.02; effusion size, odds ratio 1.26, p = 0.01). Additionally, ten patients with RPT had larger effusion size and higher levels of VEGF and PAI-1/tPA ratio than did those without. Conclusions In PPE, VEGF and IL-8 levels are valuable to identify CPPE, and higher VEGF level or larger effusion is associated with decreased fibrinolytic activity, development of pleural loculation and fibrosis, and higher risk of medical treatment failure. PMID:23308155

Impulsivity profiles in pathological slot machine gamblers.

PubMed

Aragay, Núria; Barrios, Maite; Ramirez-Gendrau, Isabel; Garcia-Caballero, Anna; Garrido, Gemma; Ramos-Grille, Irene; Galindo, Yésika; Martin-Dombrowski, Jonatan; Vallès, Vicenç

2018-05-01

In gambling disorder (GD), impulsivity has been related with severity, treatment outcome and a greater dropout rate. The aim of the study is to obtain an empirical classification of GD patients based on their impulsivity and compare the resulting groups in terms of sociodemographic, clinical and gambling behavior variables. 126 patients with slot machine GD attending the Pathological Gambling Unit between 2013 and 2016 were included. The UPPS-P Impulsive Behavior Scale was used to assess impulsivity, and the severity of past-year gambling behavior was established with the Screen for Gambling problems questionnaire (NODS). Depression and anxiety symptoms and executive function were also assessed. A two-step cluster analysis was carried out to determine impulsivity profiles. According to the UPPS-P data, two clusters were generated. Cluster 1 showed the highest scores on all the UPPS-P subscales, whereas patients from cluster 2 exhibited only high scores on two UPPS-P subscales: Negative Urgency and Lack of premeditation. Additionally, patients on cluster 1 were younger and showed significantly higher scores on the Beck Depression Inventory and on the State-Trait Anxiety Inventory questionnaires, worse emotional regulation and executive functioning, and reported more psychiatric comorbidity compared to patients in cluster 2. With regard to gambling behavior, cluster 1 patients had significantly higher NODS scores and a higher percentage presented active gambling behavior at treatment start than in cluster 2. We found two impulsivity subtypes of slot machine gamblers. Patients with high impulsivity showed more severe gambling behavior, more clinical psychopathology and worse emotional regulation and executive functioning than those with lower levels of impulsivity. These two different clinical profiles may require different therapeutic approaches. Copyright © 2018 Elsevier Inc. All rights reserved.

Role of ubiquitin-proteasome in protein quality control and signaling: implication in the pathogenesis of eye diseases

USDA-ARS?s Scientific Manuscript database

The ubiquitin–proteasome pathway (UPP) plays important roles in many cellular functions, such as protein quality control, cell cycle control, and signal transduction. The selective degradation of aberrant proteins by the UPP is essential for the timely removal of potential cytotoxic damaged or other...

Genome engineering and gene expression control for bacterial strain development.

PubMed

Song, Chan Woo; Lee, Joungmin; Lee, Sang Yup

2015-01-01

In recent years, a number of techniques and tools have been developed for genome engineering and gene expression control to achieve desired phenotypes of various bacteria. Here we review and discuss the recent advances in bacterial genome manipulation and gene expression control techniques, and their actual uses with accompanying examples. Genome engineering has been commonly performed based on homologous recombination. During such genome manipulation, the counterselection systems employing SacB or nucleases have mainly been used for the efficient selection of desired engineered strains. The recombineering technology enables simple and more rapid manipulation of the bacterial genome. The group II intron-mediated genome engineering technology is another option for some bacteria that are difficult to be engineered by homologous recombination. Due to the increasing demands on high-throughput screening of bacterial strains having the desired phenotypes, several multiplex genome engineering techniques have recently been developed and validated in some bacteria. Another approach to achieve desired bacterial phenotypes is the repression of target gene expression without the modification of genome sequences. This can be performed by expressing antisense RNA, small regulatory RNA, or CRISPR RNA to repress target gene expression at the transcriptional or translational level. All of these techniques allow efficient and rapid development and screening of bacterial strains having desired phenotypes, and more advanced techniques are expected to be seen. Copyright © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Antibiotic Combinations That Enable One-Step, Targeted Mutagenesis of Chromosomal Genes.

PubMed

Lee, Wonsik; Do, Truc; Zhang, Ge; Kahne, Daniel; Meredith, Timothy C; Walker, Suzanne

2018-06-08

Targeted modification of bacterial chromosomes is necessary to understand new drug targets, investigate virulence factors, elucidate cell physiology, and validate results of -omics-based approaches. For some bacteria, reverse genetics remains a major bottleneck to progress in research. Here, we describe a compound-centric strategy that combines new negative selection markers with known positive selection markers to achieve simple, efficient one-step genome engineering of bacterial chromosomes. The method was inspired by the observation that certain nonessential metabolic pathways contain essential late steps, suggesting that antibiotics targeting a late step can be used to select for the absence of genes that control flux into the pathway. Guided by this hypothesis, we have identified antibiotic/counterselectable markers to accelerate reverse engineering of two increasingly antibiotic-resistant pathogens, Staphylococcus aureus and Acinetobacter baumannii. For S. aureus, we used wall teichoic acid biosynthesis inhibitors to select for the absence of tarO and for A. baumannii, we used colistin to select for the absence of lpxC. We have obtained desired gene deletions, gene fusions, and promoter swaps in a single plating step with perfect efficiency. Our method can also be adapted to generate markerless deletions of genes using FLP recombinase. The tools described here will accelerate research on two important pathogens, and the concept we outline can be readily adapted to any organism for which a suitable target pathway can be identified.

Multiple Pathways of Plasmid DNA Transfer in Helicobacter pylori

PubMed Central

Rohrer, Stefanie; Holsten, Lea; Weiss, Evelyn; Benghezal, Mohammed; Fischer, Wolfgang; Haas, Rainer

2012-01-01

Many Helicobacter pylori (Hp) strains carry cryptic plasmids of different size and gene content, the function of which is not well understood. A subgroup of these plasmids (e.g. pHel4, pHel12), contain a mobilisation region, but no cognate type IV secretion system (T4SS) for conjugative transfer. Instead, certain H. pylori strains (e.g. strain P12 carrying plasmid pHel12) can harbour up to four T4SSs in their genome (cag-T4SS, comB, tfs3, tfs4). Here, we show that such indigenous plasmids can be efficiently transferred between H. pylori strains, even in the presence of extracellular DNaseI eliminating natural transformation. Knockout of a plasmid-encoded mobA relaxase gene significantly reduced plasmid DNA transfer in the presence of DNaseI, suggesting a DNA conjugation or mobilisation process. To identify the T4SS involved in this conjugative DNA transfer, each individual T4SS was consecutively deleted from the bacterial chromosome. Using a marker-free counterselectable gene deletion procedure (rpsL counterselection method), a P12 mutant strain was finally obtained with no single T4SS (P12ΔT4SS). Mating experiments using these mutants identified the comB T4SS in the recipient strain as the major mediator of plasmid DNA transfer between H. pylori strains, both in a DNaseI-sensitive (natural transformation) as well as a DNaseI-resistant manner (conjugative transfer). However, transfer of a pHel12::cat plasmid from a P12ΔT4SS donor strain into a P12ΔT4SS recipient strain provided evidence for the existence of a third, T4SS-independent mechanism of DNA transfer. This novel type of plasmid DNA transfer, designated as alternate DNaseI-Resistant (ADR) mechanism, is observed at a rather low frequency under in vitro conditions. Taken together, our study describes for the first time the existence of three distinct pathways of plasmid DNA transfer between H. pylori underscoring the importance of horizontal gene transfer for this species. PMID:23029142

Multiple pathways of plasmid DNA transfer in Helicobacter pylori.

PubMed

Rohrer, Stefanie; Holsten, Lea; Weiss, Evelyn; Benghezal, Mohammed; Fischer, Wolfgang; Haas, Rainer

2012-01-01

Many Helicobacter pylori (Hp) strains carry cryptic plasmids of different size and gene content, the function of which is not well understood. A subgroup of these plasmids (e.g. pHel4, pHel12), contain a mobilisation region, but no cognate type IV secretion system (T4SS) for conjugative transfer. Instead, certain H. pylori strains (e.g. strain P12 carrying plasmid pHel12) can harbour up to four T4SSs in their genome (cag-T4SS, comB, tfs3, tfs4). Here, we show that such indigenous plasmids can be efficiently transferred between H. pylori strains, even in the presence of extracellular DNaseI eliminating natural transformation. Knockout of a plasmid-encoded mobA relaxase gene significantly reduced plasmid DNA transfer in the presence of DNaseI, suggesting a DNA conjugation or mobilisation process. To identify the T4SS involved in this conjugative DNA transfer, each individual T4SS was consecutively deleted from the bacterial chromosome. Using a marker-free counterselectable gene deletion procedure (rpsL counterselection method), a P12 mutant strain was finally obtained with no single T4SS (P12ΔT4SS). Mating experiments using these mutants identified the comB T4SS in the recipient strain as the major mediator of plasmid DNA transfer between H. pylori strains, both in a DNaseI-sensitive (natural transformation) as well as a DNaseI-resistant manner (conjugative transfer). However, transfer of a pHel12::cat plasmid from a P12ΔT4SS donor strain into a P12ΔT4SS recipient strain provided evidence for the existence of a third, T4SS-independent mechanism of DNA transfer. This novel type of plasmid DNA transfer, designated as alternate DNaseI-Resistant (ADR) mechanism, is observed at a rather low frequency under in vitro conditions. Taken together, our study describes for the first time the existence of three distinct pathways of plasmid DNA transfer between H. pylori underscoring the importance of horizontal gene transfer for this species.

The A-Like Faker Assay for Measuring Yeast Chromosome III Stability.

PubMed

Novoa, Carolina A; Ang, J Sidney; Stirling, Peter C

2018-01-01

The ability to rapidly assess chromosome instability (CIN) has enabled profiling of most yeast genes for potential effects on genome stability. The A-like faker (ALF) assay is one of several qualitative and quantitative marker loss assays that indirectly measure loss or conversion of genetic material using a counterselection step. The ALF assay relies on the ability to count spurious mating events that occur upon loss of the MATα locus of haploid Saccharomyces cerevisiae strains. Here, we describe the deployment of the ALF assay for both rapid and simple qualitative, and more in-depth quantitative analysis allowing determination of absolute ALF frequencies.

Novel copper complexes as potential proteasome inhibitors for cancer treatment (Review).

PubMed

Zhang, Zhen; Wang, Huiyun; Yan, Maocai; Wang, Huannan; Zhang, Chunyan

2017-01-01

The use of metal complexes in the pharmaceutical industry has recently increased and as a result, novel metal‑based complexes have initiated an interest as potential anticancer agents. Copper (Cu), which is an essential trace element in all living organisms, is important in maintaining the function of numerous proteins and enzymes. It has recently been demonstrated that Cu complexes may be used as tumor‑specific proteasome inhibitors and apoptosis inducers, by targeting the ubiquitin‑proteasome pathway (UPP). Cu complexes have demonstrated promising results in preclinical studies. The UPP is important in controlling the expression, activity and location of various proteins. Therefore, selective proteasome inhibition and apoptotic induction in cancer cells have been regarded as potential anticancer strategies. The present short review discusses recent progress in the development of Cu complexes, including clioquinol, dithiocarbamates and Schiff bases, as proteasome inhibitors for cancer treatment. A discussion of recent research regarding the understanding of metal inhibitors based on Cu and ligand platforms is presented.

Differential Associations of UPPS-P Impulsivity Traits With Alcohol Problems.

PubMed

McCarty, Kayleigh N; Morris, David H; Hatz, Laura E; McCarthy, Denis M

2017-07-01

The UPPS-P model posits that impulsivity comprises five factors: positive urgency, negative urgency, lack of planning, lack of perseverance, and sensation seeking. Negative and positive urgency are the traits most consistently associated with alcohol problems. However, previous work has examined alcohol problems either individually or in the aggregate, rather than examining multiple problem domains simultaneously. Recent work has also questioned the utility of distinguishing between positive and negative urgency, as this distinction did not meaningfully differ in predicting domains of psychopathology. The aims of this study were to address these issues by (a) testing unique associations of UPPS-P with specific domains of alcohol problems and (b) determining the utility of distinguishing between positive and negative urgency as risk factors for specific alcohol problems. Associations between UPPS-P traits and alcohol problem domains were examined in two cross-sectional data sets using negative binomial regression models. In both samples, negative urgency was associated with social/interpersonal, self-perception, risky behaviors, and blackout drinking problems. Positive urgency was associated with academic/occupational and physiological dependence problems. Both urgency traits were associated with impaired control and self-care problems. Associations for other UPPS-P traits did not replicate across samples. Results indicate that negative and positive urgency have differential associations with alcohol problem domains. Results also suggest a distinction between the type of alcohol problems associated with these traits-negative urgency was associated with problems experienced during a drinking episode, whereas positive urgency was associated with alcohol problems that result from longer-term drinking trends.

Impulsivity and the Sexes: Measurement and Structural Invariance of the UPPS-P Impulsive Behavior Scale

ERIC Educational Resources Information Center

Cyders, Melissa A.

2013-01-01

Before it is possible to test whether men and women differ in impulsivity, it is necessary to evaluate whether impulsivity measures are invariant across sex. The UPPS-P Impulsive Behavior Scale (negative urgency, lack of premeditation, lack of perseverance, and sensation seeking, with added subscale of positive urgency) is one measure of five…

CRISPR/Cas9-coupled recombineering for metabolic engineering of Corynebacterium glutamicum.

PubMed

Cho, Jae Sung; Choi, Kyeong Rok; Prabowo, Cindy Pricilia Surya; Shin, Jae Ho; Yang, Dongsoo; Jang, Jaedong; Lee, Sang Yup

2017-07-01

Genome engineering of Corynebacterium glutamicum, an important industrial microorganism for amino acids production, currently relies on random mutagenesis and inefficient double crossover events. Here we report a rapid genome engineering strategy to scarlessly knock out one or more genes in C. glutamicum in sequential and iterative manner. Recombinase RecT is used to incorporate synthetic single-stranded oligodeoxyribonucleotides into the genome and CRISPR/Cas9 to counter-select negative mutants. We completed the system by engineering the respective plasmids harboring CRISPR/Cas9 and RecT for efficient curing such that multiple gene targets can be done iteratively and final strains will be free of plasmids. To demonstrate the system, seven different mutants were constructed within two weeks to study the combinatorial deletion effects of three different genes on the production of γ-aminobutyric acid, an industrially relevant chemical of much interest. This genome engineering strategy will expedite metabolic engineering of C. glutamicum. Copyright © 2017 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.

Development of resources for the analysis of gene function in Pucciniomycotina red yeasts.

PubMed

Ianiri, Giuseppe; Wright, Sandra A I; Castoria, Raffaello; Idnurm, Alexander

2011-07-01

The Pucciniomycotina is an important subphylum of basidiomycete fungi but with limited tools to analyze gene functions. Transformation protocols were established for a Sporobolomyces species (strain IAM 13481), the first Pucciniomycotina species with a completed draft genome sequence, to enable assessment of gene function through phenotypic characterization of mutant strains. Transformation markers were the URA3 and URA5 genes that enable selection and counter-selection based on uracil auxotrophy and resistance to 5-fluoroorotic acid. The wild type copies of these genes were cloned into plasmids that were used for transformation of Sporobolomyces sp. by both biolistic and Agrobacterium-mediated approaches. These resources have been deposited to be available from the Fungal Genetics Stock Center. To show that these techniques could be used to elucidate gene functions, the LEU1 gene was targeted for specific homologous replacement, and also demonstrating that this gene is required for the biosynthesis of leucine in basidiomycete fungi. T-DNA insertional mutants were isolated and further characterized, revealing insertions in genes that encode the homologs of Chs7, Erg3, Kre6, Kex1, Pik1, Sad1, Ssu1 and Tlg1. Phenotypic analysis of these mutants reveals both conserved and divergent functions compared with other fungi. Some of these strains exhibit reduced resistance to detergents, the antifungal agent fluconazole or sodium sulfite, or lower recovery from heat stress. While there are current experimental limitations for Sporobolomyces sp. such as the lack of Mendelian genetics for conventional mating, these findings demonstrate the facile nature of at least one Pucciniomycotina species for genetic manipulation and the potential to develop these organisms into new models for understanding gene function and evolution in the fungi. Copyright © 2011 Elsevier Inc. All rights reserved.

Individual Differences in Impulsivity Predict Anticipatory Eye Movements

PubMed Central

Cirilli, Laetitia; de Timary, Philippe; Lefèvre, Phillipe; Missal, Marcus

2011-01-01

Impulsivity is the tendency to act without forethought. It is a personality trait commonly used in the diagnosis of many psychiatric diseases. In clinical practice, impulsivity is estimated using written questionnaires. However, answers to questions might be subject to personal biases and misinterpretations. In order to alleviate this problem, eye movements could be used to study differences in decision processes related to impulsivity. Therefore, we investigated correlations between impulsivity scores obtained with a questionnaire in healthy subjects and characteristics of their anticipatory eye movements in a simple smooth pursuit task. Healthy subjects were asked to answer the UPPS questionnaire (Urgency Premeditation Perseverance and Sensation seeking Impulsive Behavior scale), which distinguishes four independent dimensions of impulsivity: Urgency, lack of Premeditation, lack of Perseverance, and Sensation seeking. The same subjects took part in an oculomotor task that consisted of pursuing a target that moved in a predictable direction. This task reliably evoked anticipatory saccades and smooth eye movements. We found that eye movement characteristics such as latency and velocity were significantly correlated with UPPS scores. The specific correlations between distinct UPPS factors and oculomotor anticipation parameters support the validity of the UPPS construct and corroborate neurobiological explanations for impulsivity. We suggest that the oculomotor approach of impulsivity put forth in the present study could help bridge the gap between psychiatry and physiology. PMID:22046334

Organic acid-tolerant microorganisms and uses thereof for producing organic acids

DOEpatents

Pfleger, Brian Frederick; Begemann, Matthew Brett

2014-05-06

Organic acid-tolerant microorganisms and methods of using same. The organic acid-tolerant microorganisms comprise modifications that reduce or ablate AcsA activity or AcsA homolog activity. The modifications increase tolerance of the microorganisms to such organic acids as 3-hydroxypropionic acid (3HP), acrylic acid, and propionic acid. Further modifications to the microorganisms such as increasing expression of malonyl-CoA reductase and/or acetyl-CoA carboxylase provide or increase the ability of the microorganisms to produce 3HP. Methods of generating an organic acid with the modified microorganisms are provided. Methods of using acsA or homologs thereof as counter-selectable markers include replacing acsA or homologs thereof in cells with genes of interest and selecting for the cells comprising the genes of interest with amounts of organic acids effective to inhibit growth of cells harboring acsA or the homologs.

Antibacterial Drug Leads: DNA and Enzyme Multitargeting

DOE PAGES

Zhu, Wei; Wang, Yang; Li, Kai; ...

2015-01-09

Here, we report the results of an investigation of the activity of a series of amidine and bisamidine compounds against Staphylococcus aureus and Escherichia coli. The most active compounds bound to an AT-rich DNA dodecamer (CGCGAATTCGCG) 2 and using DSC were found to increase the melting transition by up to 24 °C. Several compounds also inhibited undecaprenyl diphosphate synthase (UPPS) with IC 50 values of 100–500 nM, and we found good correlations (R 2 = 0.89, S. aureus; R 2 = 0.79, E. coli) between experimental and predicted cell growth inhibition by using DNA ΔT m and UPPS IC 50more » experimental results together with one computed descriptor. Finally, we also solved the structures of three bisamidines binding to DNA as well as three UPPS structures. Overall, the results are of general interest in the context of the development of resistance-resistant antibiotics that involve multitargeting.« less

Advanced Technology Multiple Criteria Decision Model.

DTIC Science & Technology

1981-11-01

ratings of the sys- tem parameters; and (3), HEADER which contains information on the structure of the problem and titles. Two supporting programs develop...in these files are given in Section V.2. 2. DATA STRUCTURE TABLES This section describes the data files used in the system selection model program ...the supporting program PPP and an input file to UPPP and SSMP. Figure 13 shows the structure of this file. b. User’s preference package (UPP) UPP is

Development and evaluation of an efficient heterologous gene knock-in reporter system in Lactococcus lactis.

PubMed

Lu, Yifei; Yan, Hongxiang; Deng, Jiezhong; Huang, Zhigang; Jin, Xurui; Yu, Yanlan; Hu, Qiwen; Hu, Fuquan; Wang, Jing

2017-09-18

Lactococcus lactis is a food grade probiotics and widely used to express heterologous proteins. Generally, target genes are knocked into the L. lactis genome through double-crossover recombination to express heterologous proteins stably. However, creating marker-less heterologous genes knocked-in clones is laborious. In this study, an efficient heterologous gene knock-in reporter system was developed in L. lactis NZ9000. Our knock-in reporter system consists of a temperature-sensitive plasmid pJW and a recombinant L. lactis strain named NZB. The pJW contains homologous arms, and was constructed to knock-in heterologous genes at a fixed locus of NZ9000 genome. lacZ (β-galactosidase) gene was knocked into the chromosome of NZ9000 as a counter-selective marker through the plasmid pJW to generate NZB. The engineered NZB strain formed blue colonies on X-Gal plate. The desired double-crossover mutants formed white colonies distinctive from the predominantly blue colonies (parental and plasmid-integrated clones) when the embedded lacZ was replaced with the target heterologous genes carried by pJW in NZB. By using the system, the heterologous gene knocked-in clones are screened by colony phenotype change rather than by checking colonies individually. Our new knock-in reporter system provides an efficient method to create heterologous genes knocked-in clones.

Validation of a Swedish version of the short UPPS-P impulsive behavior scale among young adults.

PubMed

Claréus, Benjamin; Daukantaitė, Daiva; Wångby-Lundh, Margit; Lundh, Lars-Gunnar

2017-12-01

The UPPS-P model of impulsivity proposes that impulsivity comprises five distinct facets-negative urgency, positive urgency, lack of premeditation, lack of perseverance, and sensation seeking. The UPPS-P Impulsive Behavior Scale has been used to measure these facets. The purpose of the current study was to develop and evaluate the psychometric properties of a Swedish version of the 20-item UPPS-P Impulsive Behavior Scale (SUPPS-P). The sample comprised 343 Swedish young adults ( M age  = 24.21, SD  = 2.01; 27% men, 2% other or undisclosed gender identity) who answered a questionnaire including the SUPPS-P; Depression, Anxiety, and Stress Scale (DASS-21); and questions regarding their alcohol consumption and substance use. Confirmatory factor analysis supported a 5-factor, inter-correlated model, where each subscale of the SUPPS-P constitutes one latent variable. The convergent validity was established by replicating previously found correlations between the different impulsivity facets and depression, anxiety, frequency of alcohol consumption, and substance use. The internal consistency was acceptable for all the SUPPS-P subscales (Cronbach's α = 0.65-0.78, McDonald's ω = 0.65-0.79), except lack of perseverance (Cronbach's α = 0.60, McDonald's ω = 0.61). Thus, while the Swedish version of the SUPPS-P is suitable for assessing impulsivity in Swedish young adult samples, further research is needed to improve the psychometric properties of the lack of perseverance subscale.

Traditional Amerindian cultivators combine directional and ideotypic selection for sustainable management of cassava genetic diversity.

PubMed

Duputié, A; Massol, F; David, P; Haxaire, C; McKey, D

2009-06-01

Plant domestication provides striking examples of rapid evolution. Yet, it involves more complex processes than plain directional selection. Understanding the dynamics of diversity in traditional agroecosystems is both a fundamental goal in evolutionary biology and a practical goal in conservation. We studied how Amerindian cultivators maintain dynamically evolving gene pools in cassava. Farmers purposely maintain diversity in the form of phenotypically distinct, clonally propagated landraces. Landrace gene pools are continuously renewed by incorporating seedlings issued from spontaneous sexual reproduction. This poses two problems: agronomic quality may decrease because some seedlings are inbred, and landrace identity may be progressively lost through the incorporation of unrelated seedlings. Using a large microsatellite dataset, we show that farmers solve these problems by applying two kinds of selection: directional selection against inbred genotypes, and counter-selection of off-type phenotypes, which maintains high intra-landrace relatedness. Thus, cultural elements such as ideotypes (a representation of the ideal phenotype of a landrace) can shape genetic diversity.

A Strategy To Isolate Modifiers of Caenorhabditis elegans Lethal Mutations: Investigating the Endoderm Specifying Ability of the Intestinal Differentiation GATA Factor ELT-2.

PubMed

Wiesenfahrt, Tobias; Duanmu, Jingjie; Snider, Frances; Moerman, Don; Au, Vinci; Li-Leger, Erica; Flibotte, Stephane; Parker, Dylan M; Marshall, Craig J; Nishimura, Erin Osborne; Mains, Paul E; McGhee, James D

2018-05-04

The ELT-2 GATA factor normally functions in differentiation of the C. elegans endoderm, downstream of endoderm specification. We have previously shown that, if ELT-2 is expressed sufficiently early, it is also able to specify the endoderm and to replace all other members of the core GATA-factor transcriptional cascade (END-1, END-3, ELT-7). However, such rescue requires multiple copies (and presumably overexpression) of the end-1p :: elt-2 cDNA transgene; a single copy of the transgene does not rescue. We have made this observation the basis of a genetic screen to search for genetic modifiers that allow a single copy of the end-1p :: elt-2 cDNA transgene to rescue the lethality of the end-1 end-3 double mutant. We performed this screen on a strain that has a single copy insertion of the transgene in an end-1 end-3 background. These animals are kept alive by virtue of an extrachromosomal array containing multiple copies of the rescuing transgene; the extrachromosomal array also contains a toxin under heat shock control to counterselect for mutagenized survivors that have been able to lose the rescuing array. A screen of ∼14,000 mutagenized haploid genomes produced 17 independent surviving strains. Whole genome sequencing was performed to identify genes that incurred independent mutations in more than one surviving strain. The C. elegans gene tasp-1 was mutated in four independent strains. tasp-1 encodes the C. elegans homolog of Taspase, a threonine-aspartic acid protease that has been found, in both mammals and insects, to cleave several proteins involved in transcription, in particular MLL1/trithorax and TFIIA. A second gene, pqn-82 , was mutated in two independent strains and encodes a glutamine-asparagine rich protein. tasp-1 and pqn-82 were verified as loss-of-function modifiers of the end-1p :: elt-2 transgene by RNAi and by CRISPR/Cas9-induced mutations. In both cases, gene loss leads to modest increases in the level of ELT-2 protein in the early endoderm although ELT-2 levels do not strictly correlate with rescue. We suggest that tasp-1 and pqn-82 represent a class of genes acting in the early embryo to modulate levels of critical transcription factors or to modulate the responsiveness of critical target genes. The screen's design, rescuing lethality with an extrachromosomal transgene followed by counterselection, has a background survival rate of <10 -4 without mutagenesis and should be readily adapted to the general problem of identifying suppressors of C. elegans lethal mutations. Copyright © 2018 Wiesenfahrt et al.

Precision-engineering the Pseudomonas aeruginosa genome with two-step allelic exchange

PubMed Central

Hmelo, Laura R.; Borlee, Bradley R.; Almblad, Henrik; Love, Michelle E.; Randall, Trevor E.; Tseng, Boo Shan; Lin, Chuyang; Irie, Yasuhiko; Storek, Kelly M.; Yang, Jaeun Jane; Siehnel, Richard J.; Howell, P. Lynne; Singh, Pradeep K.; Tolker-Nielsen, Tim; Parsek, Matthew R.; Schweizer, Herbert P.; Harrison, Joe J.

2016-01-01

Allelic exchange is an efficient method of bacterial genome engineering. This protocol describes the use of this technique to make gene knockouts and knockins, as well as single nucleotide insertions, deletions and substitutions in Pseudomonas aeruginosa. Unlike other approaches to allelic exchange, this protocol does not require heterologous recombinases to insert or excise selective markers from the target chromosome. Rather, positive and negative selection are enabled solely by suicide vector-encoded functions and host cell proteins. Here, mutant alleles, which are flanked by regions of homology to the recipient chromosome, are synthesized in vitro and then cloned into allelic exchange vectors using standard procedures. These suicide vectors are then introduced into recipient cells by conjugation. Homologous recombination then results in antibiotic resistant single-crossover mutants in which the plasmid has integrated site-specifically into the chromosome. Subsequently, unmarked double-crossover mutants are isolated directly using sucrose-mediated counter-selection. This two-step process yields seamless mutations that are precise to a single base pair of DNA. The entire procedure requires ~2 weeks. PMID:26492139

[Mode of action of microbial anti-MRSA agents].

PubMed

Tomoda, Hiroshi

2012-01-01

Methicillin-resistant Staphylococcus aureus (MRSA) is known as a major nosocomial pathogen that has also developed resistance to many antibiotics. Moreover, MRSA resistance to a last-resort antibiotic, vancomycin, has been reported. Therefore, new anti-infectious agents to prevent and treat MRSA infection are needed. Based on this background, our group has focused on the discovery of new microbial agents active against MRSA infection. Viridicatumtoxin and spirohexaline, produced by Penicillium sp. FKI-3368, were isolated as inhibitors of undecaprenyl pyrophosphate (UPP) synthase of Staphylococcus aureus, which was involved in cell wall synthesis. Viridicatumtoxin and spirohexaline with a pentacyclic spiro skeleton inhibited UPP synthase activity with an IC(50) value of 4.0 and 9.0 µM, respectively. Actually, the growth of gram-positive bacteria including MRSA was strongly inhibited by the compounds. Our computational modeling experiments indicated that spirohexaline A was inserted into the substrate pocket of UPP synthase and interacted with Glu(88) via a carbamoyl group of the compound, with Ala(76), Met(54) and Asn(35) via three hydroxyl groups, and with certain hydrophobic amino acids via a spiro ring. Cyslabdan, produced by Streptomyces sp. K04-0144, was isolated as a potentiator of β-lactam imipenem activity against MRSA. The compound consisted of a labdan skeleton and an N-acetylcysteine. Cyslabdan potentiated imipenem activity by over 1000 fold, drastically reducing the MIC value of imipenem against MRSA from 16 to 0.03 µg/mL. The binding proteins of cyslabdan were investigated in the lysate of MRSA to identify FemA, which was involved in the formation of the pentaglycine interpeptide bridge in MRSA peptidoglycan.

Construction of new cloning, lacZ reporter and scarless-markerless suicide vectors for genetic studies in Aggregatibacter actinomycetemcomitans

PubMed Central

Juárez-Rodríguez, María Dolores; Torres-Escobar, Ascención; Demuth, Donald R.

2013-01-01

To elucidate the putative function of a gene, effective tools are required for genetic characterization that facilitate its inactivation, deletion or modification on the bacterial chromosome. In the present study, the nucleotide sequence of the Escherichia coli/Aggregatibacter actinomycetemcomitans shuttle vector pYGK was determined, allowing us to redesign and construct a new shuttle cloning vector, pJT4, and promoterless lacZ transcriptional/translational fusion plasmids, pJT3 and pJT5. Plasmids pJT4 and pJT5 contain the origin of replication necessary to maintain shuttle vector replication. In addition, a new suicide vector, pJT1, was constructed for the generation of scarless and markerless deletion mutations of genes in the oral pathogen A. actinomycetemcomitans. Plasmid pJT1 is a pUC-based suicide vector that is counter-selectable for sucrose sensitivity. This vector does not leave antibiotic markers or scars on the chromosome after gene deletion and thus provides the option to combine several mutations in the same genetic background. The effectiveness of pJT1 was demonstrated by the construction of A. actinomycetemcomitans isogenic qseB single deletion (ΔqseB) mutant and lsrRK double deletion mutants (ΔlsrRK). These new vectors may offer alternatives for genetic studies in A. actinomycetemcomitans and other members of the HACEK (Haemophilus spp., A. actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella kingae) group of Gram-negative bacteria. PMID:23353051

On the Link Between Emotionally Driven Impulsivity and Aggression: Evidence From a Validation Study on the Dutch UPPS-P.

PubMed

Bousardt, A M C; Noorthoorn, E O; Hoogendoorn, A W; Nijman, H L I; Hummelen, J W

2018-06-01

The UPPS-P seems to be a promising instrument for measuring different domains of impulsivity in forensic psychiatric patients. Validation studies of the instrument however, have been conducted only in student groups. In this validation study, three groups completed the Dutch UPPS-P: healthy student ( N = 94) and community ( N = 134) samples and a forensic psychiatric sample ( N = 73). The five-factor structure reported previously could only be substantiated in a confirmatory factor analysis over the combined groups but not in the subsamples. Subgroup sample sizes might be too small to allow such complex analyses. Internal consistency, as assessed by Cronbach's alpha, was high on most subscale and sample combinations. In explaining aggression, especially the initial subscale negative urgency (NU) was related to elevated scores on self-reported aggression in the healthy samples (student and community). The current study is the second study that found a relationship between self-reported NU and aggression highlighting the importance of addressing this behavioural domain in aggression management therapy.

Impulsivity and reasons for living among African American youth: a risk-protection framework of suicidal ideation.

PubMed

Salami, Temilola K; Brooks, Bianca A; Lamis, Dorian A

2015-05-15

This study aims to explore the impact of specific facets of impulsivity as measured by the UPPS Impulsive Behavior Scale (UPPS), as well as reasons for living in predicting suicidal ideation among African American college-aged students. The incremental validity of each facet of the UPPS interacting with reasons for living, a construct meant to buffer against risk for suicide, was explored in a sample of African American students (N = 130; ages 18-24). Results revealed significant interactions between reasons for living and two factors of impulsivity, (lack of) premeditation and sensation seeking. Higher levels of sensation seeking and lack of premeditation in conjunction with lower reasons for living was associated with increased suicidal ideation. Neither urgency nor (lack of) perseverance significantly interacted with reasons for living in association with suicidal ideation. These results suggest including elements of impulsivity, specifically sensation seeking and (lack of) premeditation, when screening for suicidal ideation among African American youth. Future investigations should continue to integrate factors of both risk and protection when determining risk for suicide.

Impulsivity and Reasons for Living Among African American Youth: A Risk-Protection Framework of Suicidal Ideation

PubMed Central

Salami, Temilola K.; Brooks, Bianca A.; Lamis, Dorian A.

2015-01-01

This study aims to explore the impact of specific facets of impulsivity as measured by the UPPS Impulsive Behavior Scale (UPPS), as well as reasons for living in predicting suicidal ideation among African American college-aged students. The incremental validity of each facet of the UPPS interacting with reasons for living, a construct meant to buffer against risk for suicide, was explored in a sample of African American students (N = 130; ages 18–24). Results revealed significant interactions between reasons for living and two factors of impulsivity, (lack of) premeditation and sensation seeking. Higher levels of sensation seeking and lack of premeditation in conjunction with lower reasons for living was associated with increased suicidal ideation. Neither urgency nor (lack of) perseverance significantly interacted with reasons for living in association with suicidal ideation. These results suggest including elements of impulsivity, specifically sensation seeking and (lack of) premeditation, when screening for suicidal ideation among African American youth. Future investigations should continue to integrate factors of both risk and protection when determining risk for suicide. PMID:25988310

CAD-Based Shielding Analysis for ITER Port Diagnostics

NASA Astrophysics Data System (ADS)

Serikov, Arkady; Fischer, Ulrich; Anthoine, David; Bertalot, Luciano; De Bock, Maartin; O'Connor, Richard; Juarez, Rafael; Krasilnikov, Vitaly

2017-09-01

Radiation shielding analysis conducted in support of design development of the contemporary diagnostic systems integrated inside the ITER ports is relied on the use of CAD models. This paper presents the CAD-based MCNP Monte Carlo radiation transport and activation analyses for the Diagnostic Upper and Equatorial Port Plugs (UPP #3 and EPP #8, #17). The creation process of the complicated 3D MCNP models of the diagnostics systems was substantially accelerated by application of the CAD-to-MCNP converter programs MCAM and McCad. High performance computing resources of the Helios supercomputer allowed to speed-up the MCNP parallel transport calculations with the MPI/OpenMP interface. The found shielding solutions could be universal, reducing ports R&D costs. The shield block behind the Tritium and Deposit Monitor (TDM) optical box was added to study its influence on Shut-Down Dose Rate (SDDR) in Port Interspace (PI) of EPP#17. Influence of neutron streaming along the Lost Alpha Monitor (LAM) on the neutron energy spectra calculated in the Tangential Neutron Spectrometer (TNS) of EPP#8. For the UPP#3 with Charge eXchange Recombination Spectroscopy (CXRS-core), an excessive neutron streaming along the CXRS shutter, which should be prevented in further design iteration.

Efficient Generation of Marker-Free Transgenic Rice Plants Using an Improved Transposon-Mediated Transgene Reintegration Strategy1

PubMed Central

Gao, Xiaoqing; Zhou, Jie; Li, Jun; Zou, Xiaowei; Zhao, Jianhua; Li, Qingliang; Xia, Ran; Yang, Ruifang; Wang, Dekai; Zuo, Zhaoxue; Tu, Jumin; Tao, Yuezhi; Chen, Xiaoyun; Xie, Qi; Zhu, Zengrong

2015-01-01

Marker-free transgenic plants can be developed through transposon-mediated transgene reintegration, which allows intact transgene insertion with defined boundaries and requires only a few primary transformants. In this study, we improved the selection strategy and validated that the maize (Zea mays) Activator/Dissociation (Ds) transposable element can be routinely used to generate marker-free transgenic plants. A Ds-based gene of interest was linked to green fluorescent protein in transfer DNA (T-DNA), and a green fluorescent protein-aided counterselection against T-DNA was used together with polymerase chain reaction (PCR)-based positive selection for the gene of interest to screen marker-free progeny. To test the efficacy of this strategy, we cloned the Bacillus thuringiensis (Bt) δ-endotoxin gene into the Ds elements and transformed transposon vectors into rice (Oryza sativa) cultivars via Agrobacterium tumefaciens. PCR assays of the transposon empty donor site exhibited transposition in somatic cells in 60.5% to 100% of the rice transformants. Marker-free (T-DNA-free) transgenic rice plants derived from unlinked germinal transposition were obtained from the T1 generation of 26.1% of the primary transformants. Individual marker-free transgenic rice lines were subjected to thermal asymmetric interlaced-PCR to determine Ds(Bt) reintegration positions, reverse transcription-PCR and enzyme-linked immunosorbent assay to detect Bt expression levels, and bioassays to confirm resistance against the striped stem borer Chilo suppressalis. Overall, we efficiently generated marker-free transgenic plants with optimized transgene insertion and expression. The transposon-mediated marker-free platform established in this study can be used in rice and possibly in other important crops. PMID:25371551

Efficient generation of marker-free transgenic rice plants using an improved transposon-mediated transgene reintegration strategy.

PubMed

Gao, Xiaoqing; Zhou, Jie; Li, Jun; Zou, Xiaowei; Zhao, Jianhua; Li, Qingliang; Xia, Ran; Yang, Ruifang; Wang, Dekai; Zuo, Zhaoxue; Tu, Jumin; Tao, Yuezhi; Chen, Xiaoyun; Xie, Qi; Zhu, Zengrong; Qu, Shaohong

2015-01-01

Marker-free transgenic plants can be developed through transposon-mediated transgene reintegration, which allows intact transgene insertion with defined boundaries and requires only a few primary transformants. In this study, we improved the selection strategy and validated that the maize (Zea mays) Activator/Dissociation (Ds) transposable element can be routinely used to generate marker-free transgenic plants. A Ds-based gene of interest was linked to green fluorescent protein in transfer DNA (T-DNA), and a green fluorescent protein-aided counterselection against T-DNA was used together with polymerase chain reaction (PCR)-based positive selection for the gene of interest to screen marker-free progeny. To test the efficacy of this strategy, we cloned the Bacillus thuringiensis (Bt) δ-endotoxin gene into the Ds elements and transformed transposon vectors into rice (Oryza sativa) cultivars via Agrobacterium tumefaciens. PCR assays of the transposon empty donor site exhibited transposition in somatic cells in 60.5% to 100% of the rice transformants. Marker-free (T-DNA-free) transgenic rice plants derived from unlinked germinal transposition were obtained from the T1 generation of 26.1% of the primary transformants. Individual marker-free transgenic rice lines were subjected to thermal asymmetric interlaced-PCR to determine Ds(Bt) reintegration positions, reverse transcription-PCR and enzyme-linked immunosorbent assay to detect Bt expression levels, and bioassays to confirm resistance against the striped stem borer Chilo suppressalis. Overall, we efficiently generated marker-free transgenic plants with optimized transgene insertion and expression. The transposon-mediated marker-free platform established in this study can be used in rice and possibly in other important crops. © 2015 American Society of Plant Biologists. All Rights Reserved.

Ultra-processed food product brands on Facebook pages: highly accessed by Brazilians through their marketing techniques.

PubMed

Horta, Paula M; Rodrigues, Fernanda T; Dos Santos, Luana C

2018-06-01

To analyse the content and extent of marketing of ultra-processed food products (UPP) and their brand pages on Facebook, which are highly accessed by Brazilians. Descriptive. Sixteen UPP brand pages on Facebook were selected from 250 pages that were the most liked by Brazilians in October 2015. We analysed the frequency of 'likes' and members 'talking about' each one of the pages, in addition to fifteen marketing techniques used in the previous year (September 2014 to October 2015). The number of posts, likes, 'shares' and 'commentaries', and the mean number of likes, shares and commentaries per post, were collected for one month, from 23 September to 23 October 2015. The two most liked pages were: Coke® (93 673 979 likes) and McDonald's® (59 749 819 likes). Regarding the number of people talking about the pages, McDonald's led with 555 891 commentaries, followed by Coke (287 274), Burger King® (246 148) and Kibon® (244 523). All pages used marketing techniques, which included photos, user conversations, presence of brand elements and links. Videos were observed on 93·8 % of the pages; promotions on 68·8 %; and celebrities on 62·5 %. In one month, Garoto®, Outback® and Coke were brands that published more than one post per day. Kibon achieved the highest ratio of likes per post (285 845·50) and Burger King had the highest mean shares per post (10 083·93), including commentaries per post (7958·13). UPP marketing is extensively used on Facebook pages and is highly accessed by Brazilians, with UPP companies employing a diversity of marketing strategies.

Defective B cell tolerance in adenosine deaminase deficiency is corrected by gene therapy

PubMed Central

Sauer, Aisha V.; Morbach, Henner; Brigida, Immacolata; Ng, Yen-Shing; Aiuti, Alessandro; Meffre, Eric

2012-01-01

Adenosine deaminase (ADA) gene defects are among the most common causes of SCID. Restoration of purine metabolism and immune functions can be achieved by enzyme replacement therapy, or more effectively by bone marrow transplant or HSC gene therapy (HSC-GT). However, autoimmune complications and autoantibody production, including anti-nuclear antibodies (ANAs), frequently occur in ADA-SCID patients after treatment. To assess whether ADA deficiency affects the establishment of B cell tolerance, we tested the reactivity of recombinant antibodies isolated from single B cells of ADA-SCID patients before and after HSC-GT. We found that before HSC-GT, new emigrant/transitional and mature naive B cells from ADA-SCID patients contained more autoreactive and ANA-expressing clones, indicative of defective central and peripheral B cell tolerance checkpoints. We further observed impaired B cell receptor (BCR) and TLR functions in B cells after ADA inhibition, which may underlie the defects in B cell tolerance. Strikingly, after HSC-GT, ADA-SCID patients displayed quasi-normal early B cell tolerance checkpoints, as evidenced by restored removal of developing autoreactive and ANA-expressing B cells. Hence, ADA plays an essential role in controlling autoreactive B cell counterselection by regulating BCR and TLR functions. PMID:22622038

Distinct lithium-induced gene expression effects in lymphoblastoid cell lines from patients with bipolar disorder.

PubMed

Fries, Gabriel R; Colpo, Gabriela D; Monroy-Jaramillo, Nancy; Zhao, Junfei; Zhao, Zhongming; Arnold, Jodi G; Bowden, Charles L; Walss-Bass, Consuelo

2017-11-01

Lithium is the most commonly prescribed medication for the treatment of bipolar disorder (BD), yet the mechanisms underlying its beneficial effects are still unclear. We aimed to compare the effects of lithium treatment in lymphoblastoid cell lines (LCLs) from BD patients and controls. LCLs were generated from sixty-two BD patients (based on DSM-IV) and seventeen healthy controls matched for age, sex, and ethnicity. Patients were recruited from outpatient clinics from February 2012 to October 2014. LCLs were treated with 1mM lithium for 7 days followed by microarray gene expression assay and validation by real-time quantitative PCR. Baseline differences between groups, as well as differences between vehicle- and lithium-treated cells within each group were analyzed. The biological significance of differentially expressed genes was examined by pathway enrichment analysis. No significant differences in baseline gene expression (adjusted p-value < 0.05) were detected between groups. Lithium treatment of LCLs from controls did not lead to any significant differences. However, lithium altered the expression of 236 genes in LCLs from patients; those genes were enriched for signaling pathways related to apoptosis. Among those genes, the alterations in the expression of PIK3CG, SERP1 and UPP1 were validated by real-time PCR. A significant correlation was also found between circadian functioning and CEBPG and FGF2 expression levels. In summary, our results suggest that lithium treatment induces expression changes in genes associated with the apoptosis pathway in BD LCLs. The more pronounced effects of lithium in patients compared to controls suggest a disease-specific effect of this drug. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Isoprenoid Biosynthesis Inhibitors Targeting Bacterial Cell Growth.

PubMed

Desai, Janish; Wang, Yang; Wang, Ke; Malwal, Satish R; Oldfield, Eric

2016-10-06

We synthesized potential inhibitors of farnesyl diphosphate synthase (FPPS), undecaprenyl diphosphate synthase (UPPS), or undecaprenyl diphosphate phosphatase (UPPP), and tested them in bacterial cell growth and enzyme inhibition assays. The most active compounds were found to be bisphosphonates with electron-withdrawing aryl-alkyl side chains which inhibited the growth of Gram-negative bacteria (Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, and Pseudomonas aeruginosa) at ∼1-4 μg mL -1 levels. They were found to be potent inhibitors of FPPS; cell growth was partially "rescued" by the addition of farnesol or overexpression of FPPS, and there was synergistic activity with known isoprenoid biosynthesis pathway inhibitors. Lipophilic hydroxyalkyl phosphonic acids inhibited UPPS and UPPP at micromolar levels; they were active (∼2-6 μg mL -1 ) against Gram-positive but not Gram-negative organisms, and again exhibited synergistic activity with cell wall biosynthesis inhibitors, but only indifferent effects with other inhibitors. The results are of interest because they describe novel inhibitors of FPPS, UPPS, and UPPP with cell growth inhibitory activities as low as ∼1-2 μg mL -1 . © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Relationship between Non-Suicidal Self-Injury and the UPPS-P Impulsivity Facets in Eating Disorders and Healthy Controls.

PubMed

Claes, Laurence; Islam, Mohammed A; Fagundo, Ana B; Jimenez-Murcia, Susana; Granero, Roser; Agüera, Zaida; Rossi, Elisa; Menchón, José M; Fernández-Aranda, Fernando

2015-01-01

In the present study, we investigated the association between Non-Suicidal Self-Injury (NSSI) and the UPPS-P impulsivity facets in eating disorder patients and healthy controls. The prevalence of NSSI in eating disorder (ED) patients ranged from 17% in restrictive anorexia nervosa (AN-R) patients to 43% in patients with bulimia nervosa (BN). In healthy controls (HC), the prevalence of NSSI was 19%. Eating disorder patients from the binge eating/purging type showed significantly more NSSI compared to restrictive ED and HC participants. Binge-eating/purging ED patients also scored significantly higher on Negative/Positive Urgency, Lack of Premeditation and Lack of Perseverance compared to HC and restrictive ED patients. Comparable findings were found between ED patients and HC with and without NSSI; ED patients and HC with NSSI scored significantly higher in four of the five UPPS-P dimensions compared to participants without NSSI; Sensation Seeking was the exception. Finally, the presence of NSSI in HC/ED patients was particularly predicted by low levels of Perseverance. Therefore, the treatment of ED patients with NSSI certainly needs to focus on the training of effortful control.

Recombineering in Streptococcus mutans Using Direct Repeat-Mediated Cloning-Independent Markerless Mutagenesis (DR-CIMM).

PubMed

Zhang, Shan; Zou, Zhengzhong; Kreth, Jens; Merritt, Justin

2017-01-01

Studies of the dental caries pathogen Streptococcus mutans have benefitted tremendously from its sophisticated genetic system. As part of our own efforts to further improve upon the S. mutans genetic toolbox, we previously reported the development of the first cloning-independent markerless mutagenesis (CIMM) system for S. mutans and illustrated how this approach could be adapted for use in many other organisms. The CIMM approach only requires overlap extension PCR (OE-PCR) protocols to assemble counterselectable allelic replacement mutagenesis constructs, and thus greatly increased the speed and efficiency with which markerless mutations could be introduced into S. mutans . Despite its utility, the system is still subject to a couple limitations. Firstly, CIMM requires negative selection with the conditionally toxic phenylalanine analog p -chlorophenylalanine (4-CP), which is efficient, but never perfect. Typically, 4-CP negative selection results in a small percentage of naturally resistant background colonies. Secondly, CIMM requires two transformation steps to create markerless mutants. This can be inherently problematic if the transformability of the strain is negatively impacted after the first transformation step, which is used to insert the counterselection cassette at the mutation site on the chromosome. In the current study, we develop a next-generation counterselection cassette that eliminates 4-CP background resistance and combine this with a new direct repeat-mediated cloning-independent markerless mutagenesis (DR-CIMM) system to specifically address the limitations of the prior approach. DR-CIMM is even faster and more efficient than CIMM for the creation of all types of deletions, insertions, and point mutations and is similarly adaptable for use in a wide range of genetically tractable bacteria.

HisB as novel selection marker for gene targeting approaches in Aspergillus niger.

PubMed

Fiedler, Markus R M; Gensheimer, Tarek; Kubisch, Christin; Meyer, Vera

2017-03-08

For Aspergillus niger, a broad set of auxotrophic and dominant resistance markers is available. However, only few offer targeted modification of a gene of interest into or at a genomic locus of choice, which hampers functional genomics studies. We thus aimed to extend the available set by generating a histidine auxotrophic strain with a characterized hisB locus for targeted gene integration and deletion in A. niger. A histidine-auxotrophic strain was established via disruption of the A. niger hisB gene by using the counterselectable pyrG marker. After curing, a hisB - , pyrG - strain was obtained, which served as recipient strain for further studies. We show here that both hisB orthologs from A. nidulans and A. niger can be used to reestablish histidine prototrophy in this recipient strain. Whereas the hisB gene from A. nidulans was suitable for efficient gene targeting at different loci in A. niger, the hisB gene from A. niger allowed efficient integration of a Tet-on driven luciferase reporter construct at the endogenous non-functional hisB locus. Subsequent analysis of the luciferase activity revealed that the hisB locus is tight under non-inducing conditions and allows even higher luciferase expression levels compared to the pyrG integration locus. Taken together, we provide here an alternative selection marker for A. niger, hisB, which allows efficient homologous integration rates as well as high expression levels which compare favorably to the well-established pyrG selection marker.

Deletion of the znuA virulence factor attenuates Actinobacillus pleuropneumoniae and confers protection against homologous or heterologous strain challenge.

PubMed

Yuan, Fangyan; Liao, Yonghong; You, Wujin; Liu, Zewen; Tan, Yongqiang; Zheng, Chengkun; BinWang; Zhou, Danna; Tian, Yongxiang; Bei, Weicheng

2014-12-05

The znuA gene is known to be important for growth and survival in Escherichia coli, Haemophilus spp., Neisseria gonorrhoeae, and Pasteurella multocida under low Zn(2+) conditions. This gene is also present in Actinobacillus pleuropneumoniae serotype 1; therefore, the aim of this study was to investigate the existence of a similar role for the znuA gene in the growth and virulence of this organism. A precisely defined ΔznuA deletion mutant of A. pleuropneumoniae was constructed based on the sequence of the wild-type SLW01 using transconjugation and counterselection. This mutation was found to be lethal in low-Zn(2+) medium. Furthermore, the ΔznuA mutant strain exhibited attenuated virulence (≥22-fold) as well as reduced mortality and morbidity in a murine (Balb/C) model of infection. The majority of the bacteria were cleared from the lungs within 2 weeks. The ΔznuA mutant strain caused no adverse effects in pigs at doses of up to 1.0×10(9) CFU/mL. The ΔznuA mutant strain induced a significant immune response and conferred 80% and 100% protection on immunised pigs against challenge with A. pleuropneumoniae strains belonging to homologous or heterologous serovars, respectively, compared to the blank controls. The data obtained in this study indicate the potential of the mutant ΔznuA strain for development as a live vaccine capable of inducing reliable cross-serovar protection following intratracheal immunisation. Copyright © 2014 Elsevier B.V. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chan, Chi Ho; Levar, Caleb E.; Zacharoff, Lori

Metal reduction by members of the Geobacteraceae is encoded by multiple gene clusters, and the study of extracellular electron transfer often requires biofilm development on surfaces. Genetic tools that utilize polar antibiotic cassette insertions limit mutant construction and complementation. In addition, unstable plasmids create metabolic burdens that slow growth, and the presence of antibiotics such as kanamycin can interfere with the rate and extent of Geobacter biofilm growth. We report here genetic system improvements for the model anaerobic metal-reducing bacterium Geobacter sulfurreducens. A motile strain of G. sulfurreducens was constructed by precise removal of a transposon interrupting the fgrM flagellarmore » regulator gene using SacB/sucrose counterselection, and Fe(III) citrate reduction was eliminated by deletion of the gene encoding the inner membrane cytochrome imcH. We also show that RK2-based plasmids were maintained in G. sulfurreducens for over 15 generations in the absence of antibiotic selection in contrast to unstable pBBR1 plasmids. Therefore, we engineered a series of new RK2 vectors containing native constitutive Geobacter promoters, and modified one of these promoters for VanR-dependent induction by the small aromatic carboxylic acid vanillate. Inducible plasmids fully complemented Δ imcH mutants for Fe(III) reduction, Mn(IV) oxide reduction, and growth on poised electrodes. A real-time, high-throughput Fe(III) citrate reduction assay is described that can screen numerous G. sulfurreducens strain constructs simultaneously and shows the sensitivity of imcH expression by the vanillate system. Lastly, these tools will enable more sophisticated genetic studies in G. sulfurreducens without polar insertion effects or need for multiple antibiotics.« less

The role of impulsivity traits and delayed reward discounting in dysregulated eating and drinking among heavy drinkers

PubMed Central

Stojek, Monika M.; Fischer, Sarah; Murphy, Cara M.; MacKillop, James

2016-01-01

Impulsivity is a multifaceted construct that has been linked to dysregulated eating and problematic alcohol use. The UPPS model identifies five personality-based impulsivity traits that have unique predictive utility: Negative Urgency, Perseverance, Premeditation, Sensation Seeking, and Positive Urgency. Delayed reward discounting (DRD) is an index of impulsive decision making characterized by preference for smaller immediate gains at the cost of larger delayed gains. In the current study, we sought to refine the influence of impulsive personality traits and DRD on disordered eating patterns and problematic drinking. One hundred and eight treatment-seeking heavy drinkers were assessed for UPPS impulsivity traits, DRD, disordered eating, alcohol use, and demographic information. With regard to disordered eating patterns, DRD predicted higher levels of Dietary Restraint and Weight and Shape Concerns. Negative Urgency predicted binge eating and Weight and Shape Concerns. Positive Urgency predicted Eating Concerns. Female sex predicted Eating, Weight, and Shape Concerns. When considering problematic alcohol use, only Negative Urgency and Sensation Seeking were predictive. This is the first study to examine both personality-based impulsivity and DRD in relation to pathological eating and drinking behavior. The results suggest the importance of disentangling the contributions of various impulsivity constructs on dysregulated eating. PMID:24816318

The role of impulsivity traits and delayed reward discounting in dysregulated eating and drinking among heavy drinkers.

PubMed

Stojek, Monika M; Fischer, Sarah; Murphy, Cara M; MacKillop, James

2014-09-01

Impulsivity is a multifaceted construct that has been linked to dysregulated eating and problematic alcohol use. The UPPS model identifies five personality-based impulsivity traits that have unique predictive utility: Negative Urgency, Perseverance, Premeditation, Sensation Seeking, and Positive Urgency. Delayed reward discounting (DRD) is an index of impulsive decision making characterized by preference for smaller immediate gains at the cost of larger delayed gains. In the current study, we sought to refine the influence of impulsive personality traits and DRD on disordered eating patterns and problematic drinking. One hundred and eight treatment-seeking heavy drinkers were assessed for UPPS impulsivity traits, DRD, disordered eating, alcohol use, and demographic information. With regard to disordered eating patterns, DRD predicted higher levels of Dietary Restraint and Weight and Shape Concerns. Negative Urgency predicted binge eating and Weight and Shape Concerns. Positive Urgency predicted Eating Concerns. Female sex predicted Eating, Weight, and Shape Concerns. When considering problematic alcohol use, only Negative Urgency and Sensation Seeking were predictive. This is the first study to examine both personality-based impulsivity and DRD in relation to pathological eating and drinking behavior. The results suggest the importance of disentangling the contributions of various impulsivity constructs on dysregulated eating. Copyright © 2014. Published by Elsevier Ltd.

Proteolysis targeting peptide (PROTAP) strategy for protein ubiquitination and degradation.

PubMed

Zheng, Jing; Tan, Chunyan; Xue, Pengcheng; Cao, Jiakun; Liu, Feng; Tan, Ying; Jiang, Yuyang

2016-02-19

Ubiquitination proteasome pathway (UPP) is the most important and selective way to degrade proteins in vivo. Here, a novel proteolysis targeting peptide (PROTAP) strategy, composed of a target protein binding peptide, a linker and a ubiquitin E3 ligase recognition peptide, was designed to recruit both target protein and E3 ligase and then induce polyubiquitination and degradation of the target protein through UPP. In our study, the PROTAP strategy was proved to be a general method with high specificity using Bcl-xL protein as model target in vitro and in cells, which indicates that the strategy has great potential for in vivo application. Copyright © 2016 Elsevier Inc. All rights reserved.

Multi-targeted priming for genome-wide gene expression assays.

PubMed

Adomas, Aleksandra B; Lopez-Giraldez, Francesc; Clark, Travis A; Wang, Zheng; Townsend, Jeffrey P

2010-08-17

Complementary approaches to assaying global gene expression are needed to assess gene expression in regions that are poorly assayed by current methodologies. A key component of nearly all gene expression assays is the reverse transcription of transcribed sequences that has traditionally been performed by priming the poly-A tails on many of the transcribed genes in eukaryotes with oligo-dT, or by priming RNA indiscriminately with random hexamers. We designed an algorithm to find common sequence motifs that were present within most protein-coding genes of Saccharomyces cerevisiae and of Neurospora crassa, but that were not present within their ribosomal RNA or transfer RNA genes. We then experimentally tested whether degenerately priming these motifs with multi-targeted primers improved the accuracy and completeness of transcriptomic assays. We discovered two multi-targeted primers that would prime a preponderance of genes in the genomes of Saccharomyces cerevisiae and Neurospora crassa while avoiding priming ribosomal RNA or transfer RNA. Examining the response of Saccharomyces cerevisiae to nitrogen deficiency and profiling Neurospora crassa early sexual development, we demonstrated that using multi-targeted primers in reverse transcription led to superior performance of microarray profiling and next-generation RNA tag sequencing. Priming with multi-targeted primers in addition to oligo-dT resulted in higher sensitivity, a larger number of well-measured genes and greater power to detect differences in gene expression. Our results provide the most complete and detailed expression profiles of the yeast nitrogen starvation response and N. crassa early sexual development to date. Furthermore, our multi-targeting priming methodology for genome-wide gene expression assays provides selective targeting of multiple sequences and counter-selection against undesirable sequences, facilitating a more complete and precise assay of the transcribed sequences within the genome.

Using the CRISPR/Cas9 system to eliminate native plasmids of Zymomonas mobilis ZM4.

PubMed

Cao, Qing-Hua; Shao, Huan-Huan; Qiu, Hui; Li, Tao; Zhang, Yi-Zheng; Tan, Xue-Mei

2017-03-01

The CRISPR/Cas system can be used to simply and efficiently edit the genomes of various species, including animals, plants, and microbes. Zymomonas mobilis ZM4 is a highly efficient, ethanol-producing bacterium that contains five native plasmids. Here, we constructed the pSUZM2a-Cas9 plasmid and a single-guide RNA expression plasmid. The pSUZM2a-Cas9 plasmid was used to express the Cas9 gene cloned from Streptococcus pyogenes CICC 10464. The single-guide RNA expression plasmid pUC-T7sgRNA, with a T7 promoter, can be used for the in vitro synthesis of single-guide RNAs. This system was successfully employed to knockout the upp gene of Escherichia coli and the replicase genes of native Z. mobilis plasmids. This is the first study to apply the CRISPR/Cas9 system of S. pyogenes to eliminate native plasmids in Z. mobilis. It provides a new method for plasmid curing and paves the way for the genomic engineering of Z. mobilis.

Rapid emergence and mechanisms of resistance by U87 glioblastoma cells to doxorubicin in an in vitro tumor microfluidic ecology

NASA Astrophysics Data System (ADS)

Austin, Robert; Lee, Sanghyuk; Park, Sungsu

We have developed a microfluidic device consisting of approximately 500 hexagonal micro-compartments which provides a complex ecology with wide ranges of drug and nutrient gradients and local populations. This ecology of a fragmented metapopulation induced the drug resistance in stage IV U87 glioblastoma cells to doxorubicin in seven days. Exome and transcriptome sequencing of the resistant cells identified mutations and differentially expressed genes. Gene ontology and pathway analyses of the genes identified showed that they were functionally relevant with the established mechanisms of doxorubicin action. Functional experiments support the in silico analyses and together demonstrate the effects of these genetic changes. Our findings suggest that given the rapid evolution of resistance and the focused response, this technology could act as a rapid screening modality for genetic aberrations leading to resistance to chemotherapy as well as counter-selection of drugs unlikely to be successful ultimately. Technology Innovation Program of the Ministry of Trade, Industry and Energy, Republic of Korea (10050154 to S.L. and S.P.), the National Research Foundation of Korea (NRF-2014M3C9A3065221 to S.L., NRF-2015K1A4A3047851 to J.K. and S.L.) funded by the Minis.

Brain Structural Differences between Normal and Obese Adults and their Links with Lack of Perseverance, Negative Urgency, and Sensation Seeking.

PubMed

Wang, Haifeng; Wen, Baohong; Cheng, Jingliang; Li, Hongpeng

2017-01-16

In order to examine the difference in brain structure between obese and normal weight individuals, and to explore the relationship between the neuroanatomical changes and impulsivity traits, this study used a voxel-based morphometry method to examine gray matter (GM) volume alterations related to impulsive personality traits in obese individuals relative to normal weight. Eighty adults that completed the UPPS-P Impulsive Behavior Scale were analyzed. Possible GM volume alterations were first analyzed at the whole brain level, and then the relationship between regional GM volume differences and UPPS-P scores were examined in selected regions of interest. Reduced GM volumes were found in the frontal and limbic regions in the obese group compared to normal weight individuals. In the normal weight group, lack of perseverance was negatively correlated with GM volume in the anterior cingulate cortex, and negative urgency was negatively correlated with GM volume in the insula. In the obese group, sensation seeking was negatively correlated with GM volume in the left amygdala and right pallidum. These findings might improve our understanding of the relationship between lack of perseverance, negative urgency, and sensation seeking and body weight fluctuations.

Brain Structural Differences between Normal and Obese Adults and their Links with Lack of Perseverance, Negative Urgency, and Sensation Seeking

PubMed Central

Wang, Haifeng; Wen, Baohong; Cheng, Jingliang; Li, Hongpeng

2017-01-01

In order to examine the difference in brain structure between obese and normal weight individuals, and to explore the relationship between the neuroanatomical changes and impulsivity traits, this study used a voxel-based morphometry method to examine gray matter (GM) volume alterations related to impulsive personality traits in obese individuals relative to normal weight. Eighty adults that completed the UPPS-P Impulsive Behavior Scale were analyzed. Possible GM volume alterations were first analyzed at the whole brain level, and then the relationship between regional GM volume differences and UPPS-P scores were examined in selected regions of interest. Reduced GM volumes were found in the frontal and limbic regions in the obese group compared to normal weight individuals. In the normal weight group, lack of perseverance was negatively correlated with GM volume in the anterior cingulate cortex, and negative urgency was negatively correlated with GM volume in the insula. In the obese group, sensation seeking was negatively correlated with GM volume in the left amygdala and right pallidum. These findings might improve our understanding of the relationship between lack of perseverance, negative urgency, and sensation seeking and body weight fluctuations. PMID:28091559

Identification of the Actinobacillus pleuropneumoniae Leucine-Responsive Regulatory Protein and Its Involvement in the Regulation of In Vivo-Induced Genes▿

PubMed Central

Wagner, Trevor K.; Mulks, Martha H.

2007-01-01

Actinobacillus pleuropneumoniae is a gram-negative bacterial pathogen that causes a severe hemorrhagic pneumonia in swine. We have previously shown that the limitation of branched-chain amino acids (BCAAs) is a cue that induces the expression of a subset of A. pleuropneumoniae genes identified as specifically induced during infection of the natural host animal by using an in vivo expression technology screen. Leucine-responsive regulatory protein (Lrp) is a global regulator and has been shown in Escherichia coli to regulate many genes, including genes involved in BCAA biosynthesis. We hypothesized that A. pleuropneumoniae contains a regulator similar to Lrp and that this protein is involved in the regulation of a subset of genes important during infection and recently shown to have increased expression in the absence of BCAAs. We report the identification of an A. pleuropneumoniae serotype 1 gene encoding a protein with similarity to amino acid sequence and functional domains of other reported Lrp proteins. We further show that purified A. pleuropneumoniae His6-Lrp binds in vitro to the A. pleuropneumoniae promoter regions for ilvI, antisense cps1AB, lrp, and nqr. A genetically defined A. pleuropneumoniae lrp mutant was constructed using an allelic replacement and sucrose counterselection method. Analysis of expression from the ilvI and antisense cps1AB promoters in wild-type, lrp mutant, and complemented lrp mutant strains indicated that Lrp is required for induction of expression of ilvI under BCAA limitation. PMID:17060463

Scarless genome editing and stable inducible expression vectors for Geobacter sulfurreducens

DOE PAGES

Chan, Chi Ho; Levar, Caleb E.; Zacharoff, Lori; ...

2015-08-07

Metal reduction by members of the Geobacteraceae is encoded by multiple gene clusters, and the study of extracellular electron transfer often requires biofilm development on surfaces. Genetic tools that utilize polar antibiotic cassette insertions limit mutant construction and complementation. In addition, unstable plasmids create metabolic burdens that slow growth, and the presence of antibiotics such as kanamycin can interfere with the rate and extent of Geobacter biofilm growth. We report here genetic system improvements for the model anaerobic metal-reducing bacterium Geobacter sulfurreducens. A motile strain of G. sulfurreducens was constructed by precise removal of a transposon interrupting the fgrM flagellarmore » regulator gene using SacB/sucrose counterselection, and Fe(III) citrate reduction was eliminated by deletion of the gene encoding the inner membrane cytochrome imcH. We also show that RK2-based plasmids were maintained in G. sulfurreducens for over 15 generations in the absence of antibiotic selection in contrast to unstable pBBR1 plasmids. Therefore, we engineered a series of new RK2 vectors containing native constitutive Geobacter promoters, and modified one of these promoters for VanR-dependent induction by the small aromatic carboxylic acid vanillate. Inducible plasmids fully complemented Δ imcH mutants for Fe(III) reduction, Mn(IV) oxide reduction, and growth on poised electrodes. A real-time, high-throughput Fe(III) citrate reduction assay is described that can screen numerous G. sulfurreducens strain constructs simultaneously and shows the sensitivity of imcH expression by the vanillate system. Lastly, these tools will enable more sophisticated genetic studies in G. sulfurreducens without polar insertion effects or need for multiple antibiotics.« less

The efficacy of Motivational Intervention and Cognitive-Behavioral Therapy for Pathological Gambling.

PubMed

Garcia-Caballero, Anna; Torrens-Lluch, Marina; Ramírez-Gendrau, Isabel; Garrido, Gemma; Vallès, Vicenç; Aragay, Núria

2018-01-15

The aim of the current study is to determine the effectiveness of an individual psychological intervention based on the motivational interview and cognitive-behavioral therapy for the treatment of pathological gambling. A sample of 18 participants, diagnosed of pathological gambling and without any other associated comorbidity, were assessed, attended at the publicly-funded Gambling and Behavioral Addictions Unit (Consorci Sanitari de Terrassa). Median age was 46 years (SD = 12). All the patients achieved abstinence and completed follow-up. The Screen for Gambling Problems (NODS), Quality of Life Enjoyment and Satisfaction (Q-LES-Q), Impulsive Behavior Scale (UPPS-P), Sheehan Disability Inventory (SDI), Beck Depression Inventory (BDI) and State-Trait Anxiety Inventory (STAI) were administered pre- and posttreatment. Results showed that patients significantly reduced the problems related to gambling behavior according to the NODS score (p < .000). Regarding impulsive behavior (UPPS-P), we found significant differences in negative urgency (p < .001), positive urgency (p < .001), (lack of) premeditation (p < .029) and (lack of) perseverance (p < .048). Some relevant aspects of quality of life as assessed by the Q-LES-Q had improved. In conclusion, the study shows that psychological intervention based on the motivational interview and cognitive-behavioral therapy not only significantly reduces gambling-related behavior problems but also leads to improvements in impulsivity and quality of life. .

A RecET-assisted CRISPR-Cas9 genome editing in Corynebacterium glutamicum.

PubMed

Wang, Bo; Hu, Qitiao; Zhang, Yu; Shi, Ruilin; Chai, Xin; Liu, Zhe; Shang, Xiuling; Zhang, Yun; Wen, Tingyi

2018-04-23

Extensive modification of genome is an efficient manner to regulate the metabolic network for producing target metabolites or non-native products using Corynebacterium glutamicum as a cell factory. Genome editing approaches by means of homologous recombination and counter-selection markers are laborious and time consuming due to multiple round manipulations and low editing efficiencies. The current two-plasmid-based CRISPR-Cas9 editing methods generate false positives due to the potential instability of Cas9 on the plasmid, and require a high transformation efficiency for co-occurrence of two plasmids transformation. Here, we developed a RecET-assisted CRISPR-Cas9 genome editing method using a chromosome-borne Cas9-RecET and a single plasmid harboring sgRNA and repair templates. The inducible expression of chromosomal RecET promoted the frequencies of homologous recombination, and increased the efficiency for gene deletion. Due to the high transformation efficiency of a single plasmid, this method enabled 10- and 20-kb region deletion, 2.5-, 5.7- and 7.5-kb expression cassette insertion and precise site-specific mutation, suggesting a versatility of this method. Deletion of argR and farR regulators as well as site-directed mutation of argB and pgi genes generated the mutant capable of accumulating L-arginine, indicating the stability of chromosome-borne Cas9 for iterative genome editing. Using this method, the model-predicted target genes were modified to redirect metabolic flux towards 1,2-propanediol biosynthetic pathway. The final engineered strain produced 6.75 ± 0.46 g/L of 1,2-propanediol that is the highest titer reported in C. glutamicum. Furthermore, this method is available for Corynebacterium pekinense 1.563, suggesting its universal applicability in other Corynebacterium species. The RecET-assisted CRISPR-Cas9 genome editing method will facilitate engineering of metabolic networks for the synthesis of interested bio-based products from renewable biomass using Corynebacterium species as cell factories.

Impulsivity and sexual assault in college men.

PubMed

Mouilso, Emily R; Calhoun, Karen S; Rosenbloom, Thomas G

2013-01-01

Although impulsivity has been consistently linked to perpetration of sexual aggression, results lack clarity because they do not account for the substantial heterogeneity associated with the construct. The UPPS-P model (Lynam, Smith, Whiteside, & Cyders, 2006), which was proposed to clarify the multidimensional nature of impulsivity, has yet to be applied to sexual aggression. We measured UPPS-P Impulsivity in a sample of male college students who also self-reported on perpetration of sexual aggression. As predicted, impulsivity distinguished perpetrators from nonperpetrators. Perpetrators scored higher than non-perpetrators on Negative Urgency, Positive Urgency, and lack of Premeditation. Results suggest that the impulsivity traits most relevant to sexual aggression are the tendency to act impulsively when experiencing intense emotions (Positive and Negative Urgency) and lack of forethought and planning (lack of Premeditation).

Open-label study evaluating outpatient urethral sphincter injections of onabotulinumtoxinA to treat women with urinary retention due to a primary disorder of sphincter relaxation (Fowler's syndrome).

PubMed

Panicker, Jalesh N; Seth, Jai H; Khan, Shahid; Gonzales, Gwen; Haslam, Collette; Kessler, Thomas M; Fowler, Clare J

2016-05-01

To assess the efficacy (defined as improvements in maximum urinary flow rate [Qmax ] of ≥50%, post-void residual urine volume [PVR] and scores on the International Prostate Symptom Score [IPSS] questionnaire) and safety of urethral sphincter injections of onabotulinumtoxinA in women with a primary disorder of urethral sphincter relaxation, characterised by an elevated urethral pressure profile (UPP) and specific findings at urethral sphincter electromyography (EMG), i.e. Fowler's syndrome. In this open-label pilot Institutional Review Board-approved study, 10 women with a primary disorder of urethral sphincter relaxation (elevated UPP, sphincter volume, and abnormal EMG) presenting with obstructed voiding (five) or in complete urinary retention (five) were recruited from a single tertiary referral centre. Baseline symptoms were assessed using the IPSS, and Qmax and PVR were measured. After 2% lidocaine injection, 100 U of onabotulinumtoxinA was injected into the striated urethral sphincter, divided on either side, under EMG guidance. Patients were reviewed at 1, 4 and 10 weeks after injection, and assessed using the IPSS, Qmax and PVR measurements. The UPP was repeated at week 4. The mean (range) patient age was 40 (25-65) years, and the mean symptom scores on the IPSS improved from 25.6 to 14.1, and the mean 'bother' score reduced from 6.1 to 3.5 at week 10. As compared with a baseline mean Qmax of 8.12 mL/s in the women who could void, the Qmax improved to 15.8 mL/s at week 10. Four of the five women in complete retention could void spontaneously, with a mean Qmax of 14.3 mL/s at week 10. The mean PVR decreased from 260 to 89 mL and the mean static UPP improved from 113 cmH2 O at baseline to 90 cmH2 O. No serious side-effects were reported. Three women with a history of recurrent urinary tract infections developed a urinary tract infection. There were no reports of stress urinary incontinence. Seven of the 10 women opted to return for repeat injections. This pilot study shows an improvement in patient-reported lower urinary tract symptoms, and the objective parameters of Qmax , PVR and UPP, at 10 weeks after urethral sphincter injections of onabotulinumtoxinA. No serious side-effects were reported. This treatment could represent a safe outpatient treatment for young women in retention due to a primary disorder of urethral sphincter relaxation. However, a larger study is required to confirm the findings of this pilot study. © 2015 The Authors BJU International © 2015 BJU International Published by John Wiley & Sons Ltd.

Spinosad resistance in female Musca domestica L. from a field-derived population.

PubMed

Markussen, Mette D K; Kristensen, Michael

2012-01-01

Bait-formulated spinosad is currently being introduced for housefly (Musca domestica L.) control around the world. Spinosad resistance was evaluated in a multiresistant field population and strains derived from this by selection with insecticides. Constitutive and spinosad-induced expression levels of three cytochrome P450 genes, CYP6A1, CYP6D1 and CYP6D3, previously reported to be involved in insecticide resistance, were examined. In 2004 a baseline for spinosad toxicity of Danish houseflies where all field populations were considered to be susceptible was established. In the present study, females of a multiresistant field population 791a were, however, 27-fold spinosad resistant at LC(50), whereas 791a male houseflies were susceptible. Strain 791a was selected with spinosad, thiamethoxam, fipronil and imidacloprid, resulting in four strains with individual characteristics. Selection of 791a with spinosad did not alter spinosad resistance in either males or females, but counterselected against resistance to the insecticides thiamethoxam and imidacloprid targeting nicotinic acetylcholine receptors. A synergist study with piperonyl butoxide, as well as gene expression studies of CYP6A1, CYP6D1 and CYP6D3, indicated a partial involvement of cytochrome P450 genes in spinosad resistance. This study reports female-linked spinosad resistance in Danish houseflies. Negative cross-resistance was observed between spinosad and neonicotinoids in one multiresistant housefly strain. Spinosad resistance involved alterations of cytochrome P450 gene expression. Copyright © 2011 Society of Chemical Industry.

Dimensions of impulsivity in relation to eating disorder recovery.

PubMed

Bardone-Cone, Anna M; Butler, Rachel M; Balk, Margaret R; Koller, Katherine A

2016-11-01

Impulsivity is associated with eating pathology, but different dimensions of impulsivity have not been extensively studied in the eating disorders. The current study examined the relationship between four facets of impulsivity and eating disorder recovery status. Females formerly seen for an eating disorder were categorized as having an eating disorder (n = 53), partially recovered (n = 15), or fully recovered (n = 20) based on a diagnostic interview and physical, behavioral, and psychological indices. These groups and non-eating disorder controls were compared on impulsivity facets from the UPPS Impulsive Behavior Scale (UPPS): Urgency (negative urgency), Premeditation (lack of), Perseverance (lack of), and Sensation Seeking. Negative urgency (the tendency to engage in impulsive behavior to alleviate negative affect) was related to recovery. The fully recovered group and controls experienced significantly less negative urgency than those with a current eating disorder; the partially recovered group did not differ from the eating disorder group. Findings suggest that negative urgency may be a particularly important facet of impulsivity to target in therapeutic intervention for eating disorders, especially among those with a history of binge eating and/or purging. Future longitudinal work is needed to test a potential causal relationship between negative urgency and eating disorder recovery. © 2016 Wiley Periodicals, Inc. (Int J Eat Disord 2016; 49:1027-1031). © 2016 Wiley Periodicals, Inc.

Genomic localization of the Z/EG transgene in the mouse genome.

PubMed

Colombo, Sophie; Kumasaka, Mayuko; Lobe, Corrinne; Larue, Lionel

2010-02-01

The Z/EG transgenic mouse line, produced by Novak et al., displays tissue-specific EGFP expression after Cre-mediated recombination. The autofluorescence of EGFP allows the visualization of cells of interest displaying Cre recombination. The initial construct was designed such that cells without Cre recombination express the beta-galactosidase marker, facilitating counterselection. We used inverse PCR to identify the site of integration of the Z/EG transgene, to improve the efficiency of homozygous Z/EG mouse production. Recombined cells produced large amounts of EGFP protein, resulting in higher levels of fluorescence and therefore greater contrast with nonrecombined cells. We mapped the transgene to the G1 region of chromosome 5. This random insertion was found to have occurred 230-bp upstream from the start codon of the Rasa4 gene. The insertion of the Z/EG transgene in the C57BL/6 genetic background had no effect on Rasa4 expression. Homozygous Z/EG mice therefore had no obvious phenotype. (c) 2009 Wiley-Liss, Inc.

High-efficiency genome editing and allele replacement in prototrophic and wild strains of Saccharomyces.

PubMed

Alexander, William G; Doering, Drew T; Hittinger, Chris Todd

2014-11-01

Current genome editing techniques available for Saccharomyces yeast species rely on auxotrophic markers, limiting their use in wild and industrial strains and species. Taking advantage of the ancient loss of thymidine kinase in the fungal kingdom, we have developed the herpes simplex virus thymidine kinase gene as a selectable and counterselectable marker that forms the core of novel genome engineering tools called the H: aploid E: ngineering and R: eplacement P: rotocol (HERP) cassettes. Here we show that these cassettes allow a researcher to rapidly generate heterogeneous populations of cells with thousands of independent chromosomal allele replacements using mixed PCR products. We further show that the high efficiency of this approach enables the simultaneous replacement of both alleles in diploid cells. Using these new techniques, many of the most powerful yeast genetic manipulation strategies are now available in wild, industrial, and other prototrophic strains from across the diverse Saccharomyces genus. Copyright © 2014 by the Genetics Society of America.

[EFFECTIVENESS OF PREPERITONEAL HERNIORRHAPHY WITH Ultrapro Plug MESH FOR UMBILICAL HERNIA REPAIR IN ADULTS].

PubMed

Xie, Yanyan; Ma, Dongyang; Song, Yinghan; Lu, Anqing; Wang, Menghong; Lei, Wenzhang

2016-06-08

To explore the effectiveness of preperitoneal herniorrhaphy with Ultrapro Plug (UPP) mesh for umbilical hernia repair in adults. Between September 2011 and June 2015, 71 patients with umbilical hernia underwent preperitoneal herniorrhaphy with UPP mesh. There were 26 males and 45 females, aged 19-92 years (mean, 54.3 years). The disease duration was 45 days to 30 years (median, 18 months). Umbilical hernia was diagnosed through physical examination, ultrasound, and other relevant auxiliary examination. According to American Society of Anesthesiologists (ASA) classification, 12 cases were rated as grade Ⅰ, 34 cases as grade Ⅱ, 21 cases as grade Ⅲ, and 4?cases as grade Ⅳ. The operation time, postoperative hospitalization time, complication, and recurrence were recorded. The diameter of hernia ring ranged 0.5-3.0 cm (mean, 1.8 cm). There was no vessel or intestine injury. The operation time was 12-35 minutes (mean, 22.4 minutes); postoperative hospitalization time was 12-48 hours (mean, 16.3 hours). Fat liquefaction of incision occurred in 2 cases, and primary healing of incision was obtained in the other cases. Sixty-nine patients were followed up 8-51 months (median, 28 months). Hernia recurrence and patch infection occurred in 1 case respectively during follow-up. No postoperative foreign body sensation and chronic pain occurred. Repairing umbilical hernia in adults with UPP mesh should be safe and reliable, because it has the advantages of short operation time, short hospital stay, less complication, and lower incidence of recurrence.

Oversize/overweight vehicle unified permitting process (UPP) : phase I.

DOT National Transportation Integrated Search

2017-08-01

Multiple jurisdictions within Minnesota process oversize/overweight (OSOW) permits for the movement of freight on state roadways, county roads, and municipal and township streets. Movement of freight has increased in recent years to help support econ...

In vitro prebiotic effects of seaweed polysaccharides

NASA Astrophysics Data System (ADS)

Chen, Xiaolin; Sun, Yuhao; Hu, Linfeng; Liu, Song; Yu, Huahua; Xing, Rong'e.; Li, Rongfeng; Wang, Xueqin; Li, Pengcheng

2017-09-01

Although prebiotic activities of alginate and agar oligosaccharides isolated from seaweeds have been reported, it remains unknown whether seaweed polysaccharides have prebiotic activity. In this study, we isolated polysaccharides from four species of seaweeds, such as Grateloupia filicina (GFP), Eucheuma spinosum (ESP), Ulva pertusa (UPP), and Ascophyllum nodosum (ANP), and characterized their structures and prebiotic effects in vitro. The results showed that these polysaccharides were different in total sugar and sulfate contents as well as monosaccharide composition. GFP and ESP significantly promoted bifidobacterium proliferation and 0.1% ESP and 0.4% GFP resulted in the highest proliferation rates of beneficial bacteria, whereas UPP and ANP inhibited the growth of beneficial bacteria at all tested concentrations (0.1%-0.5%). The different behaviors of the four seaweed-originated polysaccharides might be reflected by differences in monosaccharide composition and structure. Therefore, polysaccharides isolated from GFP and ESP could be utilized as prebiotics. However, more studies must be carried out in vivo.

Bacterial Cell Growth Inhibitors Targeting Undecaprenyl Diphosphate Synthase and Undecaprenyl Diphosphate Phosphatase.

PubMed

Wang, Yang; Desai, Janish; Zhang, Yonghui; Malwal, Satish R; Shin, Christopher J; Feng, Xinxin; Sun, Hong; Liu, Guizhi; Guo, Rey-Ting; Oldfield, Eric

2016-10-19

We synthesized a series of benzoic acids and phenylphosphonic acids and investigated their effects on the growth of Staphylococcus aureus and Bacillus subtilis. One of the most active compounds, 5-fluoro-2-(3-(octyloxy)benzamido)benzoic acid (7, ED 50 ∼0.15 μg mL -1 ) acted synergistically with seven antibiotics known to target bacterial cell-wall biosynthesis (a fractional inhibitory concentration index (FICI) of ∼0.35, on average) but had indifferent effects in combinations with six non-cell-wall biosynthesis inhibitors (average FICI∼1.45). The most active compounds were found to inhibit two enzymes involved in isoprenoid/bacterial cell-wall biosynthesis: undecaprenyl diphosphate synthase (UPPS) and undecaprenyl diphosphate phosphatase (UPPP), but not farnesyl diphosphate synthase, and there were good correlations between bacterial cell growth inhibition, UPPS inhibition, and UPPP inhibition. © 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Transposon Invasion of the Paramecium Germline Genome Countered by a Domesticated PiggyBac Transposase and the NHEJ Pathway

PubMed Central

Dubois, Emeline; Bischerour, Julien; Marmignon, Antoine; Mathy, Nathalie; Régnier, Vinciane; Bétermier, Mireille

2012-01-01

Sequences related to transposons constitute a large fraction of extant genomes, but insertions within coding sequences have generally not been tolerated during evolution. Thanks to their unique nuclear dimorphism and to their original mechanism of programmed DNA elimination from their somatic nucleus (macronucleus), ciliates are emerging model organisms for the study of the impact of transposable elements on genomes. The germline genome of the ciliate Paramecium, located in its micronucleus, contains thousands of short intervening sequences, the IESs, which interrupt 47% of genes. Recent data provided support to the hypothesis that an evolutionary link exists between Paramecium IESs and Tc1/mariner transposons. During development of the macronucleus, IESs are excised precisely thanks to the coordinated action of PiggyMac, a domesticated piggyBac transposase, and of the NHEJ double-strand break repair pathway. A PiggyMac homolog is also required for developmentally programmed DNA elimination in another ciliate, Tetrahymena. Here, we present an overview of the life cycle of these unicellular eukaryotes and of the developmentally programmed genome rearrangements that take place at each sexual cycle. We discuss how ancient domestication of a piggyBac transposase might have allowed Tc1/mariner elements to spread throughout the germline genome of Paramecium, without strong counterselection against insertion within genes. PMID:22888464

Exploring associations between self-regulatory mechanisms and neuropsychological functioning and driver behaviour after brain injury.

PubMed

Rike, Per-Ola; Johansen, Hans J; Ulleberg, Pål; Lundqvist, Anna; Schanke, Anne-Kristine

2018-04-01

The objective of this prospective one-year follow-up study was to explore the associations between self-regulatory mechanisms and neuropsychological tests as well as baseline and follow-up ratings of driver behaviour. The participants were a cohort of subjects with stroke and traumatic brain injury (TBI) who were found fit to drive after a multi-disciplinary driver assessment (baseline). Baseline measures included neuropsychological tests and ratings of self-regulatory mechanisms, i.e., executive functions (Behavior Rating Inventory of Executive Function-Adult Version; BRIEF-A) and impulsive personality traits (UPPS Impulsive Behavior Scale). The participants rated pre-injury driving behaviour on the Driver Behaviour Qestionnaire (DBQ) retrospectively at baseline and after one year of post-injury driving (follow-up). Better performance on neuropsychological tests was significantly associated with more post-injury DBQ Violations. The BRIEF-A main indexes were significantly associated with baseline and follow-up ratings of DBQ Mistakes and follow-up DBQ Inattention. UPPS (lack of) Perseverance was significantly associated with baseline DBQ Inattention, whereas UPPS Urgency was significantly associated with baseline DBQ Inexperience and post-injury DBQ Mistakes. There were no significant changes in DBQ ratings from baseline (pre-injury) to follow-up (post-injury). It was concluded that neuropsychological functioning and self-regulatory mechanisms are related to driver behaviour. Some aspects of driver behaviour do not necessarily change after brain injury, reflecting the influence of premorbid driving behaviour or impaired awareness of deficits on post-injury driving behaviour. Further evidence is required to predict the role of self-regulatory mechanisms on driver behaviour and crashes or near misses.

Measurement of Dynamic Urethral Pressures with a High Resolution Manometry System in Continent and Incontinent Women

PubMed Central

Kirby, Anna C; Tan-Kim, Jasmine; Nager, Charles W.

2015-01-01

Objectives Female stress urinary incontinence (SUI) is caused by urethral dysfunction during dynamic conditions, but current technology has limitations in measuring urethral pressures under dynamic conditions. An 8-French high resolution manometry catheter (HRM) currently in clinical use in gastroenterology may accurately measure urethral pressures under dynamic conditions because it has a 25ms response rate and circumferential pressure sensors along the length of the catheter (ManoScan® ESO, Given Imaging). We evaluated the concordance, repeatability, and tolerability of this catheter. Methods We measured resting, cough, and strain maximum urethral closure pressures (MUCPs) using HRM and measured resting MUCPs with water perfusion side-hole catheter urethral pressure profilometry (UPP) in 37 continent and 28 stress incontinent subjects. Maneuvers were repeated after moving the HRM catheter along the urethral length to evaluate whether results depend on catheter positioning. Visual analog pain scores evaluated the comfort of HRM compared to UPP. Results The correlation coefficient for resting MUCPs measured by HRM vs. UPP was high (r = 0.79, p<0.001). Repeatability after catheter repositioning was high for rest, cough, and strain with HRM: r= 0.92, 0.89, and 0.89. Mean MUCPs (rest, cough, strain) were higher in continent than incontinent subjects (all p < 0.001) and decreased more in incontinent subjects than continent subjects during cough and strain maneuvers compared to rest. Conclusions This preliminary study shows that HRM is concordant with standard technology, repeatable, and well tolerated in the urethra. Incontinent women have more impairment of their urethral closure pressures during cough and strain than continent women. PMID:25185595

Measurement of dynamic urethral pressures with a high-resolution manometry system in continent and incontinent women.

PubMed

Kirby, Anna C; Tan-Kim, Jasmine; Nager, Charles W

2015-01-01

Female stress urinary incontinence is caused by urethral dysfunction during dynamic conditions, but current technology has limitations in measuring urethral pressures under these conditions. An 8-French high-resolution manometry (HRM) catheter currently in clinical use in gastroenterology may accurately measure urethral pressures under dynamic conditions because it has a 25-millisecond response rate and circumferential pressure sensors along the length of the catheter (ManoScan ESO; Given Imaging, Yoqneam, Israel). We evaluated the concordance, repeatability, and tolerability of this catheter. We measured resting, cough, and strain maximum urethral closure pressures (MUCPs) using HRM and measured resting MUCPs with water-perfusion side-hole catheter urethral pressure profilometry (UPP) in 37 continent and 28 stress-incontinent subjects. Maneuvers were repeated after moving the HRM catheter along the urethral length to evaluate whether results depend on catheter positioning. Visual analog pain scores evaluated the comfort of HRM compared to UPP. The correlation coefficient for resting MUCPs measured by HRM versus UPP was high (r = 0.79, P < 0.001). Repeatability after catheter repositioning was high for rest, cough, and strain with HRM: r = 0.92, 0.89, and 0.89. Mean MUCPs (rest, cough, and strain) were higher in continent than in incontinent subjects (all P < 0.001) and decreased more in incontinent subjects than in continent subjects during cough and strain maneuvers compared to rest. This preliminary study shows that HRM is concordant with standard technology, repeatable, and well tolerated in the urethra. Incontinent women have more impairment of their urethral closure pressures during cough and strain than continent women.

High definition urethral pressure profilometry: Evaluating a novel microtip catheter.

PubMed

Klünder, Mario; Amend, Bastian; Vaegler, Martin; Kelp, Alexandra; Feuer, Ronny; Sievert, Karl-Dietrich; Stenzl, Arnulf; Sawodny, Oliver; Ederer, Michael

2016-11-01

Urethral pressure profilometry (UPP) is used in the diagnosis of stress urinary incontinence (SUI). SUI is a significant medical, social, and economic problem, affecting about 12.5% of the population. A novel microtip catheter was developed for UPP featuring an inclination sensor and higher angular resolution compared to systems in clinical use today. Therewith, the location of each measured pressure sample can be determined and the spatial pressure distribution inside the urethra reconstructed. In order to assess the performance and plausibility of data from the microtip catheter, we compare it to data from a double balloon air charged system. Both catheters are used on sedated female minipigs. Data from the microtip catheter are processed through a signal reconstruction algorithm, plotted and compared against data from the air-charged catheter. The microtip catheter delivers results in agreement with previous comparisons of microtip and air-charged systems. It additionally provides a new level of detail in the reconstructed UPPs which may lead to new insights into the sphincter mechanism of minipigs. The ability of air-charged catheters to measure pressure circumferentially is widely considered a main advantage over microtip catheters. However, directional pressure readings can provide additional information on angular fluctuations in the urethral pressure distribution. It is shown that the novel microtip catheter in combination with a signal reconstruction algorithm delivers plausible data. It offers the opportunity to evaluate urethral structures, especially the sphincter, in context of the correct location within the anatomical location of the pelvic floor. Neurourol. Urodynam. 35:888-894, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

MTOR signaling and ubiquitin-proteosome gene expression in the preservation of fat free mass following high protein, calorie restricted weight loss

PubMed Central

2012-01-01

Caloric restriction is one of the most efficient ways to promote weight loss and is known to activate protective metabolic pathways. Frequently reported with weight loss is the undesirable consequence of fat free (lean muscle) mass loss. Weight loss diets with increased dietary protein intake are popular and may provide additional benefits through preservation of fat free mass compared to a standard protein, high carbohydrate diet. However, the precise mechanism by which a high protein diet may mitigate dietary weight loss induced reductions in fat free mass has not been fully elucidated. Maintenance of fat free mass is dependent upon nutrient stimulation of protein synthesis via the mTOR complex, although during caloric restriction a decrease (atrophy) in skeletal muscle may be driven by a homeostatic shift favouring protein catabolism. This review evaluates the relationship between the macronutrient composition of calorie restricted diets and weight loss using metabolic indicators. Specifically we evaluate the effect of increased dietary protein intake and caloric restricted diets on gene expression in skeletal muscle, particularly focusing on biosynthesis, degradation and the expression of genes in the ubiquitin-proteosome (UPP) and mTOR signaling pathways, including MuRF-1, MAFbx/atrogin-1, mTORC1, and S6K1. PMID:22974011

Understanding wireless communications in public safety : a guidebook to technology, issues, planning, and management. 2nd ed.

DOT National Transportation Integrated Search

2003-01-01

This guidebook was created to help unravel the confusing issues, terms, and options surrounding wireless communications, particularly as it involves commercially available communications services. The target audience consists of those middle and uppe...

Miniaturized high-precision piezo driven two axes stepper goniometer

NASA Astrophysics Data System (ADS)

Zhong, H.; Schwarz, A.; Wiesendanger, R.

2014-04-01

A miniaturized inertial stepper goniometer with two orthogonal axes (θ and φ axes) has been realized using four shear piezo based actuators arranged in a tetrahedral configuration tangent with a polished sapphire spherical rotor. The measured sensitivity is about 11.5 microdegree (μ°) per Volt. The smallest angular step size, achieved with a minimal peak-to-peak voltage Upp of 200 V is about 0.6 millidegree (m°). The crosstalk between both axes is below 10%. Our specific design is used to accurately position a glass fiber, but the concept can be utilized for many different applications as well.

Exoproteome and Secretome Derived Broad Spectrum Novel Drug and Vaccine Candidates in Vibrio cholerae Targeted by Piper betel Derived Compounds

PubMed Central

Barh, Debmalya; Barve, Neha; Gupta, Krishnakant; Chandra, Sudha; Jain, Neha; Tiwari, Sandeep; Leon-Sicairos, Nidia; Canizalez-Roman, Adrian; Rodrigues dos Santos, Anderson; Hassan, Syed Shah; Almeida, Síntia; Thiago Jucá Ramos, Rommel; Augusto Carvalho de Abreu, Vinicius; Ribeiro Carneiro, Adriana; de Castro Soares, Siomar; Luiz de Paula Castro, Thiago; Miyoshi, Anderson; Silva, Artur; Kumar, Anil; Narayan Misra, Amarendra; Blum, Kenneth; Braverman, Eric R.; Azevedo, Vasco

2013-01-01

Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC) for most of the pathogenic Vibrio strains. Two targets (uppP and yajC) are novel to Vibrio, and two targets (uppP and ompU) can be used to develop both drugs and vaccines (dual targets) against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species. PMID:23382822

Stress, anxiety, and depression among medical students in a multiethnic setting.

PubMed

Kulsoom, Bibi; Afsar, Nasir Ali

2015-01-01

Contemporary literature suggests that medical education might adversely affect students' mental health. Alfaisal University in Riyadh, Saudi Arabia is a developing institution; hence, there has been a concern regarding the mental well-being of the students. This study was designed to assess the traits of depression, anxiety, and stress among students in relation to potential underlying reasons. All 575 medical students across the 5 years of study participated by filling out the Depression, Anxiety, and Stress Scale-21 (DASS-21) questionnaire anonymously twice. Firstly, 2-3 weeks before a major examination (pre-examination), and secondly, during regular classes (post-examination). Correlation was sought regarding sex, year of scholarship, attendance of a premedical university preparatory program (UPP), housing, and smoking. Subjective comments from students were also obtained. A total of 76.8% and 74.9% of students participated in pre-and post-examination groups, respectively. The majority were the children of expatriate workers in Saudi Arabia, and included Arabs, South Asians, and North Americans. Prevalence of depression, anxiety, and stress was high (43%, 63%, and 41%, respectively) which reduced (to 30%, 47%, and 30%, respectively) to some extent after examinations. Saudis and those who had attended UPP had higher DASS-21 scores. Smoking and female sex predicted higher levels of "baseline" depression, anxiety, or stress. The students perceived the curriculum and schedule to be the primary causes of their high DASS-21 scores. The students had high "baseline" traits of depression, anxiety, and stress, and these were higher if an examination was near, especially among Saudis and those who had attended UPP. Smoking and female sex predicted higher levels of "baseline" depression, anxiety, or stress. Students suggested that study burden and a busy schedule were the major reasons for their high DASS-21 scores.

“ How Reliable is the Couple of WRF & VIC Models”

EPA Science Inventory

The ability of the fully coupling of Weather Research & Forecasting Model (WRF) and Variable Infiltration Capacity (VIC) model to produce hydrological and climate variables was evaluated. First, the VIC model was run by using observed meteorological data and calibrated in the Upp...

Nursing workload and occurrence of adverse events in intensive care: a systematic review.

PubMed

Oliveira, Andrea Carvalho de; Garcia, Paulo Carlos; Nogueira, Lilia de Souza

2016-01-01

To identifyevidences of the influence of nursing workload on the occurrence of adverse events (AE) in adult patients admitted to the intensive care unit (ICU). A systematic literature review was conducted in the databases MEDLINE, CINAHL, LILACS, SciELO, BDENF, and Cochrane from studies in English, Portuguese, or Spanish, published by 2015. The analyzed AE were infection, pressure ulcer (PU), patient falls, and medication errors. Of 594 potential studies, eight comprised the final sample of the review. TheNursing Activities Score (NAS; 37.5%) and the Therapeutic Intervention Scoring System(TISS; 37.5%) were the instruments most frequently used for assessing nursing workload. Six studies (75.0%) identified the influence of work overload in events of infection, PU, and medicationerrors. An investigation found that the NAS was a protective factor for PU. The nursing workload required by patients in the ICU influenced the occurrence of AE, and nurses must monitor this variable daily to ensure proper sizing of staff and safety of care. Identificar evidências sobre a influência da carga de trabalho de enfermagem na ocorrência de eventos adversos (EA) em pacientes adultos internados em Unidade de Terapia Intensiva (UTI). Revisão sistemática da literatura realizada nas bases de dados MEDLINE, CINAHL, LILACS, SciELO, BDENF e Cochrane deestudosem inglês, português ou espanhol, publicados até 2015. Os EA analisados foram infecção, úlcera por pressão (UPP), quedas e erros associados a medicamentos. Das 594 pesquisas potenciais identificadas, oito compuseram a amostra final da revisão. O NursingActivities Score -NAS (37,5%) e o TherapeuticInterventionScoring System -TISS (37,5%) foram os instrumentos mais utilizados para avaliação da carga de trabalho de enfermagem. Seis pesquisas (75,0%) identificaram influência da sobrecarga de trabalho na ocorrência de infecção, UPP e uso de medicamentos. Uma investigação identificou que o NAS foi fator de proteção para UPP. A carga de trabalho de enfermagem requerida por pacientes na UTI influenciou a ocorrência de EA, e os enfermeiros devem monitorar diariamente esta variável para garantir o correto dimensionamento da equipe e a segurança da assistência prestada.

Step-down versus outpatient psychotherapeutic treatment for personality disorders: 6-year follow-up of the Ullevål personality project

PubMed Central

2014-01-01

Background Although psychotherapy is considered the treatment of choice for patients with personality disorders (PDs), there is no consensus about the optimal level of care for this group of patients. This study reports the results from the 6-year follow-up of the Ullevål Personality Project (UPP), a randomized clinical trial comparing outpatient individual psychotherapy with a long-term step-down treatment program that included a short-term day hospital treatment followed by combined group and individual psychotherapy. Methods The UPP included 113 patients with PDs. Outcome was evaluated after 8 months, 18 months, 3 years and 6 years and was based on a wide range of clinical measures, such as psychosocial functioning, interpersonal problems, symptom severity, and axis I and II diagnoses. Results At the 6-year follow-up, there were no statistically significant differences in outcome between the treatment groups. Effect sizes ranged from medium to large for all outcome variables in both treatment arms. However, patients in the outpatient group had a marked decline in psychosocial functioning during the period between the 3- and 6-year follow-ups; while psychosocial functioning continued to improve in the step-down group during the same period. This difference between groups was statistically significant. Conclusions The findings suggest that both hospital-based long-term step-down treatment and long-term outpatient individual psychotherapy may improve symptoms and psychosocial functioning in poorly functioning PD patients. Social and interpersonal functioning continued to improve in the step-down group during the post-treatment phase, indicating that longer-term changes were stimulated during treatment. Trial registration NCT00378248. PMID:24758722

Impulsivity and Alcohol Demand in relation to Combined Alcohol and Caffeine Use

PubMed Central

Amlung, Michael; Few, Lauren R.; Howland, Jonathan; Rohsenow, Damaris J.; Metrik, Jane; MacKillop, James

2014-01-01

Problematic alcohol use among college students continues to be a prominent concern in the United States, including the growing trend of consuming caffeine with alcoholic beverages (CABs). Epidemiologically, CAB use is associated with incremental risks from drinking, although these relationships could be due to common predisposing factors rather than specifically due to CABs. This study investigated the relationship between CAB use, alcohol misuse, and person-level characteristics including impulsive personality traits, delayed reward discounting, and behavioral economic demand for alcohol use. Participants were 273 regularly drinking undergraduate students. Frequency of CAB use was assessed over the past month. A multidimensional assessment of impulsivity included the UPPS-P questionnaire and a validated, questionnaire-based measure of delayed reward discounting. Demand was assessed via a hypothetical alcohol purchase task. Frequency of CAB consumption was significantly higher in males compared to females and was also associated with higher impulsivity on the majority of the UPPS-P subscales, steeper delayed reward discounting, and greater demand for alcohol. Significant correlations between CAB use and both alcohol demand and lack of premeditation remained present after including level of alcohol misuse in partial correlations. In a hierarchical linear regression incorporating demographic, demand, and impulsivity variables, CAB frequency continued to be a significant predictor of hazardous alcohol use. These results suggest that although there are significant associations between CAB consumption and gender, impulsivity, and alcohol demand, CAB use continues to be associated with alcohol misuse after controlling for these variables. PMID:24364537

Conceptual Assessment Tool for Advanced Undergraduate Electrodynamics

ERIC Educational Resources Information Center

Baily, Charles; Ryan, Qing X.; Astolfi, Cecilia; Pollock, Steven J.

2017-01-01

As part of ongoing investigations into student learning in advanced undergraduate courses, we have developed a conceptual assessment tool for upper-division electrodynamics (E&M II): the Colorado UppeR-division ElectrodyNamics Test (CURrENT). This is a free response, postinstruction diagnostic with 6 multipart questions, an optional 3-question…

A Discovery Resource of Rare Copy Number Variations in Individuals with Autism Spectrum Disorder

PubMed Central

Prasad, Aparna; Merico, Daniele; Thiruvahindrapuram, Bhooma; Wei, John; Lionel, Anath C.; Sato, Daisuke; Rickaby, Jessica; Lu, Chao; Szatmari, Peter; Roberts, Wendy; Fernandez, Bridget A.; Marshall, Christian R.; Hatchwell, Eli; Eis, Peggy S.; Scherer, Stephen W.

2012-01-01

The identification of rare inherited and de novo copy number variations (CNVs) in human subjects has proven a productive approach to highlight risk genes for autism spectrum disorder (ASD). A variety of microarrays are available to detect CNVs, including single-nucleotide polymorphism (SNP) arrays and comparative genomic hybridization (CGH) arrays. Here, we examine a cohort of 696 unrelated ASD cases using a high-resolution one-million feature CGH microarray, the majority of which were previously genotyped with SNP arrays. Our objective was to discover new CNVs in ASD cases that were not detected by SNP microarray analysis and to delineate novel ASD risk loci via combined analysis of CGH and SNP array data sets on the ASD cohort and CGH data on an additional 1000 control samples. Of the 615 ASD cases analyzed on both SNP and CGH arrays, we found that 13,572 of 21,346 (64%) of the CNVs were exclusively detected by the CGH array. Several of the CGH-specific CNVs are rare in population frequency and impact previously reported ASD genes (e.g., NRXN1, GRM8, DPYD), as well as novel ASD candidate genes (e.g., CIB2, DAPP1, SAE1), and all were inherited except for a de novo CNV in the GPHN gene. A functional enrichment test of gene-sets in ASD cases over controls revealed nucleotide metabolism as a potential novel pathway involved in ASD, which includes several candidate genes for follow-up (e.g., DPYD, UPB1, UPP1, TYMP). Finally, this extensively phenotyped and genotyped ASD clinical cohort serves as an invaluable resource for the next step of genome sequencing for complete genetic variation detection. PMID:23275889

U.S. EPA, Pesticide Product Label, MEADOWS FLEA & TICK SPRAY, 01/12/1983

EPA Pesticide Factsheets

2011-04-14

... w.eping .. utlun,huld\\!I!I the di.p.II.lIr approxilllllt .. ly on .. foot ftom f"lt..g". <;I,r:>y botb upp.r .ud lo .... r leAf .. urf.c •• unttl visibly Wilt. Rp •• t •• n •• od ,--- ...

Combining Bayesian methods and aircraft observations to constrain the HO. + NO2 reaction rate

EPA Science Inventory

Tropospheric ozone is the third strongest greenhouse gas, and has the highest uncertainty in radiative forcing of the top five greenhouse gases. Throughout the troposphere, ozone is produced by radical oxidation of nitrogen oxides (NO,_x =NO+NO₂). In the uppe...

Shuttle OFT Level C navigation requirements

NASA Technical Reports Server (NTRS)

1980-01-01

Detailed requirements for the orbital operations computer loads, OPS 2, and OPS 8 are given. These requirements represent the total on-orbit/rendezvous navigation baseline requirements for the following principal functions: on-orbital/rendezvous navigation sequencer; on-orbit/rendezvous UPP sequencer; on-orbit rendezvous navigation; on-orbit prediction; on-orbit user parameter processing; and landing Site update.

Mechanical lifting energy consumption in work activities designed by means of the "revised NIOSH lifting equation".

PubMed

Ranavolo, Alberto; Varrecchia, Tiwana; Rinaldi, Martina; Silvetti, Alessio; Serrao, Mariano; Conforto, Silvia; Draicchio, Francesco

2017-10-07

The aims of the present work were: to calculate lifting energy consumption (LEC) in work activities designed to have a growing lifting index (LI) by means of revised NIOSH lifting equation; to evaluate the relationship between LEC and forces at the L 5 -S 1 joint. The kinematic and kinetic data of 20 workers were recorded during the execution of lifting tasks in three conditions. We computed kinetic, potential and mechanical energy and the corresponding LEC by considering three different centers of mass of: 1) the load (CoM L ); 2) the multi-segment upper body model and load together (CoM Upp+L ); 3) the whole body and load together (CoM Tot ). We also estimated compression and shear forces. Results shows that LEC calculated for CoM Upp+L and CoM Tot grew significantly with the LI and that all the lifting condition pairs are discriminated. The correlation analysis highlighted a relationship between LEC and forces that determine injuries at the L 5 -S 1 joint.

A study on uterine lymphatic anatomy for standardization of pelvic sentinel lymph node detection in endometrial cancer.

PubMed

Geppert, Barbara; Lönnerfors, Céline; Bollino, Michele; Arechvo, Anastasija; Persson, Jan

2017-05-01

To describe the anatomy of uterine lymphatic drainage following cervical or fundal tracer injection to enable standardization of a pelvic sentinel lymph node (SLN) concept in endometrial cancer (EC). A prospective consecutive study of women with EC was conducted. A fluorescent dye (Indocyanine green) was injected into the cervix (n=60) or the uterine fundus (n=30). A systematic trans- and retroperitoneal mapping of uterine lymphatic drainage was performed. Positions of the pelvic SLNs, defined by afferent lymph vessels, and lymph node metastases were compared. Two consistent lymphatic pathways with pelvic SLNs were identified irrespective of injection site; an upper paracervical pathway (UPP) with draining medial external and/or obturator lymph nodes and a lower paracervical pathway (LPP) with draining internal iliac and/or presacral lymph nodes. Bilateral display of at least one pelvic pathway following cervical and fundal injection occurred in 98% and 80% respectively (p=0.005). Bilateral display of both pelvic pathways occurred in 30% and 20% respectively (p=0.6) as the LPP was less often displayed. Nearly one third of the 19% node positive patients had metastases along the LPP. No false negative SLNs were identified. Based on uterine lymphatic anatomy a bilateral detection of at least one SLN in both the UPP and LPP should be aimed for. Absence of display of the LPP may warrant a full presacral lymphadenectomy. Although pelvic pathways and positions of SLNs are independent of the tracer injection site, cervical injection is preferable due to a higher technical success rate. Copyright © 2017 Elsevier Inc. All rights reserved.

Impulsivity and alcohol demand in relation to combined alcohol and caffeine use.

PubMed

Amlung, Michael; Few, Lauren R; Howland, Jonathan; Rohsenow, Damaris J; Metrik, Jane; MacKillop, James

2013-12-01

Problematic alcohol use among college students continues to be a prominent concern in the United States, including the growing trend of consuming caffeinated alcoholic beverages (CABs). Epidemiologically, CAB use is associated with incremental risks from drinking, although these relationships could be due to common predisposing factors rather than specifically due to CABs. This study investigated the relationship between CAB use, alcohol misuse, and person-level characteristics, including impulsive personality traits, delayed reward discounting, and behavioral economic demand for alcohol use. Participants were 273 regularly drinking undergraduate students. Frequency of CAB use was assessed over the past month. A multidimensional assessment of impulsivity included the UPPS-P questionnaire, which measures positive and negative urgency, premeditation (lack thereof), perseverance (lack thereof), and sensation seeking (Lynam, Smith, Whiteside, & Cyders, 2007), and a validated questionnaire-based measure of delayed reward discounting. Demand was assessed via a hypothetical alcohol purchase task. Frequency of CAB consumption was significantly higher in men than in women and was also associated with higher impulsivity on the majority of the UPPS-P subscales, steeper delayed reward discounting, and greater demand for alcohol. Significant correlations between CAB use and both alcohol demand and lack of premeditation remained present after including level of alcohol misuse in partial correlations. In a hierarchical linear regression incorporating demographic, demand, and impulsivity variables, CAB frequency continued to be a significant predictor of hazardous alcohol use. These results suggest that although there are significant associations between CAB consumption and gender, impulsivity, and alcohol demand, CAB use continues to be associated with alcohol misuse after controlling for these variables.

Gene introgression into Coffea arabica by way of triploid hybrids (C. arabica x C. canephora).

PubMed

Herrera, J C; Combes, M C; Cortina, H; Alvarado, G; Lashermes, P

2002-12-01

Interspecific triploid hybrid plants between the tetraploid species Coffea arabica L. and the diploid species C. canephora P. were backcrossed to C. arabica. Although characterised by a low production and an important fruit dropping, all attempted crosses (ie, 6) generated BC(1) progenies. Flow cytometric analysis of the nuclear DNA content revealed that most of the BC1 individuals were nearly tetraploid. Among the male gametes produced by the interspecific triploid hybrids, those presenting a high number of chromosomes appeared strongly favoured. Only pollen mother cells having nearly 22 chromosomes were effective, the others leading to deficient endosperm and fruit dropping. Molecular markers (ie, microsatellite and AFLP) combined with evaluations of morphological characteristics and resistance to leaf rust were applied to verify the occurrence of gene transfer from C. canephora into C. arabica, and to estimate the amount of introgression present in BC(1) individuals. The results reveal a strong deficiency in the C. canephroa alleles indicating a severe counter-selection against the introgression of genetic material from C. canephora into C. arabica by way of triploid hybrids. However, introgressants displaying desirable traits such as a high resistance to leaf rust were obtained. The low level of introgression could be an advantage by facilitating the recovery of the recurrent parent and possibly reducing the number of required backcrosses. On the other hand, this could be a limitation when attempting the transfer of a complex trait or several simply inherited traits.

Personality Correlates of Aggression: Evidence from Measures of the Five-Factor Model, UPPS Model of Impulsivity, and BIS/BAS

ERIC Educational Resources Information Center

Miller, Joshua D.; Zeichner, Amos; Wilson, Lauren F.

2012-01-01

Although many studies of personality and aggression focus on multidimensional traits and higher order personality disorders (e.g., psychopathy), lower order, unidimensional traits may provide more precision in identifying specific aspects of personality that relate to aggression. The current study includes a comprehensive measurement of lower…

Evaluation of Flammability of Footwear Upper Materials. Patent and Regular Shoe Upper Leather vs. Porvair and Clarino Poromerics

DTIC Science & Technology

1984-09-01

leather is thus designated ŗ-ounce leather." -ll specimens, except the UL, had high-gloss polyurethane finishes. The UL ’eLi wr contained a...ITT Research Institute, October 1965, p. 18. 4.4 %d :i.bie 2. Comparativ ~e heat transfer values of shoe uppe materials vs. shoe upper materials with

Spanish validation of the Domain-Specific Risk-Taking (DOSPERT-30) Scale.

PubMed

Lozano, Luis M; Megías, Alberto; Catena, Andrés; Perales, José C; Baltruschat, Sabina; Cándido, Antonio

2017-02-01

The aim of the present study was to develop and validate a Spanish version of the short Domain-Specific Risk-Taking (DOSPERT-30) scale, measuring risk-taking behavior, risk perception, and expected beneficial consequences (from taking risks) in five life domains: ethics, finance, health/security, recreational, and social decisions. The scale was back-translated, and administered online to 826 participants. Validity evidence was tested using correlations with construct-related instruments (UPPS-P and SSS-V), as well as using factor analysis. Internal consistency reliability was calculated with the ordinal Alpha coefficient, and gender differences were considered. Internal consistency was good, and factor analysis confirmed the five factors proposed by the authors. With respect to the external validity, high correlations with the positive urgency and the sensation seeking subscales of the UPPS-P, as well as with the thrill and adventure seeking and disinhibition subscales of the SSS-V were found. Finally, gender differences were found in all subscales and domains, with men tending to take more risks, perceive less risk and expect more beneficial consequences, except for the social domain where an inverse pattern was found. As these findings are in line with the original version, they indicate the scale was successfully adapted.

A multidimensional approach of impulsivity in adult attention deficit hyperactivity disorder.

PubMed

Lopez, Régis; Dauvilliers, Yves; Jaussent, Isabelle; Billieux, Joël; Bayard, Sophie

2015-06-30

We aimed to compare adult patients with attention deficit hyperactivity disorder (ADHD) and matched controls on four dimensions of impulsivity (urgency, lack of premeditation, lack of perseverance, and sensation seeking) and to examine the association between impulsivity and ADHD symptoms. The study was conducted on 219 participants: 72 adult ADHD patients and 147 aged and gender matched controls. All participants completed questionnaires measuring the various facets of impulsivity (UPPS Impulsive Behavior Scale), ADHD and depressive symptoms severity. Patients were also assessed for ADHD subtypes, mood disorders, and addictive behaviors. ADHD patients exhibited higher urgency, lower premeditation and lower perseverance in comparison to controls. Lack of perseverance showed the strongest association with ADHD (area under curve=0.95). Patients with combined inattentive and hyperactive/impulsive subtypes reported more frequently substance abuse problems and had higher scores on urgency and sensation seeking dimensions of impulsivity than those with predominantly inattentive subtype. We report for the first time a multidimensional evaluation of impulsivity in adult ADHD patients. The UPPS Impulsive Behavior Scale may constitute a useful screening tool for ADHD in adults and may help to further understanding the psychological mechanisms underlying the differences between the ADHD subgroups. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

A reverse genetic approach identifies an ancestral frameshift mutation in RP1 causing recessive progressive retinal degeneration in European cattle breeds.

PubMed

Michot, Pauline; Chahory, Sabine; Marete, Andrew; Grohs, Cécile; Dagios, Dimitri; Donzel, Elise; Aboukadiri, Abdelhak; Deloche, Marie-Christine; Allais-Bonnet, Aurélie; Chambrial, Matthieu; Barbey, Sarah; Genestout, Lucie; Boussaha, Mekki; Danchin-Burge, Coralie; Fritz, Sébastien; Boichard, Didier; Capitan, Aurélien

2016-08-10

Domestication and artificial selection have resulted in strong genetic drift, relaxation of purifying selection and accumulation of deleterious mutations. As a consequence, bovine breeds experience regular outbreaks of recessive genetic defects which might represent only the tip of the iceberg since their detection depends on the observation of affected animals with distinctive symptoms. Thus, recessive mutations resulting in embryonic mortality or in non-specific symptoms are likely to be missed. The increasing availability of whole-genome sequences has opened new research avenues such as reverse genetics for their investigation. Our aim was to characterize the genetic load of 15 European breeds using data from the 1000 bull genomes consortium and prove that widespread harmful mutations remain to be detected. We listed 2489 putative deleterious variants (in 1923 genes) segregating at a minimal frequency of 5 % in at least one of the breeds studied. Gene enrichment analysis showed major enrichment for genes related to nervous, visual and auditory systems, and moderate enrichment for genes related to cardiovascular and musculoskeletal systems. For verification purposes, we investigated the phenotypic consequences of a frameshift variant in the retinitis pigmentosa-1 gene segregating in several breeds and at a high frequency (27 %) in Normande cattle. As described in certain human patients, clinical and histological examination revealed that this mutation causes progressive degeneration of photoreceptors leading to complete blindness in homozygotes. We established that the deleterious allele was even more frequent in the Normande breed before 1975 (>40 %) and has been progressively counter-selected likely because of its associated negative effect on udder morphology. Finally, using identity-by-descent analysis we demonstrated that this mutation resulted from a unique ancestral event that dates back to ~2800 to 4000 years. We provide a list of mutations that likely represent a substantial part of the genetic load of domestication in European cattle. We demonstrate that they accumulated non-randomly and that genes related to cognition and sensory functions are particularly affected. Finally, we describe an ancestral deleterious variant segregating in different breeds causing progressive retinal degeneration and irreversible blindness in adult animals.

Orthotopic ileal bladder substitution in women: factors influencing urinary incontinence and hypercontinence.

PubMed

Gross, Tobias; Meierhans Ruf, Susan D; Meissner, Claudia; Ochsner, Katharina; Studer, Urs E

2015-10-01

Urinary incontinence or the inability to void spontaneously after ileal orthotopic bladder substitution is a frequent finding in female patients. To evaluate how hysterectomy and nerve sparing affect functional outcomes and whether these relate to pre- and postoperative urethral pressure profile (UPP) results. Prospectively performed pre- and postoperative UPPs of 73 female patients who had undergone cystectomy and bladder substitution were correlated with postoperative voiding and continence status. Outcome analyses were performed with the Kruskal-Wallis test, Wilcoxon-Mann-Whitney, or two-group post hoc testing with the Bonferroni correction. Chi-square or Fisher exact tests were applied for the categorical data. Of postoperatively continent or hypercontinent patients, 22 of 43 (51.2%) had the uterus preserved; of incontinent patients, only 4 of 30 (13.3%, p<0.01) had the uterus preserved. Of postoperatively continent or hypercontinent patients, 27 of 43 patients (62.8%) had bilateral and 15 of 43 (34.9%) had unilateral attempted nerve sparing. In incontinent patients, 11 of 30 (36.7%) had bilateral and 16 of 30 (53.3%) had unilateral attempted nerve sparing (p=0.02). When compared with postoperatively incontinent patients, postoperatively continent patients had a longer functional urethral length (median: 32mm vs 24mm; p<0.001), a higher postoperative urethral closing pressure at rest (56cm H2O vs 35cm H2O; p<0.001) as well as a higher preoperative urethral closing pressure at rest (74cm H2O vs 47.5cm H2O; p=0.01). The main limitation was the limited number of patients. In female patients undergoing radical cystectomy and bladder substitution, preservation of the uterus and attempted nerve sparing results in better functional outcomes. The preoperative UPPs correlate with postoperative voiding and continence status and may predict which patients are at a higher risk of functional failure after bladder substitution. If preservation of the urethra's innervation is not possible during cystectomy, poor functional results with bladder substitutes are likely. Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.

TRNA mutations that affect decoding fidelity deregulate development and the proteostasis network in zebrafish

PubMed Central

Reverendo, Marisa; Soares, Ana R; Pereira, Patrícia M; Carreto, Laura; Ferreira, Violeta; Gatti, Evelina; Pierre, Philippe; Moura, Gabriela R; Santos, Manuel A

2014-01-01

Mutations in genes that encode tRNAs, aminoacyl-tRNA syntheases, tRNA modifying enzymes and other tRNA interacting partners are associated with neuropathies, cancer, type-II diabetes and hearing loss, but how these mutations cause disease is unclear. We have hypothesized that levels of tRNA decoding error (mistranslation) that do not fully impair embryonic development can accelerate cell degeneration through proteome instability and saturation of the proteostasis network. To test this hypothesis we have induced mistranslation in zebrafish embryos using mutant tRNAs that misincorporate Serine (Ser) at various non-cognate codon sites. Embryo viability was affected and malformations were observed, but a significant proportion of embryos survived by activating the unfolded protein response (UPR), the ubiquitin proteasome pathway (UPP) and downregulating protein biosynthesis. Accumulation of reactive oxygen species (ROS), mitochondrial and nuclear DNA damage and disruption of the mitochondrial network, were also observed, suggesting that mistranslation had a strong negative impact on protein synthesis rate, ER and mitochondrial homeostasis. We postulate that mistranslation promotes gradual cellular degeneration and disease through protein aggregation, mitochondrial dysfunction and genome instability. PMID:25483040

Microorganisms for producing organic acids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Pfleger, Brian Frederick; Begemann, Matthew Brett

Organic acid-producing microorganisms and methods of using same. The organic acid-producing microorganisms comprise modifications that reduce or ablate AcsA activity or AcsA homolog activity. The modifications increase tolerance of the microorganisms to such organic acids as 3-hydroxypropionic acid, acrylic acid, propionic acid, lactic acid, and others. Further modifications to the microorganisms increase production of such organic acids as 3-hydroxypropionic acid, lactate, and others. Methods of producing such organic acids as 3-hydroxypropionic acid, lactate, and others with the modified microorganisms are provided. Methods of using acsA or homologs thereof as counter-selectable markers are also provided.

Microorganisms for producing organic acids

DOEpatents

Pfleger, Brian Frederick; Begemann, Matthew Brett

2014-09-30

Organic acid-producing microorganisms and methods of using same. The organic acid-producing microorganisms comprise modifications that reduce or ablate AcsA activity or AcsA homolog activity. The modifications increase tolerance of the microorganisms to such organic acids as 3-hydroxypropionic acid, acrylic acid, propionic acid, lactic acid, and others. Further modifications to the microorganisms increase production of such organic acids as 3-hydroxypropionic acid, lactate, and others. Methods of producing such organic acids as 3-hydroxypropionic acid, lactate, and others with the modified microorganisms are provided. Methods of using acsA or homologs thereof as counter-selectable markers are also provided.

Testing the Relations Between Impulsivity-Related Traits, Suicidality, and Nonsuicidal Self-Injury: A Test of the Incremental Validity of the UPPS Model

PubMed Central

Lynam, Donald R.; Miller, Joshua D.; Miller, Drew J.; Bornovalova, Marina A.; Lejuez, C. W.

2011-01-01

Borderline personality disorder (BPD) has received significant attention as a predictor of suicidal behavior (SB) and nonsuicidal self-injury (NSSI). Despite significant promise, trait impulsivity has received less attention. Understanding the relations between impulsivity and SB and NSSI is confounded, unfortunately, by the heterogeneous nature of impulsivity. This study examined the relations among 4 personality pathways to impulsive behavior studied via the UPPS model of impulsivity and SB and NSSI in a residential sample of drug abusers (N = 76). In this study, we tested whether these 4 impulsivity-related traits (i.e., Negative Urgency, Sensation Seeking, Lack of Premeditation, and Lack of Perseverance) provide incremental validity in the statistical prediction of SB and NSSI above and beyond BPD; they do. We also tested whether BPD symptoms provide incremental validity in the prediction of SB and NSSI above and beyond these impulsivity-related traits; they do not. In addition to the main effects of Lack of Premeditation and Negative Urgency, we found evidence of a robust interaction between these 2 personality traits. The current results argue strongly for the consideration of these 2 impulsivity-related domains—alone and in interaction—when attempting to understand and predict SB and NSSI. PMID:21833346

Testing the relations between impulsivity-related traits, suicidality, and nonsuicidal self-injury: a test of the incremental validity of the UPPS model.

PubMed

Lynam, Donald R; Miller, Joshua D; Miller, Drew J; Bornovalova, Marina A; Lejuez, C W

2011-04-01

Borderline personality disorder (BPD) has received significant attention as a predictor of suicidal behavior (SB) and nonsuicidal self-injury (NSSI). Despite significant promise, trait impulsivity has received less attention. Understanding the relations between impulsivity and SB and NSSI is confounded, unfortunately, by the heterogeneous nature of impulsivity. This study examined the relations among 4 personality pathways to impulsive behavior studied via the UPPS model of impulsivity and SB and NSSI in a residential sample of drug abusers (N = 76). In this study, we tested whether these 4 impulsivity-related traits (i.e., Negative Urgency, Sensation Seeking, Lack of Premeditation, and Lack of Perseverance) provide incremental validity in the statistical prediction of SB and NSSI above and beyond BPD; they do. We also tested whether BPD symptoms provide incremental validity in the prediction of SB and NSSI above and beyond these impulsivity-related traits; they do not. In addition to the main effects of Lack of Premeditation and Negative Urgency, we found evidence of a robust interaction between these 2 personality traits. The current results argue strongly for the consideration of these 2 impulsivity-related domains--alone and in interaction--when attempting to understand and predict SB and NSSI.

Psychometric Testing of INTEGRARE, an Instrument for the Assesment of Pressure Ulcer Risk in Inpatients.

PubMed

Porcel-Gálvez, Ana María; Romero-Castillo, Rocío; Fernández-García, Elena; Barrientos-Trigo, Sergio

2017-08-21

The aim of this study is to evaluate the psychometric properties of INTEGRARE, an instrument based on Nursing Outcome Classification. A multicenter, cross-sectional, methodological design was used. The study included 3,835 patients. Internal consistency α = 0.86. Confirmatory factor analysis demonstrated the unidimensionality of the scale, indicating a good model fit (CMIN/DF = 4; GFI, CFI, NFI, IFI = 0.999; RMSEA = 0.028). INTEGRARE is a valid and reliable instrument with high sensitivity, specificity, and diagnostic accuracy in measuring pressure ulcer (PU) risk in inpatients. This instrument allows us to know the effectiveness of nursing interventions, providing evidence for the validation of the diagnosis Risk for pressure ulcer (00249) as well as on health outcomes, due to the fact that PUs are nursing-sensitive outcomes. Evaluar las propiedades psicométricas de INTEGRARE, un instrumento basado en la Clasificación de Resultados de Enfermería. MÉTODO: Se optó por un diseño transversal multicéntrico. El estudio incluyó a 3,835 pacientes. Consistencia interna α = 0.86. El análisis factorial confirmatorio demostró la unidimensionalidad de la escala, indicando un buen ajuste del modelo (CMIN/DF = 4; GFI, CFI, NFI, IFI = 0.999; RMSEA = 0.028). INTEGRARE es un instrumento válido y fiable con alta sensibilidad, especificidad y precisión diagnóstica en la medición de riesgo de úlcera por presión (UPP) en pacientes hospitalizados. IMPLICACIONES PARA LA PRÁCTICA ENFERMERA: Este instrumento nos permite conocer la efectividad de las intervenciones enfermeras, aportando evidencia para la validación del diagnóstico Riesgo de úlcera por presión (00249), así como sobre los resultados de salud, debido a que las UPP son resultados sensibles a la práctica enfermera. © 2017 NANDA International, Inc.

Coast of California Storm and Tidal Waves Study. Geomorphology Framework Report Monterey Bay,

DTIC Science & Technology

1985-12-01

practices have lessened the severity of this problem. 3. Extensive agricultural development has increased siitation rates and altered the na- tural...surface stream flow. The primary economy of both the Pajaro ard Salinas basins is agriculture . For 1975, in the Salinas Valley alone, more than 809 kn...fossiliferous hWhite diatomit ed uppe rt; Moniterey formation-a- - 900 light brown siliceous shale in lower fa Duff colored weathering orkcosie send and .Ji

Influence of temperature during grain filling on gluten viscoelastic properties and gluten protein composition.

PubMed

Koga, Shiori; Böcker, Ulrike; Moldestad, Anette; Tosi, Paola; Shewry, Peter R; Mosleth, Ellen F; Uhlen, Anne Kjersti

2016-01-15

The aim of this study was to investigate the effects of low to moderate temperatures on gluten functionality and gluten protein composition. Four spring wheat cultivars were grown in climate chambers with three temperature regimes (day/night temperatures of 13/10, 18/15 and 23/20 °C) during grain filling. The temperature strongly influenced grain weight and protein content. Gluten quality measured by maximum resistance to extension (Rmax ) was highest in three cultivars grown at 13 °C. Rmax was positively correlated with the proportion of sodium dodecyl sulfate-unextractable polymeric proteins (%UPP). The proportions of ω-gliadins and D-type low-molecular-weight glutenin subunits (LMW-GS) increased and the proportions of α- and γ-gliadins and B-type LMW-GS decreased with higher temperature, while the proportion of high-molecular-weight glutenin subunits (HMW-GS) was constant between temperatures. The cultivar Berserk had strong and constant Rmax between the different temperatures. Constant low temperature, even as low as 13 °C, had no negative effects on gluten quality. The observed variation in Rmax related to temperature could be explained more by %UPP than by changes in the proportions of HMW-GS or other gluten proteins. The four cultivars responded differently to temperature, as gluten from Berserk was stronger and more stable over a wide range of temperatures. © 2015 Society of Chemical Industry.

Mitochondrial Neurogastrointestinal Encephalomyopathy Caused by Thymidine Phosphorylase Enzyme Deficiency: From Pathogenesis to Emerging Therapeutic Options

PubMed Central

Yadak, Rana; Sillevis Smitt, Peter; van Gisbergen, Marike W.; van Til, Niek P.; de Coo, Irenaeus F. M.

2017-01-01

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a progressive metabolic disorder caused by thymidine phosphorylase (TP) enzyme deficiency. The lack of TP results in systemic accumulation of deoxyribonucleosides thymidine (dThd) and deoxyuridine (dUrd). In these patients, clinical features include mental regression, ophthalmoplegia, and fatal gastrointestinal complications. The accumulation of nucleosides also causes imbalances in mitochondrial DNA (mtDNA) deoxyribonucleoside triphosphates (dNTPs), which may play a direct or indirect role in the mtDNA depletion/deletion abnormalities, although the exact underlying mechanism remains unknown. The available therapeutic approaches include dialysis and enzyme replacement therapy, both can only transiently reverse the biochemical imbalance. Allogeneic hematopoietic stem cell transplantation is shown to be able to restore normal enzyme activity and improve clinical manifestations in MNGIE patients. However, transplant related complications and disease progression result in a high mortality rate. New therapeutic approaches, such as adeno-associated viral vector and hematopoietic stem cell gene therapy have been tested in Tymp-/-Upp1-/- mice, a murine model for MNGIE. This review provides background information on disease manifestations of MNGIE with a focus on current management and treatment options. It also outlines the pre-clinical approaches toward future treatment of the disease. PMID:28261062

Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice.

PubMed

Kil, Laurens P; de Bruijn, Marjolein J W; van Nimwegen, Menno; Corneth, Odilia B J; van Hamburg, Jan Piet; Dingjan, Gemma M; Thaiss, Friedrich; Rimmelzwaan, Guus F; Elewaut, Dirk; Delsing, Dianne; van Loo, Pieter Fokko; Hendriks, Rudi W

2012-04-19

On antigen binding by the B-cell receptor (BCR), B cells up-regulate protein expression of the key downstream signaling molecule Bruton tyrosine kinase (Btk), but the effects of Btk up-regulation on B-cell function are unknown. Here, we show that transgenic mice overexpressing Btk specifically in B cells spontaneously formed germinal centers and manifested increased plasma cell numbers, leading to antinuclear autoantibody production and systemic lupus erythematosus (SLE)-like autoimmune pathology affecting kidneys, lungs, and salivary glands. Autoimmunity was fully dependent on Btk kinase activity, because Btk inhibitor treatment (PCI-32765) could normalize B-cell activation and differentiation, and because autoantibodies were absent in Btk transgenic mice overexpressing a kinase inactive Btk mutant. B cells overexpressing wild-type Btk were selectively hyperresponsive to BCR stimulation and showed enhanced Ca(2+) influx, nuclear factor (NF)-κB activation, resistance to Fas-mediated apoptosis, and defective elimination of selfreactive B cells in vivo. These findings unravel a crucial role for Btk in setting the threshold for B-cell activation and counterselection of autoreactive B cells, making Btk an attractive therapeutic target in systemic autoimmune disease such as SLE. The finding of in vivo pathology associated with Btk overexpression may have important implications for the development of gene therapy strategies for X-linked agammaglobulinemia, the immunodeficiency associated with mutations in BTK.

Investigation of the Representation of OLEs and Terrain Effects Within the Coastal Zone in the EDMF Parameterization Scheme: An Airborne Doppler Wind Lidar Perspective

DTIC Science & Technology

2013-10-07

OLEs and Terrain Effects Within the Coastal Zone in the EDMF Parameterization Scheme: An Airborne Doppler Wind Lidar Perspective Annual Report Under...UPP related investigations that will be carried out in Year 3. RELATED PROJECTS ONR contract to study the utilization of Doppler wind lidar (DWL...MATERHORN2012) Paper presented at the Coherent Laser Radar Conference, June 2013 Airborne DWL investigations of flow over complex terrain (MATERHORN

Multilevel selection in a resource-based model.

PubMed

Ferreira, Fernando Fagundes; Campos, Paulo R A

2013-07-01

In the present work we investigate the emergence of cooperation in a multilevel selection model that assumes limiting resources. Following the work by R. J. Requejo and J. Camacho [Phys. Rev. Lett. 108, 038701 (2012)], the interaction among individuals is initially ruled by a prisoner's dilemma (PD) game. The payoff matrix may change, influenced by the resource availability, and hence may also evolve to a non-PD game. Furthermore, one assumes that the population is divided into groups, whose local dynamics is driven by the payoff matrix, whereas an intergroup competition results from the nonuniformity of the growth rate of groups. We study the probability that a single cooperator can invade and establish in a population initially dominated by defectors. Cooperation is strongly favored when group sizes are small. We observe the existence of a critical group size beyond which cooperation becomes counterselected. Although the critical size depends on the parameters of the model, it is seen that a saturation value for the critical group size is achieved. The results conform to the thought that the evolutionary history of life repeatedly involved transitions from smaller selective units to larger selective units.

Genomic Insight into Mechanisms of Reversion of Antibiotic Resistance in Multidrug Resistant Mycobacterium tuberculosis Induced by a Nanomolecular Iodine-Containing Complex FS-1.

PubMed

Ilin, Aleksandr I; Kulmanov, Murat E; Korotetskiy, Ilya S; Islamov, Rinat A; Akhmetova, Gulshara K; Lankina, Marina V; Reva, Oleg N

2017-01-01

Drug induced reversion of antibiotic resistance is a promising way to combat multidrug resistant infections. However, lacking knowledge of mechanisms of drug resistance reversion impedes employing this approach in medicinal therapies. Induction of antibiotic resistance reversion by a new anti-tuberculosis drug FS-1 has been reported. FS-1 was used in this work in combination with standard anti-tuberculosis antibiotics in an experiment on laboratory guinea pigs infected with an extensively drug resistant (XDR) strain Mycobacterium tuberculosis SCAID 187.0. During the experimental trial, genetic changes in the population were analyzed by sequencing of M. tuberculosis isolates followed by variant calling. In total 11 isolates obtained from different groups of infected animals at different stages of disease development and treatment were sequenced. It was found that despite the selective pressure of antibiotics, FS-1 caused a counter-selection of drug resistant variants that speeded up the recovery of the infected animals from XDR tuberculosis. Drug resistance mutations reported in the genome of the initial strain remained intact in more sensitive isolates obtained in this experiment. Variant calling in the sequenced genomes revealed that the drug resistance reversion could be associated with a general increase in genetic heterogeneity of the population of M. tuberculosis . Accumulation of mutations in PpsA and PpsE subunits of phenolpthiocerol polyketide synthase was observed in the isolates treated with FS-1 that may indicate an increase of persisting variants in the population. It was hypothesized that FS-1 caused an active counter-selection of drug resistant variants from the population by aggravating the cumulated fitness cost of the drug resistance mutations. Action of FS-1 on drug resistant bacteria exemplified the theoretically predicted induced synergy mechanism of drug resistance reversion. An experimental model to study the drug resistance reversion phenomenon is hereby introduced.

Impulsivity and cognitive distortions in pathological gamblers attending the UK National Problem Gambling Clinic: a preliminary report.

PubMed

Michalczuk, R; Bowden-Jones, H; Verdejo-Garcia, A; Clark, L

2011-12-01

Pathological gambling (PG) is a form of behavioural addiction that has been associated with elevated impulsivity and also cognitive distortions in the processing of chance, probability and skill. We sought to assess the relationship between the level of cognitive distortions and state and trait measures of impulsivity in treatment-seeking pathological gamblers. Thirty pathological gamblers attending the National Problem Gambling Clinic, the first National Health Service clinic for gambling problems in the UK, were compared with 30 healthy controls in a case-control design. Cognitive distortions were assessed using the Gambling-Related Cognitions Scale (GRCS). Trait impulsivity was assessed using the UPPS-P, which includes scales of urgency, the tendency to be impulsive in positive or negative mood states. Delay discounting rates were taken as a state measure of impulsive choice. Pathological gamblers had elevated impulsivity on several UPPS-P subscales but effect sizes were largest (Cohen's d>1.4) for positive and negative urgency. The pathological gamblers also displayed higher levels of gambling distortions, and elevated preference for immediate rewards, compared to controls. Within the pathological gamblers, there was a strong relationship between the preference for immediate rewards and the level of cognitive distortions (R2=0.41). Impulsive choice in the gamblers was correlated with the level of gambling distortions, and we hypothesize that an impulsive decision-making style may increase the acceptance of erroneous beliefs during gambling play.

Binge Eating, But Not Other Disordered Eating Symptoms, Is a Significant Contributor of Binge Drinking Severity: Findings from a Cross-Sectional Study among French Students.

PubMed

Rolland, Benjamin; Naassila, Mickael; Duffau, Céline; Houchi, Hakim; Gierski, Fabien; André, Judith

2017-01-01

Many studies have suggested the co-occurrence of eating disorders and alcohol use disorders but in which extent binge eating (BE) and other disordered eating symptoms (DES) are associated with the severity of binge drinking (BD) remains unknown. We conducted a online cross-sectional study among 1,872 French students. Participants were asked their age, gender, tobacco and cannabis use status. They completed the Alcohol Use Questionnaire (AUQ), Eating Disorder Examination Questionnaire (EDE-Q), and UPPS impulsive behavior questionnaire. BD score was calculated using the AUQ. Three items of the EDE-Q were used to construct a BE score. The predictors of the BD score were determined using a linear regression model. Our results showed that the BE score was correlated with the BD score (β 0 = 0.051 ± 0.022; p = 0.019), but no other DES was associated with BD, including purging behaviors. The severity of BD was also correlated with younger age, male gender, tobacco and cannabis use, and with the 'positive urgency,' 'premeditation,' and 'sensation seeking' UPPS subscores ( R 2 of the model: 25%). Within DES, BE appeared as an independent determinant of the BD severity. This is in line with the recent hypothesis that BE is not a subtype of DES, but more a general vulnerability factor of emotional dysregulation, which could be shared by different behavioral and addictive disorders.

Validation of an Automated Torsional and Warping Stress Analysis Program

DTIC Science & Technology

1992-08-19

AT ftA NC[ VIPS’ Af $UPP69T ds (ZqOoo x,~)(23.6 ui7)( .000012433) 127672 P~s Af .SL Cq6"): dws (2qOOC KcI)(21Ci;)2)G-.OOOQQ 3623):’ -2uqO KSI AT M~C...TORSIONAL ,’KMENT .50000000 ENDING AT 1,2.04000 FMD • LE3 END PHIZ .00)OOE+00 PHI: .o0000Eo0f PHI2: .38240E-04 PHI3: -. 33�E-05 I"OR. SHR. WEL

Anatomy of the bacitracin resistance network in Bacillus subtilis.

PubMed

Radeck, Jara; Gebhard, Susanne; Orchard, Peter Shevlin; Kirchner, Marion; Bauer, Stephanie; Mascher, Thorsten; Fritz, Georg

2016-05-01

Protection against antimicrobial peptides (AMPs) often involves the parallel production of multiple, well-characterized resistance determinants. So far, little is known about how these resistance modules interact and how they jointly protect the cell. Here, we studied the interdependence between different layers of the envelope stress response of Bacillus subtilis when challenged with the lipid II cycle-inhibiting AMP bacitracin. The underlying regulatory network orchestrates the production of the ABC transporter BceAB, the UPP phosphatase BcrC and the phage-shock proteins LiaIH. Our systems-level analysis reveals a clear hierarchy, allowing us to discriminate between primary (BceAB) and secondary (BcrC and LiaIH) layers of bacitracin resistance. Deleting the primary layer provokes an enhanced induction of the secondary layer to partially compensate for this loss. This study reveals a direct role of LiaIH in bacitracin resistance, provides novel insights into the feedback regulation of the Lia system, and demonstrates a pivotal role of BcrC in maintaining cell wall homeostasis. The compensatory regulation within the bacitracin network can also explain how gene expression noise propagates between resistance layers. We suggest that this active redundancy in the bacitracin resistance network of B. subtilis is a general principle to be found in many bacterial antibiotic resistance networks. © 2016 John Wiley & Sons Ltd.

Plant X-tender: An extension of the AssemblX system for the assembly and expression of multigene constructs in plants.

PubMed

Lukan, Tjaša; Machens, Fabian; Coll, Anna; Baebler, Špela; Messerschmidt, Katrin; Gruden, Kristina

2018-01-01

Cloning multiple DNA fragments for delivery of several genes of interest into the plant genome is one of the main technological challenges in plant synthetic biology. Despite several modular assembly methods developed in recent years, the plant biotechnology community has not widely adopted them yet, probably due to the lack of appropriate vectors and software tools. Here we present Plant X-tender, an extension of the highly efficient, scar-free and sequence-independent multigene assembly strategy AssemblX, based on overlap-depended cloning methods and rare-cutting restriction enzymes. Plant X-tender consists of a set of plant expression vectors and the protocols for most efficient cloning into the novel vector set needed for plant expression and thus introduces advantages of AssemblX into plant synthetic biology. The novel vector set covers different backbones and selection markers to allow full design flexibility. We have included ccdB counterselection, thereby allowing the transfer of multigene constructs into the novel vector set in a straightforward and highly efficient way. Vectors are available as empty backbones and are fully flexible regarding the orientation of expression cassettes and addition of linkers between them, if required. We optimised the assembly and subcloning protocol by testing different scar-less assembly approaches: the noncommercial SLiCE and TAR methods and the commercial Gibson assembly and NEBuilder HiFi DNA assembly kits. Plant X-tender was applicable even in combination with low efficient homemade chemically competent or electrocompetent Escherichia coli. We have further validated the developed procedure for plant protein expression by cloning two cassettes into the newly developed vectors and subsequently transferred them to Nicotiana benthamiana in a transient expression setup. Thereby we show that multigene constructs can be delivered into plant cells in a streamlined and highly efficient way. Our results will support faster introduction of synthetic biology into plant science.

Plant X-tender: An extension of the AssemblX system for the assembly and expression of multigene constructs in plants

PubMed Central

Machens, Fabian; Coll, Anna; Baebler, Špela; Messerschmidt, Katrin; Gruden, Kristina

2018-01-01

Cloning multiple DNA fragments for delivery of several genes of interest into the plant genome is one of the main technological challenges in plant synthetic biology. Despite several modular assembly methods developed in recent years, the plant biotechnology community has not widely adopted them yet, probably due to the lack of appropriate vectors and software tools. Here we present Plant X-tender, an extension of the highly efficient, scar-free and sequence-independent multigene assembly strategy AssemblX, based on overlap-depended cloning methods and rare-cutting restriction enzymes. Plant X-tender consists of a set of plant expression vectors and the protocols for most efficient cloning into the novel vector set needed for plant expression and thus introduces advantages of AssemblX into plant synthetic biology. The novel vector set covers different backbones and selection markers to allow full design flexibility. We have included ccdB counterselection, thereby allowing the transfer of multigene constructs into the novel vector set in a straightforward and highly efficient way. Vectors are available as empty backbones and are fully flexible regarding the orientation of expression cassettes and addition of linkers between them, if required. We optimised the assembly and subcloning protocol by testing different scar-less assembly approaches: the noncommercial SLiCE and TAR methods and the commercial Gibson assembly and NEBuilder HiFi DNA assembly kits. Plant X-tender was applicable even in combination with low efficient homemade chemically competent or electrocompetent Escherichia coli. We have further validated the developed procedure for plant protein expression by cloning two cassettes into the newly developed vectors and subsequently transferred them to Nicotiana benthamiana in a transient expression setup. Thereby we show that multigene constructs can be delivered into plant cells in a streamlined and highly efficient way. Our results will support faster introduction of synthetic biology into plant science. PMID:29300787

A quasi-exclusive European ancestry in the Senepol tropical cattle breed highlights the importance of the slick locus in tropical adaptation.

PubMed

Flori, Laurence; Gonzatti, Mary Isabel; Thevenon, Sophie; Chantal, Isabelle; Pinto, Joar; Berthier, David; Aso, Pedro M; Gautier, Mathieu

2012-01-01

The Senepol cattle breed (SEN) was created in the early XX(th) century from a presumed cross between a European (EUT) breed (Red Poll) and a West African taurine (AFT) breed (N'Dama). Well adapted to tropical conditions, it is also believed trypanotolerant according to its putative AFT ancestry. However, such origins needed to be verified to define relevant husbandry practices and the genetic background underlying such adaptation needed to be characterized. We genotyped 153 SEN individuals on 47,365 SNPs and combined the resulting data with those available on 18 other populations representative of EUT, AFT and Zebu (ZEB) cattle. We found on average 89% EUT, 10.4% ZEB and 0.6% AFT ancestries in the SEN genome. We further looked for footprints of recent selection using standard tests based on the extent of haplotype homozygosity. We underlined i) three footprints on chromosome (BTA) 01, two of which are within or close to the polled locus underlying the absence of horns and ii) one footprint on BTA20 within the slick hair coat locus, involved in thermotolerance. Annotation of these regions allowed us to propose three candidate genes to explain the observed signals (TIAM1, GRIK1 and RAI14). Our results do not support the accepted concept about the AFT origin of SEN breed. Initial AFT ancestry (if any) might have been counter-selected in early generations due to breeding objectives oriented in particular toward meat production and hornless phenotype. Therefore, SEN animals are likely susceptible to African trypanosomes which questions the importation of SEN within the West African tsetse belt, as promoted by some breeding societies. Besides, our results revealed that SEN breed is predominantly a EUT breed well adapted to tropical conditions and confirmed the importance in thermotolerance of the slick locus.

A Quasi-Exclusive European Ancestry in the Senepol Tropical Cattle Breed Highlights the Importance of the slick Locus in Tropical Adaptation

PubMed Central

Flori, Laurence; Gonzatti, Mary Isabel; Thevenon, Sophie; Chantal, Isabelle; Pinto, Joar; Berthier, David; Aso, Pedro M.; Gautier, Mathieu

2012-01-01

Background The Senepol cattle breed (SEN) was created in the early XXth century from a presumed cross between a European (EUT) breed (Red Poll) and a West African taurine (AFT) breed (N’Dama). Well adapted to tropical conditions, it is also believed trypanotolerant according to its putative AFT ancestry. However, such origins needed to be verified to define relevant husbandry practices and the genetic background underlying such adaptation needed to be characterized. Methodology/Principal Findings We genotyped 153 SEN individuals on 47,365 SNPs and combined the resulting data with those available on 18 other populations representative of EUT, AFT and Zebu (ZEB) cattle. We found on average 89% EUT, 10.4% ZEB and 0.6% AFT ancestries in the SEN genome. We further looked for footprints of recent selection using standard tests based on the extent of haplotype homozygosity. We underlined i) three footprints on chromosome (BTA) 01, two of which are within or close to the polled locus underlying the absence of horns and ii) one footprint on BTA20 within the slick hair coat locus, involved in thermotolerance. Annotation of these regions allowed us to propose three candidate genes to explain the observed signals (TIAM1, GRIK1 and RAI14). Conclusions/Significance Our results do not support the accepted concept about the AFT origin of SEN breed. Initial AFT ancestry (if any) might have been counter-selected in early generations due to breeding objectives oriented in particular toward meat production and hornless phenotype. Therefore, SEN animals are likely susceptible to African trypanosomes which questions the importation of SEN within the West African tsetse belt, as promoted by some breeding societies. Besides, our results revealed that SEN breed is predominantly a EUT breed well adapted to tropical conditions and confirmed the importance in thermotolerance of the slick locus. PMID:22675421

Internet Gamblers Differ on Social Variables: A Latent Class Analysis.

PubMed

Khazaal, Yasser; Chatton, Anne; Achab, Sophia; Monney, Gregoire; Thorens, Gabriel; Dufour, Magali; Zullino, Daniele; Rothen, Stephane

2017-09-01

Online gambling has gained popularity in the last decade, leading to an important shift in how consumers engage in gambling and in the factors related to problem gambling and prevention. Indebtedness and loneliness have previously been associated with problem gambling. The current study aimed to characterize online gamblers in relation to indebtedness, loneliness, and several in-game social behaviors. The data set was obtained from 584 Internet gamblers recruited online through gambling websites and forums. Of these gamblers, 372 participants completed all study assessments and were included in the analyses. Questionnaires included those on sociodemographics and social variables (indebtedness, loneliness, in-game social behaviors), as well as the Gambling Motives Questionnaire, Gambling Related Cognitions Scale, Internet Addiction Test, Problem Gambling Severity Index, Short Depression-Happiness Scale, and UPPS-P Impulsive Behavior Scale. Social variables were explored with a latent class model. The clusters obtained were compared for psychological measures and three clusters were found: lonely indebted gamblers (cluster 1: 6.5%), not lonely not indebted gamblers (cluster 2: 75.4%), and not lonely indebted gamblers (cluster 3: 18%). Participants in clusters 1 and 3 (particularly in cluster 1) were at higher risk of problem gambling than were those in cluster 2. The three groups differed on most assessed variables, including the Problem Gambling Severity Index, the Short Depression-Happiness Scale, and the UPPS-P subscales (except the sensation seeking subscore). Results highlight significant between-group differences, suggesting that Internet gamblers are not a homogeneous group. Specific intervention strategies could be implemented for groups at risk.

Induction of bphA, encoding biphenyl dioxygenase, in two polychlorinated biphenyl-degrading bacteria, psychrotolerant Pseudomonas strain Cam-1 and mesophilic Burkholderia strain LB400.

PubMed

Master, E R; Mohn, W W

2001-06-01

We investigated induction of biphenyl dioxygenase in the psychrotolerant polychlorinated biphenyl (PCB) degrader Pseudomonas strain Cam-1 and in the mesophilic PCB degrader Burkholderia strain LB400. Using a counterselectable gene replacement vector, we inserted a lacZ-Gm(r) fusion cassette between chromosomal genes encoding the large subunit (bphA) and small subunit (bphE) of biphenyl dioxygenase in Cam-1 and LB400, generating Cam-10 and LB400-1, respectively. Potential inducers of bphA were added to cell suspensions of Cam-10 and LB400-1 incubated at 30 degrees C, and then beta-galactosidase activity was measured. Biphenyl induced beta-galactosidase activity in Cam-10 to a level approximately six times greater than the basal level in cells incubated with pyruvate. In contrast, the beta-galactosidase activities in LB400-1 incubated with biphenyl and in LB400-1 incubated with pyruvate were indistinguishable. At a concentration of 1 mM, most of the 40 potential inducers tested were inhibitory to induction by biphenyl of beta-galactosidase activity in Cam-10. The exceptions were naphthalene, salicylate, 2-chlorobiphenyl, and 4-chlorobiphenyl, which induced beta-galactosidase activity in Cam-10, although at levels that were no more than 30% of the levels induced by biphenyl. After incubation for 24 h at 7 degrees C, biphenyl induced beta-galactosidase activity in Cam-10 to a level approximately four times greater than the basal level in cells incubated with pyruvate. The constitutive level of beta-galactosidase activity in LB400-1 grown at 15 degrees C was approximately five times less than the level in LB400-1 grown at 30 degrees C. Thus, there are substantial differences in the effects of physical and chemical environmental conditions on genetic regulation of PCB degradation in different bacteria.

Constructive thinking skills and impulsivity dimensions in conduct and substance use disorders: differences and relationships in an adolescents' sample.

PubMed

Urben, Sébastien; Suter, Maya; Pihet, Sandrine; Straccia, Claudio; Stéphan, Philippe

2015-06-01

Impact of conduct disorder (CD) and substance use disorder (SUD) on constructive thinking skills and impulsivity was explored. 71 offending adolescents were assessed for CD and SUD. Furthermore, the constructive thinking inventory, the immediate and delayed memory tasks and the UPPS impulsive behaviour scale were administered. Results showed that youths with CD, independently from SUD, presented higher personality impulsivity (urgency) and altered constructive thinking skills (categorical thinking and personal superstitious thinking). Furthermore, trait-impulsivity explained variation in constructive thinking skills. The implications of these results were discussed.

Multilevel selection in a resource-based model

NASA Astrophysics Data System (ADS)

Ferreira, Fernando Fagundes; Campos, Paulo R. A.

2013-07-01

In the present work we investigate the emergence of cooperation in a multilevel selection model that assumes limiting resources. Following the work by R. J. Requejo and J. Camacho [Phys. Rev. Lett.0031-900710.1103/PhysRevLett.108.038701 108, 038701 (2012)], the interaction among individuals is initially ruled by a prisoner's dilemma (PD) game. The payoff matrix may change, influenced by the resource availability, and hence may also evolve to a non-PD game. Furthermore, one assumes that the population is divided into groups, whose local dynamics is driven by the payoff matrix, whereas an intergroup competition results from the nonuniformity of the growth rate of groups. We study the probability that a single cooperator can invade and establish in a population initially dominated by defectors. Cooperation is strongly favored when group sizes are small. We observe the existence of a critical group size beyond which cooperation becomes counterselected. Although the critical size depends on the parameters of the model, it is seen that a saturation value for the critical group size is achieved. The results conform to the thought that the evolutionary history of life repeatedly involved transitions from smaller selective units to larger selective units.

Highly specific and cost-efficient detection of Salmonella Paratyphi A combining aptamers with single-walled carbon nanotubes.

PubMed

Yang, Ming; Peng, Zhihui; Ning, Yi; Chen, Yongzhe; Zhou, Qin; Deng, Le

2013-05-22

In this paper, a panel of single-stranded DNA aptamers with high affinity and specificity against Salmonella Paratyphi A was selected from an enriched oligonucleotide pool by a whole-cell-Systematic Evolution of Ligands by Exponential Enrichment (SELEX) procedure, during which four other Salmonella serovars were used as counter-selection targets. It was determined through a fluorescence assay that the selected aptamers had high binding ability and specificity to this pathogen. The dissociation constant of these aptamers were up to nanomolar range, and aptamer Apt22 with the lowest Kd (47 ± 3 nM) was used in cell imaging experiments. To detect this bacteria with high specificity and cost-efficiently, a novel useful detection method was also constructed based on the noncovalent self-assembly of single-walled carbon nanotubes (SWNTs) and DNAzyme-labeled aptamer detection probes. The amounts of target bacteria could be quantified by exploiting chemoluminescence intensity changes at 420 nm and the detection limit of the method was 103 cfu/mL. This study demonstrated the applicability of Salmonella specific aptamers and their potential for use in the detection of Salmonella in food, clinical and environmental samples.

[Mindfulness-based-relapse prevention (MBRP): Evaluation of the impact of a group of Mindfulness Therapy in alcohol relapse prevention for alcohol use disorders].

PubMed

Carpentier, D; Romo, L; Bouthillon-Heitzmann, P; Limosin, F

2015-12-01

For several years, the learning of mindfulness has developed in a psychological intervention perspective, particularly in the field of addiction. Presently, the management of addictions with substances is centered on two questions: the motivation in the change of behaviour and in a significant change in alcohol consumption. Concerning alcohol dependence, the evolution of behaviour is variable and characterized by forgiveness episodes and relapses. Over many years, a treatment for the abuse of substance associated with techniques based on full consciousness (Kabat-Zinn, 1990; Segal et al., 2002) Mindfulness-based relapse prevention (MBRP) was developed by Marlatt et al. (2011). The prevention of the relapse therapy, based on full consciousness, is a program of eight sessions integrating techniques of "mindfulness" into the techniques of prevention of the relapse. However, not much research has focused on the MBRP, the publication of the manual regarding this intervention is too recent (Bowen S et al., 2011). We are interested in the active mechanisms, which are at stake in the MBRP. Indeed, the meditation acts presents many mechanisms in the addicting disorders. Our non-controlled research was based on a protocol in order to evaluate the alcohol consummation, mindfulness, impulsiveness, automatic thoughts, anxiety and abilities to cope. The first results are interesting: reduction of alcohol consummation, increase of mindfulness, reduction of trigger relapse, increasing cognitive flexibility and high degree of satisfaction among participants. An intervention MBRP was proposed to 26 patients who were assigned to three groups. They were questioned about their alcohol consumption and assessed by a protocol of seven evaluations before and after the group MBRP: Five Facets Mindfulness (FFMQ), Impulsive Behavior Scale (UPPS), Acceptance and Action Questionnaire (AAQ II), State Trait Anxiety Inventory (STAI-A, STAI-B), Questionnaire of the automatic thoughts (QPA), and The Drug-Taking Confidence Questionnaire (DTCQ-8). This study exposes the preliminary results of an intervention for substance use disorders called mindfulness-based relapse prevention (mbrp) administered to five groups of alcohol dependent patients in a psychiatric department and a department of alcohol science in France. The results show maintained abstinence and a moderation leading to abstinence for the still consuming patients. According to our evaluations, we obtained several significant results after the therapy, despite our small cohort: patients accepted their thoughts and feelings better (FFMQ-judgment); the tendency to give in to the impulses decreased (urgency-UPPS), and their tolerance to anxiety increased (STAI-YA-YB). Moreover, this study appears to confirm that the MBRP program allows an improvement of self-efficiency. The study continues in order to confirm these results on a larger sample and to explore the long-term results, so as to propose a new work-tool for patients and caregivers. Copyright © 2015 L’Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Comparison of 2,4-Dichlorophenoxyacetic Acid Degradation and Plasmid Transfer in Soil Resulting from Bioaugmentation with Two Different pJP4 Donors

PubMed Central

Newby, D. T.; Gentry, T. J.; Pepper, I. L.

2000-01-01

A pilot field study was conducted to assess the impact of bioaugmentation with two plasmid pJP4-bearing microorganisms: the natural host, Ralstonia eutropha JMP134, and a laboratory-generated strain amenable to donor counterselection, Escherichia coli D11. The R. eutropha strain contained chromosomal genes necessary for mineralization of 2,4-dichlorophenoxyacetic acid (2,4-D), while the E. coli strain did not. The soil system was contaminated with 2,4-D alone or was cocontaminated with 2,4-D and Cd. Plasmid transfer to indigenous populations, plasmid persistence in soil, and degradation of 2,4-D were monitored over a 63-day period in the bioreactors. To assess the impact of contaminant reexposure, aliquots of bioreactor soil were reamended with additional 2,4-D. Both introduced donors remained culturable and transferred plasmid pJP4 to indigenous recipients, although to different extents. Isolated transconjugants were members of the Burkholderia and Ralstonia genera, suggesting multiple, if not successive, plasmid transfers. Upon a second exposure to 2,4-D, enhanced degradation was observed for all treatments, suggesting microbial adaptation to 2,4-D. Upon reexposure, degradation was most rapid for the E. coli D11-inoculated treatments. Cd did not significantly impact 2,4-D degradation or transconjugant formation. This study demonstrated that the choice of donor microorganism might be a key factor to consider for bioaugmentation efforts. In addition, the establishment of an array of stable indigenous plasmid hosts at sites with potential for reexposure or long-term contamination may be particularly useful. PMID:10919798

[Emotional and impulsive dimensions in bipolar disorder and borderline personality disorder].

PubMed

Leblanc, A; Jarroir, M; Vorspan, F; Bellivier, F; Leveillee, S; Romo, L

2017-05-01

Studies have shown that patients with borderline personality disorder are often misdiagnosed to have bipolar disorder and conversely. Indeed, a number of characteristics common to both disorders could explain this problem: emotional instability as well as impulsivity represent confounding factors and contribute to the risk of misdiagnosis. However, it appears that these characteristics manifest themselves in different ways according to the pathology. The aim of the study is to show differences between affective lability, emotional intensity and impulsivity dimensions. The clinical aim is to refine bipolar disorder and borderline personality disorder diagnosis, to improve psychological care for these patients in the long-term. We compared the emotional and impulsive dimensions in two groups of patients: a group of 21 patients with bipolar disorder and a group of 19 patients with borderline personality disorder. Tools: ALS, a self-report questionnaire to evaluate affective lability, AIM, a self-report questionnaire to see affective intensity, and UPPS, a self-report questionnaire to measure impulsivity according to several dimensions. The results indicate that borderline patients scored significantly higher than bipolar patients at the ALS and AIM scales. Regarding the UPPS, borderline patients scored significantly higher than bipolar patients for the dimensions "lack of premeditation" and "lack of perseverance"; however, bipolar patients had significantly higher scores than borderline patients for the dimension "negative emergency". This study shows that bipolar disorder and borderline personality can be differentiated thanks to emotional dimensions as well as different dimensions of impulsivity: borderline patients appear to have an affective lability and intensity more important than bipolar patients; it also appears that impulsivity manifests itself differently according to the disorder. Copyright © 2016 L'Encéphale, Paris. Published by Elsevier Masson SAS. All rights reserved.

Effect of Selective Prostaglandin E2 EP2 Receptor Agonist CP-533,536 on Voiding Efficiency in Rats with Midodrine-Induced Functional Urethral Obstruction.

PubMed

Kurihara, Ryoko; Imazumi, Katsunori; Takamatsu, Hajime; Ishizu, Kenichiro; Yoshino, Taiji; Masuda, Noriyuki

2016-05-01

We investigated the effect of the selective prostaglandin E2 EP2 receptor agonist CP-533,536 on voiding efficiency in rats with midodrine-induced functional urethral obstruction. The effect of CP-533,536 (0.03-0.3 mg/kg, intravenous [i.v.]) on urethral perfusion pressure (UPP) was investigated in anesthetized rats pre-treated with midodrine (1 mg/kg, i.v.), which forms an active metabolite that acts as an α1 -adrenoceptor agonist. The effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on cystometric parameters was also investigated in anesthetized rats. In addition, the effect of CP-533,536 (0.03-0.3 mg/kg, i.v.) on residual urine volume (RV) and voiding efficiency (VE) was investigated in conscious rats treated with midodrine (1 mg/kg, i.v.). CP-533,536 dose-dependently decreased UPP elevated by midodrine in anesthetized rats. In contrast, CP-533,536 did not affect maximum voiding pressure, intercontraction interval, or intravesical threshold pressure. In conscious rats, midodrine (1 mg/kg, i.v.) markedly increased RV and reduced VE. CP-533,536 dose-dependently ameliorated increases in RV and decreases in VE induced by midodrine. These results suggest that a selective EP2 receptor agonist could ameliorate the elevation of RV and improve the reduction of VE in rats with functional urethral obstruction caused by stimulation of α1 -adrenoceptors. The mechanism of action might be not potentiation of bladder contraction but rather preferential relief of urethral constriction. © 2014 Wiley Publishing Asia Pty Ltd.

Altered expression of p97/Valosin containing protein and impaired autophagy in preeclamptic human placenta.

PubMed

Ozsoy, Asker Zeki; Cayli, Sevil; Sahin, Cansu; Ocakli, Seda; Sanci, Tuba Ozdemir; Ilhan, Delibas Bahri

2018-07-01

Autophagy increases in placenta-related obstetrical diseases such as preeclampsia and intrauterine growth retardation but the regulation of autophagy by ubiquitin proteasome pathway (UPP) proteins, p97/Valosin containing protein (VCP) and ubiquitin (Ub) have not been previuosly studied in preeclampsia. The objective of this study is to investigate the expression of UPP (p97/VCP and Ub), autophagosomal (p62 and LC3) and autolysosomal proteins (Lamp1 and Lamp2) in the normal and preeclamptic human placentas and to explore the regulatory mechanism of these proteins in autophagic pathway. Different portions of normal term placentas (n = 20) and preeclamptic placentas (n = 10) were snap-frozen in liquid nitrogen for Western blotting and coimmunoprecipitation and others were fixed-embedded in paraffin for immunohistochemistry. Colocalization and coimmunoprecipitation experiments were done for the detection of interaction between p97/VCP and autophagic proteins. Compared with normal placentas, expression of p97/VCP was significantly reduced; however accumulation of ubiquitinlated proteins were significantly increased in preeclamptic placentas. The expression of autophagosomal proteins (LC3-II and p62) were significantly increased and no significant alterations of the expression of autolysosomal proteins were observed in preeclamptic placentas. Additionally, p97/VCP was found to colocalized and interact with autophagosomal and autolysosomal markers in normal and preeclamptic placentas. Autophagosome maturation diminished and autophagosomes had decreased localization with lysosomal markers in preeclamptic human placentas. Decreased expression of p97/VCP and increased expression of Ub in preeclampsia might be related to impaired autophagy and pathophysiology of preeclampsia. Therefore, our study highlights an important potential relationship between p97/VCP and autophagic proteins in preeclampsia. Copyright © 2018 Elsevier Ltd. All rights reserved.

Adaptive Evolution of Signaling Partners

PubMed Central

Urano, Daisuke; Dong, Taoran; Bennetzen, Jeffrey L.; Jones, Alan M.

2015-01-01

Proteins that interact coevolve their structures. When mutation disrupts the interaction, compensation by the partner occurs to restore interaction otherwise counterselection occurs. We show in this study how a destabilizing mutation in one protein is compensated by a stabilizing mutation in its protein partner and their coevolving path. The pathway in this case and likely a general principle of coevolution is that the compensatory change must tolerate both the original and derived structures with equivalence in function and activity. Evolution of the structure of signaling elements in a network is constrained by specific protein pair interactions, by requisite conformational changes, and by catalytic activity. The heterotrimeric G protein-coupled signaling is a paragon of this protein interaction/function complexity and our deep understanding of this pathway in diverse organisms lends itself to evolutionary study. Regulators of G protein Signaling (RGS) proteins accelerate the intrinsic GTP hydrolysis rate of the Gα subunit of the heterotrimeric G protein complex. An important RGS-contact site is a hydroxyl-bearing residue on the switch I region of Gα subunits in animals and most plants, such as Arabidopsis. The exception is the grasses (e.g., rice, maize, sugarcane, millets); these plants have Gα subunits that replaced the critical hydroxyl-bearing threonine with a destabilizing asparagine shown to disrupt interaction between Arabidopsis RGS protein (AtRGS1) and the grass Gα subunit. With one known exception (Setaria italica), grasses do not encode RGS genes. One parsimonious deduction is that the RGS gene was lost in the ancestor to the grasses and then recently acquired horizontally in the lineage S. italica from a nongrass monocot. Like all investigated grasses, S. italica has the Gα subunit with the destabilizing asparagine residue in the protein interface but, unlike other known grass genomes, still encodes an expressed RGS gene, SiRGS1. SiRGS1 accelerates GTP hydrolysis at similar concentration of both Gα subunits containing either the stabilizing (AtGPA1) or destabilizing (RGA1) interface residue. SiRGS1 does not use the hydroxyl-bearing residue on Gα to promote GAP activity and has a larger Gα-interface pocket fitting to the destabilizing Gα. These findings indicate that SiRGS1 adapted to a deleterious mutation on Gα using existing polymorphism in the RGS protein population. PMID:25568345

Cloning, sequencing, and expression of the apa gene coding for the Mycobacterium tuberculosis 45/47-kilodalton secreted antigen complex.

PubMed

Laqueyrerie, A; Militzer, P; Romain, F; Eiglmeier, K; Cole, S; Marchal, G

1995-10-01

Effective protection against a virulent challenge with Mycobacterium tuberculosis is induced mainly by previous immunization with living attenuated mycobacteria, and it has been hypothesized that secreted proteins serve as major targets in the specific immune response. To identify and purify molecules present in culture medium filtrate which are dominant antigens during effective vaccination, a two-step selection procedure was used to select antigens able to interact with T lymphocytes and/or antibodies induced by immunization with living bacteria and to counterselect antigens interacting with the immune effectors induced by immunization with dead bacteria. A Mycobacterium bovis BCG 45/47-kDa antigen complex, present in BCG culture filtrate, has been previously identified and isolated (F. Romain, A. Laqueyrerie, P. Militzer, P. Pescher, P. Chavarot, M. Lagranderie, G. Auregan, M. Gheorghiu, and G. Marchal, Infect. Immun. 61:742-750, 1993). Since the cognate antibodies recognize the very same antigens present in M. tuberculosis culture medium filtrates, a project was undertaken to clone, express, and sequence the corresponding gene of M. tuberculosis. An M. tuberculosis shuttle cosmid library was transferred in Mycobacterium smegmatis and screened with a competitive enzyme-linked immunosorbent assay to detect the clones expressing the proteins. A clone containing a 40-kb DNA insert was selected, and by means of subcloning in Escherichia coli, a 2-kb fragment that coded for the molecules was identified. An open reading frame in the 2,061-nucleotide sequence codes for a secreted protein with a consensus signal peptide of 39 amino acids and a predicted molecular mass of 28,779 Da. The gene was referred to as apa because of the high percentages of proline (21.7%) and alanine (19%) in the purified protein. Southern hybridization analysis of digested total genomic DNA from M. tuberculosis (reference strains H37Rv and H37Ra) indicated that the apa gene was present as a single copy on the genome. The N-terminal identity or homology of the M. tuberculosis and M. bovis BCG purified molecules and their similar global and deduced amino acid compositions demonstrated the perfect correspondence between the molecular and chemical analyses. The presence of a high percentage of proline (21.7%) was confirmed and explained the apparent higher molecular mass (45/47 kDa) determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis resulting from the increased rigidity of molecules due to proline residues.(ABSTRACT TRUNCATED AT 400 WORDS)

Antiseptic resistance: what do we know and what does it mean?

PubMed

Sheldon, Albert T

2005-01-01

Biocides (antiseptics, disinfectants, preservatives, sterilants) are used in clinical medicine as intervention strategies that prevent the dissemination of nosocomial pathogens. Biocides are also used for personal hygiene and to prevent cross-contamination of food-borne pathogens in homes, restaurants, day care centers, and nursing homes. However, laboratory evidence has emerged suggesting that the mechanism of nonsusceptibility to biocides may counter-select for resistance to antibiotics. Nature conserves successful survival strategies. Using existing mechanisms of resistance to antibiotics and their means of dissemination, microorganisms have adopted this same survival strategy for biocide nonsusceptibility. These mechanisms are intrinsic in nature or are acquired. The consequences to biocide efficacy in the clinical setting are probably not significant from the biocide perspective. But, the selective pressure biocides exert on bacterial populations that have mechanisms of resistance similar to those to antibiotics or that are also substrates for antibiotic resistance is of concern.

Detection of haplotypes associated with prenatal death in dairy cattle and identification of deleterious mutations in GART, SHBG and SLC37A2.

PubMed

Fritz, Sébastien; Capitan, Aurelien; Djari, Anis; Rodriguez, Sabrina C; Barbat, Anne; Baur, Aurélia; Grohs, Cécile; Weiss, Bernard; Boussaha, Mekki; Esquerré, Diane; Klopp, Christophe; Rocha, Dominique; Boichard, Didier

2013-01-01

The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10(-4)) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle.

Human scFv antibody fragments specific for hepatocellular carcinoma selected from a phage display library.

PubMed

Yu, Bing; Ni, Ming; Li, Wen-Han; Lei, Ping; Xing, Wei; Xiao, Dai-Wen; Huang, Yu; Tang, Zhen-Jie; Zhu, Hui-Fen; Shen, Guan-Xin

2005-07-14

To identify the scFv antibody fragments specific for hepatocellular carcinoma by biopanning from a large human naive scFv phage display library. A large human naive scFv phage library was used to search for the specific targets by biopanning with the hepatocellular carcinoma cell line HepG2 for the positive-selecting and the normal liver cell line L02 for the counter-selecting. After three rounds of biopanning, individual scFv phages binding selectively to HepG2 cells were picked out. PCR was carried out for identification of the clones containing scFv gene sequence. The specific scFv phages were selected by ELISA and flow cytometry. DNA sequences of positive clones were analyzed by using Applied Biosystem Automated DNA sequencers 3 730. The expression proteins of the specific scFv antibody fragments in E.coli HB2151 were purified by the affinity chromatography and detected by SDS-PAGE, Western blot and ELISA. The biological effect of the soluble antibody fragments on the HepG2 cells was investigated by observing the cell proliferation. Two different positive clones were obtained and the functional variable sequences were identified. Their DNA sequences of the scFv antibody fragments were submitted to GenBank (accession nos: AY686498 and AY686499). The soluble scFv antibody fragments were successfully expressed in E.coli HB2151. The relative molecular mass of the expression products was about 36 ku, according to its predicted M(r) value. The two soluble scFv antibody fragments also had specific binding activity and obvious growth inhibition properties to HepG2 cells. The phage library biopanning permits identification of specific antibody fragments for hepatocellular carcinoma and affords experiment evidence for its immunotherapy study.

Characterization of the RpoS Status of Clinical Isolates of Salmonella enterica

PubMed Central

Robbe-Saule, Véronique; Algorta, Gabriela; Rouilhac, Isabelle; Norel, Françoise

2003-01-01

The stationary-phase-inducible sigma factor, σS (RpoS), is the master regulator of the general stress response in Salmonella and is required for virulence in mice. rpoS mutants can frequently be isolated from highly passaged laboratory strains of Salmonella. We examined the rpoS status of 116 human clinical isolates of Salmonella, including 41 Salmonella enterica serotype Typhi strains isolated from blood, 38 S. enterica serotype Typhimurium strains isolated from blood, and 37 Salmonella serotype Typhimurium strains isolated from feces. We examined the abilities of these strains to produce the σS protein, to express RpoS-dependent catalase activity, and to resist to oxidative stress in the stationary phase of growth. We also carried out complementation experiments with a cloned wild-type rpoS gene. Our results showed that 15 of the 41 Salmonella serotype Typhi isolates were defective in RpoS. We sequenced the rpoS allele of 12 strains. This led to identification of small insertions, deletions, and point mutations resulting in premature stop codons or affecting regions 1 and 2 of σS, showing that the rpoS mutations are not clonal. Thus, mutant rpoS alleles can be found in freshly isolated clinical strains of Salmonella serotype Typhi, and they may affect virulence properties. Interestingly however, no rpoS mutants were found among the 75 Salmonella serotype Typhimurium isolates. Strains that differed in catalase activity and resistance to hydrogen peroxide were found, but the differences were not linked to the rpoS status. This suggests that Salmonella serotype Typhimurium rpoS mutants are counterselected because rpoS plays a role in the pathogenesis of Salmonella serotype Typhimurium in humans or in the transmission cycle of the disease. PMID:12902215

Conceptual assessment tool for advanced undergraduate electrodynamics

NASA Astrophysics Data System (ADS)

Baily, Charles; Ryan, Qing X.; Astolfi, Cecilia; Pollock, Steven J.

2017-12-01

As part of ongoing investigations into student learning in advanced undergraduate courses, we have developed a conceptual assessment tool for upper-division electrodynamics (E&M II): the Colorado UppeR-division ElectrodyNamics Test (CURrENT). This is a free response, postinstruction diagnostic with 6 multipart questions, an optional 3-question preinstruction test, and accompanying grading rubrics. The instrument's development was guided by faculty-consensus learning goals and research into common student difficulties. It can be used to gauge the effectiveness of transformed pedagogy, and to gain insights into student thinking in the covered topic areas. We present baseline data representing 500 students across 9 institutions, along with validity, reliability, and discrimination measures of the instrument and scoring rubric.

Personality correlates of aggression: evidence from measures of the five-factor model, UPPS model of impulsivity, and BIS/BAS.

PubMed

Miller, Joshua D; Zeichner, Amos; Wilson, Lauren F

2012-09-01

Although many studies of personality and aggression focus on multidimensional traits and higher order personality disorders (e.g., psychopathy), lower order, unidimensional traits may provide more precision in identifying specific aspects of personality that relate to aggression. The current study includes a comprehensive measurement of lower order personality traits in relation to three forms of aggression: reactive, proactive, and relational. Traits related to interpersonal antagonism and impulsivity, especially impulsive behavior in the context of negative affect, were consistently related to aggression across multiple indices. These findings suggest that certain lower order traits are of critical importance to understanding who engages in aggressive behavior and why this behavior occurs.

Developmental Neurogenetics and Multimodal Neuroimaging of Sex Differences in Autism

PubMed Central

Chen, Christina; Van Horn, John Darrell

2016-01-01

Examining sex differences in the brain has been contentious but is nonetheless important for advancing mental health for both girls and boys. Unfortunately, females in biomedical research remain underrepresented in most mental health conditions including autism spectrum disorders (ASD), even though equal inclusion of females would improve treatment for girls and yield benefits to boys. This review examines sex differences in the relationship between neuroanatomy and neurogenetics of ASD. Recent findings reveal that girls diagnosed with ASD exhibit more intellectual and behavioral problems compared to their male counterparts, suggesting that girls may be less likely diagnosed in the absence of such problems or that they require a higher mutational load to meet the diagnostic criteria. Thus far, the female biased effect of chromosome 4, 5p15.33, 8p, 9p24.1, 11p12-13, 15q, and Xp22.3 and the male biased effect of 1p31.3, 5q12.3, 7q, 9q33.3, 11q13.4, 13q33.3, 16p11.2, 17q11-21, Xp22.33/Yp11.31, DRD1, NLGN3, MAOA, and SHANK1 deletion have been discovered in ASD. The SNPs of genes such as RYR2, UPP2, and the androgen receptor gene have been shown to have sex-biasing factors in both girls and boys diagnosed with ASD. These sex-related genetic factors may drive sex differences in the neuroanatomy of these girls and boys, including abnormal enlargement in temporal gray and white matter volumes, and atypical reduction in cerebellar gray matter volumes and corpus callosum fibers projecting to the anterior frontal cortex in ASD girls relative to boys. Such factors may also be responsible for the attenuation of brain sexual differentiation in adult men and women with ASD; however, much remains to be uncovered or replicated. Future research should leverage further the association between neuroanatomy and genetics in girls for an integrated and interdisciplinary understanding of ASD. PMID:26781567

Developmental neurogenetics and multimodal neuroimaging of sex differences in autism.

PubMed

Chen, Christina; Van Horn, John Darrell

2017-02-01

Examining sex differences in the brain has been historically contentious but is nonetheless important for advancing mental health for both girls and boys. Unfortunately, females in biomedical research remain underrepresented in most mental health conditions including autism spectrum disorders (ASD), even though equal inclusion of females would improve treatment for girls and yield benefits to boys. This review examines sex differences in the relationship between neuroanatomy and neurogenetics of ASD. Recent findings reveal that girls diagnosed with ASD exhibit more intellectual and behavioral problems compared to their male counterparts, suggesting that girls may be less likely diagnosed in the absence of such problems or that they require a higher mutational load to meet the diagnostic criteria. Thus far, the female biased effect of chromosome 4, 5p15.33, 8p, 9p24.1, 11p12-13, 15q, and Xp22.3 and the male biased effect of 1p31.3, 5q12.3, 7q, 9q33.3, 11q13.4, 13q33.3, 16p11.2, 17q11-21, Xp22.33/Yp11.31, DRD1, NLGN3, MAOA, and SHANK1 deletion have been discovered in ASD. The SNPs of genes such as RYR2, UPP2, and the androgen receptor gene have been shown to have sex-biasing factors in both girls and boys diagnosed with ASD. These sex-related genetic factors may drive sex differences in the neuroanatomy of these girls and boys, including abnormal enlargement in temporal gray and white matter volumes, and atypical reduction in cerebellar gray matter volumes and corpus callosum fibers projecting to the anterior frontal cortex in ASD girls relative to boys. Such factors may also be responsible for the attenuation of brain sexual differentiation in adult men and women with ASD; however, much remains to be uncovered or replicated. Future research should leverage further the association between neuroanatomy and genetics in girls for an integrated and interdisciplinary understanding of ASD.

Comparing different policy scenarios to reduce the consumption of ultra-processed foods in UK: impact on cardiovascular disease mortality using a modelling approach.

PubMed

Moreira, Patricia V L; Baraldi, Larissa Galastri; Moubarac, Jean-Claude; Monteiro, Carlos Augusto; Newton, Alex; Capewell, Simon; O'Flaherty, Martin

2015-01-01

The global burden of non-communicable diseases partly reflects growing exposure to ultra-processed food products (UPPs). These heavily marketed UPPs are cheap and convenient for consumers and profitable for manufacturers, but contain high levels of salt, fat and sugars. This study aimed to explore the potential mortality reduction associated with future policies for substantially reducing ultra-processed food intake in the UK. We obtained data from the UK Living Cost and Food Survey and from the National Diet and Nutrition Survey. By the NOVA food typology, all food items were categorized into three groups according to the extent of food processing: Group 1 describes unprocessed/minimally processed foods. Group 2 comprises processed culinary ingredients. Group 3 includes all processed or ultra-processed products. Using UK nutrient conversion tables, we estimated the energy and nutrient profile of each food group. We then used the IMPACT Food Policy model to estimate reductions in cardiovascular mortality from improved nutrient intakes reflecting shifts from processed or ultra-processed to unprocessed/minimally processed foods. We then conducted probabilistic sensitivity analyses using Monte Carlo simulation. Approximately 175,000 cardiovascular disease (CVD) deaths might be expected in 2030 if current mortality patterns persist. However, halving the intake of Group 3 (processed) foods could result in approximately 22,055 fewer CVD related deaths in 2030 (minimum estimate 10,705, maximum estimate 34,625). An ideal scenario in which salt and fat intakes are reduced to the low levels observed in Group 1 and 2 could lead to approximately 14,235 (minimum estimate 6,680, maximum estimate 22,525) fewer coronary deaths and approximately 7,820 (minimum estimate 4,025, maximum estimate 12,100) fewer stroke deaths, comprising almost 13% mortality reduction. This study shows a substantial potential for reducing the cardiovascular disease burden through a healthier food system. It highlights the crucial importance of implementing healthier UK food policies.

[Correlation between body mass index and development of pressure ulcers in intensive care medicine].

PubMed

Catalá Espinosa, A I; Hidalgo Encinas, Y; Cherednichenko, T; Flores Lucas, I; González Tamayo, R; García-Martínez, M Á; Herrero-Gutiérrez, E

2014-01-01

This study aims to evaluate the association between body mass index (BMI), incidence and severity of pressure ulcers (PU) in patients admitted to the Intensive Care Unit (ICU), and describe the differential prognosis of patients with PU and factors that modify it. Case-control study with observation period of 15 months. We collected baseline variables, prognostic scales, therapies and clinical outcome. Univariate analysis was performed for each outcome variable between cases and controls using the appropriate hypothesis test depending on the nature of the variables. ROC curve for BMI and PU. Logistic regression with PU as dependent variable and the covariates that reached p<0.05 in the bivariate analysis. Correlation using Pearson or Spearman was made between BMI, albumin, days to diagnosis of UPP, immobilization, and PU degree. Significance level at p <0.05. 77 patients developed PU and 231 controls were chosen. The cases had higher APACHE II (p=0.043) and SAPS 3 (p=0.023), length of stay in ICU and mechanical ventilation (p<0.001). BMI≥40 was associated with UPP (p=0.024 OR=3.23 CI95% 1.17-8.93). There was a significant association between PU degree, length of stay and MV (p<0,001), but not with immobilization, dynamic support surface and death rate. Multivariate analysis found association between PU, length of MV (p=0.013, OR 1.08, CI95% 1.01-1.16) and kidney replacement therapy (p=0.013, OR 3.55 CI95% 1.31-9.64), with BMI≥40 as a confounding factor. Length of mechanical ventilation and renal replacement therapy are risk factors for pressure ulcer development, and BMI≥40 acts as a confounding factor. PU development and its maximum degree are not associated with a worse prognosis. Copyright © 2013 Elsevier España, S.L.U. y SEEIUC. All rights reserved.

Examination of the heterogeneity in PTSD and impulsivity facets: A latent profile analysis.

PubMed

Contractor, Ateka A; Caldas, Stephanie; Weiss, Nicole H; Armour, Cherie

2018-04-15

The experience of traumatizing events and resulting posttraumatic stress disorder (PTSD) symptomology relates to a range of impulsive behaviors. While both PTSD and impulsivity are heterogeneous and multidimensional constructs, no research has used person-centered approaches to examine subgroups of individuals based on these response endorsements. Hence, our study examined PTSD-impulsivity typologies and their construct validity in two samples: university students ( n = 412) and community participants recruited through Amazon's MTurk ( n = 346). Measures included the Stressful Life Events Screening Questionnaire (PTEs), PTSD Checklist for DSM-5 (PTSD severity), UPPS Impulsive Behavior Scale (negative urgency, lack of premeditation, lack of perseverance, sensation seeking). Dimensions of Anger Reaction Scale (anger), and the Patient Health Questionnaire-9 (depression). For both samples, results of latent profile analyses indicated a best-fitting 3-class solution: High, Moderate, and Low PTSD-Negative Urgency. Negative urgency was the most distinguishing impulsivity facet. Anger and depression severity significantly predicted membership in the more severe symptomatology classes. Thus, individuals can be meaningfully categorized into three subgroups based on PTSD and impulsivity item endorsements. We provide some preliminary evidence for a negative urgency subtype of PTSD characterized by greater depression and anger regulation difficulties; and underscore addressing emotional regulation skills for these subgroup members.

What prevents phenological adjustment to climate change in migrant bird species? Evidence against the ``arrival constraint'' hypothesis

NASA Astrophysics Data System (ADS)

Goodenough, Anne E.; Hart, Adam G.; Elliot, Simon L.

2011-01-01

Phenological studies have demonstrated changes in the timing of seasonal events across multiple taxonomic groups as the climate warms. Some northern European migrant bird populations, however, show little or no significant change in breeding phenology, resulting in synchrony with key food sources becoming mismatched. This phenological inertia has often been ascribed to migration constraints (i.e. arrival date at breeding grounds preventing earlier laying). This has been based primarily on research in The Netherlands and Germany where time between arrival and breeding is short (often as few as 9 days). Here, we test the arrival constraint hypothesis over a 15-year period for a U.K. pied flycatcher ( Ficedula hypoleuca) population where laying date is not constrained by arrival as the period between arrival and breeding is substantial and consistent (average 27 ± 4.57 days SD). Despite increasing spring temperatures and quantifiably stronger selection for early laying on the basis of number of offspring to fledge, we found no significant change in breeding phenology, in contrast with co-occurring resident blue tits ( Cyanistes caeruleus). We discuss possible non-migratory constraints on phenological adjustment, including limitations on plasticity, genetic constraints and competition, as well as the possibility of counter-selection pressures relating to adult survival, longevity or future reproductive success. We propose that such factors need to be considered in conjunction with the arrival constraint hypothesis.

Extensive paternal mtDNA leakage in natural populations of Drosophila melanogaster.

PubMed

Nunes, Maria D S; Dolezal, Marlies; Schlötterer, Christian

2013-04-01

Strict maternal inheritance is considered a hallmark of animal mtDNA. Although recent reports suggest that paternal leakage occurs in a broad range of species, it is still considered an exceptionally rare event. To evaluate the impact of paternal leakage on the evolution of mtDNA, it is essential to reliably estimate the frequency of paternal leakage in natural populations. Using allele-specific real-time quantitative PCR (RT-qPCR), we show that heteroplasmy is common in natural populations with at least 14% of the individuals carrying multiple mitochondrial haplotypes. However, the average frequency of the minor mtDNA haplotype is low (0.8%), which suggests that this pervasive heteroplasmy has not been noticed before due to a lack of power in sequencing surveys. Based on the distribution of mtDNA haplotypes in the offspring of heteroplasmic mothers, we found no evidence for strong selection against one of the haplotypes. We estimated that the rate of paternal leakage is 6% and that at least 100 generations are required for complete sorting of mtDNA haplotypes. Despite the high proportion of heteroplasmic individuals in natural populations, we found no evidence for recombination between mtDNA molecules, suggesting that either recombination is rare or recombinant haplotypes are counter-selected. Our results indicate that evolutionary studies using mtDNA as a marker might be biased by paternal leakage in this species. © 2013 Blackwell Publishing Ltd.

What prevents phenological adjustment to climate change in migrant bird species? Evidence against the "arrival constraint" hypothesis.

PubMed

Goodenough, Anne E; Hart, Adam G; Elliot, Simon L

2011-01-01

Phenological studies have demonstrated changes in the timing of seasonal events across multiple taxonomic groups as the climate warms. Some northern European migrant bird populations, however, show little or no significant change in breeding phenology, resulting in synchrony with key food sources becoming mismatched. This phenological inertia has often been ascribed to migration constraints (i.e. arrival date at breeding grounds preventing earlier laying). This has been based primarily on research in The Netherlands and Germany where time between arrival and breeding is short (often as few as 9 days). Here, we test the arrival constraint hypothesis over a 15-year period for a U.K. pied flycatcher (Ficedula hypoleuca) population where laying date is not constrained by arrival as the period between arrival and breeding is substantial and consistent (average 27 ± 4.57 days SD). Despite increasing spring temperatures and quantifiably stronger selection for early laying on the basis of number of offspring to fledge, we found no significant change in breeding phenology, in contrast with co-occurring resident blue tits (Cyanistes caeruleus). We discuss possible non-migratory constraints on phenological adjustment, including limitations on plasticity, genetic constraints and competition, as well as the possibility of counter-selection pressures relating to adult survival, longevity or future reproductive success. We propose that such factors need to be considered in conjunction with the arrival constraint hypothesis.

Linking autoimmunity to the origin of the adaptive immune system.

PubMed

Bayersdorf, Robert; Fruscalzo, Arrigo; Catania, Francesco

2018-01-01

In jawed vertebrates, the adaptive immune system (AIS) cooperates with the innate immune system (IIS) to protect hosts from infections. Although targeting non-self-components, the AIS also generates self-reactive antibodies which, when inadequately counter-selected, can give rise to autoimmune diseases (ADs). ADs are on the rise in western countries. Why haven't ADs been eliminated during the evolution of a ∼500 million-year old system? And why have they become more frequent in recent decades? Self-recognition is an attribute of the phylogenetically more ancient IIS and empirical data compellingly show that some self-reactive antibodies, which are classifiable as elements of the IIS rather then the AIS, may protect from (rather than cause) ADs. Here, we propose that the IIS's self-recognition system originally fathered the AIS and, as a consequence of this relationship, its activity is dampened in hygienic environments. Rather than a mere breakdown or failure of the mechanisms of self-tolerance, ADs might thus arise from architectural constraints.

Guidelines for diagnosis and management of chronic obstructive pulmonary disease: Joint ICS/NCCP (I) recommendations

PubMed Central

Gupta, Dheeraj; Agarwal, Ritesh; Aggarwal, Ashutosh Nath; Maturu, V. N.; Dhooria, Sahajal; Prasad, K. T.; Sehgal, Inderpaul S.; Yenge, Lakshmikant B.; Jindal, Aditya; Singh, Navneet; Ghoshal, A. G.; Khilnani, G. C.; Samaria, J. K.; Gaur, S. N.; Behera, D.

2013-01-01

Chronic obstructive pulmonary disease (COPD) is a major public health problem in India. Although several International guidelines for diagnosis and management of COPD are available, yet there are lot of gaps in recognition and management of COPD in India due to vast differences in availability and affordability of healthcare facilities across the country. The Indian Chest Society (ICS) and the National College of Chest Physicians (NCCP) of India have joined hands to come out with these evidence-based guidelines to help the physicians at all levels of healthcare to diagnose and manage COPD in a scientific manner. Besides the International literature, the Indian studies were specifically analyzed to arrive at simple and practical recommendations. The evidence is presented under these five headings: (a) definitions, epidemiology, and disease burden; (b) disease assessment and diagnosis; (c) pharmacologic management of stable COPD; (d) management of acute exacerbations; and (e) nonpharmacologic and preventive measures. The modified grade system was used for classifying the quality of evidence as 1, 2, 3, or usual practice point (UPP). The strength of recommendation was graded as A or B depending upon the level of evidence. PMID:24049265

Striatal dopamine D2/D3 receptor binding in pathological gambling is correlated with mood-related impulsivity

PubMed Central

Clark, Luke; Stokes, Paul R.; Wu, Kit; Michalczuk, Rosanna; Benecke, Aaf; Watson, Ben J.; Egerton, Alice; Piccini, Paola; Nutt, David J.; Bowden-Jones, Henrietta; Lingford-Hughes, Anne R.

2012-01-01

Pathological gambling (PG) is a behavioural addiction associated with elevated impulsivity and suspected dopamine dysregulation. Reduced striatal dopamine D2/D3 receptor availability has been reported in drug addiction, and may constitute a premorbid vulnerability marker for addictive disorders. The aim of the present study was to assess striatal dopamine D2/D3 receptor availability in PG, and its association with trait impulsivity. Males with PG (n = 9) and male healthy controls (n = 9) underwent [11C]-raclopride positron emission tomography imaging and completed the UPPS-P impulsivity scale. There was no significant difference between groups in striatal dopamine D2/D3 receptor availability, in contrast to previous reports in drug addiction. However, mood-related impulsivity (‘Urgency’) was negatively correlated with [11C]-raclopride binding potentials in the PG group. The absence of a group difference in striatal dopamine binding implies a distinction between behavioural addictions and drug addictions. Nevertheless, our data indicate heterogeneity in dopamine receptor availability in disordered gambling, such that individuals with high mood-related impulsivity may show differential benefits from dopamine-based medications. PMID:22776462

Hermes Transposon Mutagenesis Shows [URE3] Prion Pathology Prevented by a Ubiquitin-Targeting Protein: Evidence for Carbon/Nitrogen Assimilation Cross-Talk and a Second Function for Ure2p in Saccharomyces cerevisiae.

PubMed

Edskes, Herman K; Mukhamedova, Maryam; Edskes, Bouke K; Wickner, Reed B

2018-05-16

[URE3] is an amyloid-based prion of Ure2p, a regulator of nitrogen catabolism. While most variants of the [URE3] prion are toxic, mild variants that only slightly slow growth are more widely studied. The existence of several anti-prion systems suggests that some components may be protecting cells from potential detrimental effects of mild [URE3] variants. Our extensive Hermes transposon mutagenesis showed that disruption of YLR352W dramatically slows growth of [URE3-1] strains. Ylr352wp is an F-box protein, directing selection of substrates for ubiquitination by a cullin-containing E- 3 ligase. For efficient ubiquitylation, cullin-dependent E 3 ubiquitin ligases must be NEDDylated, modified by a ubiquitin-related peptide called NEDD8 (Rub1p in yeast). Indeed, we find that disruption of NEDDylation-related genes, RUB1, ULA1, UBA3 and UBC12 is also counterselected in our screen. We find that like ylr352w Δ [URE3] strains, ylr352w Δ ure2 Δ strains do not grow on non-fermentable carbon sources. Overexpression of Hap4p, a transcription factor stimulating expression of mitochondrial proteins, or mutation of GLN1 , encoding glutamine synthetase, allow growth of ylr352w Δ [URE3] strains on glycerol media. Supplying proline as a nitrogen source shuts off the nitrogen catabolite repression (NCR) function of Ure2p, but does not slow growth of ylr352w Δ strains, suggesting a distinct function of Ure2p in carbon catabolism. Also, gln1 mutations impair NCR, but actually relieve the growth defect of ylr352w Δ [URE3] and ylr352w Δ ure2 Δ strains, again showing that loss of NCR is not producing the growth defect and suggesting Ure2p has another function. YLR352W largely protects cells from the deleterious effects of otherwise mild [URE3] variants, or of a ure2 mutation (the latter a rarer event), and we name it LUG1 (lets [URE3]/ ure2 grow). Copyright © 2018, Genetics.

The Paramecium germline genome provides a niche for intragenic parasitic DNA: evolutionary dynamics of internal eliminated sequences.

PubMed

Arnaiz, Olivier; Mathy, Nathalie; Baudry, Céline; Malinsky, Sophie; Aury, Jean-Marc; Denby Wilkes, Cyril; Garnier, Olivier; Labadie, Karine; Lauderdale, Benjamin E; Le Mouël, Anne; Marmignon, Antoine; Nowacki, Mariusz; Poulain, Julie; Prajer, Malgorzata; Wincker, Patrick; Meyer, Eric; Duharcourt, Sandra; Duret, Laurent; Bétermier, Mireille; Sperling, Linda

2012-01-01

Insertions of parasitic DNA within coding sequences are usually deleterious and are generally counter-selected during evolution. Thanks to nuclear dimorphism, ciliates provide unique models to study the fate of such insertions. Their germline genome undergoes extensive rearrangements during development of a new somatic macronucleus from the germline micronucleus following sexual events. In Paramecium, these rearrangements include precise excision of unique-copy Internal Eliminated Sequences (IES) from the somatic DNA, requiring the activity of a domesticated piggyBac transposase, PiggyMac. We have sequenced Paramecium tetraurelia germline DNA, establishing a genome-wide catalogue of -45,000 IESs, in order to gain insight into their evolutionary origin and excision mechanism. We obtained direct evidence that PiggyMac is required for excision of all IESs. Homology with known P. tetraurelia Tc1/mariner transposons, described here, indicates that at least a fraction of IESs derive from these elements. Most IES insertions occurred before a recent whole-genome duplication that preceded diversification of the P. aurelia species complex, but IES invasion of the Paramecium genome appears to be an ongoing process. Once inserted, IESs decay rapidly by accumulation of deletions and point substitutions. Over 90% of the IESs are shorter than 150 bp and present a remarkable size distribution with a -10 bp periodicity, corresponding to the helical repeat of double-stranded DNA and suggesting DNA loop formation during assembly of a transpososome-like excision complex. IESs are equally frequent within and between coding sequences; however, excision is not 100% efficient and there is selective pressure against IES insertions, in particular within highly expressed genes. We discuss the possibility that ancient domestication of a piggyBac transposase favored subsequent propagation of transposons throughout the germline by allowing insertions in coding sequences, a fraction of the genome in which parasitic DNA is not usually tolerated.

The Paramecium Germline Genome Provides a Niche for Intragenic Parasitic DNA: Evolutionary Dynamics of Internal Eliminated Sequences

PubMed Central

Arnaiz, Olivier; Mathy, Nathalie; Baudry, Céline; Malinsky, Sophie; Aury, Jean-Marc; Denby Wilkes, Cyril; Garnier, Olivier; Labadie, Karine; Lauderdale, Benjamin E.; Le Mouël, Anne; Marmignon, Antoine; Nowacki, Mariusz; Poulain, Julie; Prajer, Malgorzata; Wincker, Patrick; Meyer, Eric; Duharcourt, Sandra; Duret, Laurent; Bétermier, Mireille; Sperling, Linda

2012-01-01

Insertions of parasitic DNA within coding sequences are usually deleterious and are generally counter-selected during evolution. Thanks to nuclear dimorphism, ciliates provide unique models to study the fate of such insertions. Their germline genome undergoes extensive rearrangements during development of a new somatic macronucleus from the germline micronucleus following sexual events. In Paramecium, these rearrangements include precise excision of unique-copy Internal Eliminated Sequences (IES) from the somatic DNA, requiring the activity of a domesticated piggyBac transposase, PiggyMac. We have sequenced Paramecium tetraurelia germline DNA, establishing a genome-wide catalogue of ∼45,000 IESs, in order to gain insight into their evolutionary origin and excision mechanism. We obtained direct evidence that PiggyMac is required for excision of all IESs. Homology with known P. tetraurelia Tc1/mariner transposons, described here, indicates that at least a fraction of IESs derive from these elements. Most IES insertions occurred before a recent whole-genome duplication that preceded diversification of the P. aurelia species complex, but IES invasion of the Paramecium genome appears to be an ongoing process. Once inserted, IESs decay rapidly by accumulation of deletions and point substitutions. Over 90% of the IESs are shorter than 150 bp and present a remarkable size distribution with a ∼10 bp periodicity, corresponding to the helical repeat of double-stranded DNA and suggesting DNA loop formation during assembly of a transpososome-like excision complex. IESs are equally frequent within and between coding sequences; however, excision is not 100% efficient and there is selective pressure against IES insertions, in particular within highly expressed genes. We discuss the possibility that ancient domestication of a piggyBac transposase favored subsequent propagation of transposons throughout the germline by allowing insertions in coding sequences, a fraction of the genome in which parasitic DNA is not usually tolerated. PMID:23071448

Detection of Haplotypes Associated with Prenatal Death in Dairy Cattle and Identification of Deleterious Mutations in GART, SHBG and SLC37A2

PubMed Central

Fritz, Sébastien; Capitan, Aurelien; Djari, Anis; Rodriguez, Sabrina C.; Barbat, Anne; Baur, Aurélia; Grohs, Cécile; Weiss, Bernard; Boussaha, Mekki; Esquerré, Diane; Klopp, Christophe; Rocha, Dominique; Boichard, Didier

2013-01-01

The regular decrease of female fertility over time is a major concern in modern dairy cattle industry. Only half of this decrease is explained by indirect response to selection on milk production, suggesting the existence of other factors such as embryonic lethal genetic defects. Genomic regions harboring recessive deleterious mutations were detected in three dairy cattle breeds by identifying frequent haplotypes (>1%) showing a deficit in homozygotes among Illumina Bovine 50k Beadchip haplotyping data from the French genomic selection database (47,878 Holstein, 16,833 Montbéliarde, and 11,466 Normande animals). Thirty-four candidate haplotypes (p<10−4) including previously reported regions associated with Brachyspina, CVM, HH1, and HH3 in Holstein breed were identified. Haplotype length varied from 1 to 4.8 Mb and frequencies from 1.7 up to 9%. A significant negative effect on calving rate, consistent in heifers and in lactating cows, was observed for 9 of these haplotypes in matings between carrier bulls and daughters of carrier sires, confirming their association with embryonic lethal mutations. Eight regions were further investigated using whole genome sequencing data from heterozygous bull carriers and control animals (45 animals in total). Six strong candidate causative mutations including polymorphisms previously reported in FANCI (Brachyspina), SLC35A3 (CVM), APAF1 (HH1) and three novel mutations with very damaging effect on the protein structure, according to SIFT and Polyphen-2, were detected in GART, SHBG and SLC37A2 genes. In conclusion, this study reveals a yet hidden consequence of the important inbreeding rate observed in intensively selected and specialized cattle breeds. Counter-selection of these mutations and management of matings will have positive consequences on female fertility in dairy cattle. PMID:23762392

Effects of Hofmeister salt series on gluten network formation: Part II. Anion series.

PubMed

Tuhumury, H C D; Small, D M; Day, L

2016-12-01

Different anion salts from the Hofmeister series were used to investigate their effects on gluten network formation. The effects of these anion salts on the mixing properties of the dough and the rheological and chemical properties of gluten samples extracted from the dough with these respective salts were compared. The aim of this work was to determine how different anion salts influence the formation of the gluten structure during dough mixing. It was found that the Hofmeister anion salts affected the gluten network formation by interacting directly with specific amino acid residues that resulted in changes in gluten protein composition, specifically the percentage of the unextractable polymeric protein fractions (%UPP). These changes consequently led to remarkable differences in the mixing profiles and microstructural features of the dough, small deformation rheological properties of the gluten and a strain hardening behaviour of both dough and gluten samples. Copyright © 2016 Elsevier Ltd. All rights reserved.

The slant of the forehead as a craniofacial feature of impulsiveness.

PubMed

Guerrero-Apolo, J David; Navarro-Pastor, J Blas; Bulbena-Vilarrasa, Antonio; Gabarre-Mir, Julián

2018-03-12

Impulsiveness has been the subject of much research, but little is known about the possible relationship between craniofacial anatomy and impulsiveness. The present study was designed to investigate the relationship between one aspect of craniofacial structure (the angle of inclination of the forehead) and impulsiveness. Photographs in profile were obtained from 131 volunteers who had been fined for driving at high speed and were undergoing a court-mandated driving license point-recovery course. They completed the Barratt Impulsiveness Scale (BIS-11), the Impulsive Behavior Scale (UPPS-P), and Zuckerman's Sensation Seeking Scale (V). The angle of the slant of the forehead was measured with a photographic support and a protractor. High positive concordance was found between forehead inclination and 14 out of the 15 impulsiveness factors studied. The angle of inclination of the forehead was significantly associated with self-reported impulsiveness in this sample of traffic violators.

Trauma exposure interacts with impulsivity in predicting emotion regulation and depressive mood

PubMed Central

Ceschi, Grazia; Billieux, Joël; Hearn, Melissa; Fürst, Guillaume; Van der Linden, Martial

2014-01-01

Background Traumatic exposure may modulate the expression of impulsive behavioral dispositions and change the implementation of emotion regulation strategies associated with depressive mood. Past studies resulted in only limited comprehension of these relationships, especially because they failed to consider impulsivity as a multifactorial construct. Objective Based on Whiteside and Lynam's multidimensional model that identifies four distinct dispositional facets of impulsive-like behaviors, namely urgency, (lack of) premeditation, (lack of) perseverance, and sensation seeking (UPPS), the current study used a sample of community volunteers to investigate whether an interaction exists between impulsivity facets and lifetime trauma exposure in predicting cognitive emotion regulation and depressive mood. Methods Ninety-three adults completed questionnaires measuring lifetime trauma exposure, impulsivity, cognitive emotion regulation, and depressive mood. Results Results showed that trauma-exposed participants with a strong disposition toward urgency (predisposition to act rashly in intense emotional contexts) tended to use fewer appropriate cognitive emotion regulation strategies than other individuals. Unexpectedly, participants lacking in perseverance (predisposition to have difficulties concentrating on demanding tasks) used more appropriate emotion regulation strategies if they had experienced traumatic events during their life than if they had not. Emotion regulation mediated the path between these two impulsivity facets and depressive mood. Conclusions Together, these findings suggest that impulsivity has a differential impact on emotion regulation and depressive mood depending on lifetime exposure to environmental factors, especially traumatic events. PMID:25317255

Multidimensional Assessment of Impulsivity in Relation to Obesity and Food Addiction

PubMed Central

VanderBroek-Stice, Lauren; Stojek, Monika K.; Beach, Steven R. H.; vanDellen, Michelle R.; MacKillop, James

2017-01-01

Based on similarities between overconsumption of food and addictive drugs, there is increasing interest in “food addiction,” a compulsive eating pattern defined using symptoms parallel to substance use disorders. Impulsivity, a multidimensional construct robustly linked to drug addiction, has been increasingly examined as an obesity determinant, but with mixed findings. This study sought to clarify relations between three major domains of impulsivity (i.e., impulsive personality traits, discounting of delayed rewards, and behavioral inhibition) in both obesity and food addiction. Based on the association between impulsivity and compulsive drug use, the general hypothesis was that the impulsivity-food addiction relation would be stronger than and responsible for the impulsivity-obesity relation. Using a cross-sectional dimensional design, participants (N = 181; 32% obese) completed a biometric assessment, the Yale Food Addiction Scale (YFAS), the UPPS-P Impulsive Behavior Scales, a Go/NoGo task, and measures of monetary delay discounting. Results revealed significantly higher prevalence of food addiction among obese participants and stronger zero-order associations between impulsivity indices and YFAS compared to obesity. Two aspects of impulsivity were independently significantly associated with food addiction: (a) a composite of Positive and Negative Urgency, reflecting proneness to act impulsively during intense mood states, and (b) steep discounting of delayed rewards. Furthermore, the results supported food addiction as a mediator connecting both urgency and delay discounting with obesity. These findings provide further evidence linking impulsivity to food addiction and obesity, and suggest that food addiction may be a candidate etiological pathway to obesity for individuals exhibiting elevations in these domains. PMID:28087369

Multidimensional assessment of impulsivity in relation to obesity and food addiction.

PubMed

VanderBroek-Stice, Lauren; Stojek, Monika K; Beach, Steven R H; vanDellen, Michelle R; MacKillop, James

2017-05-01

Based on similarities between overconsumption of food and addictive drugs, there is increasing interest in "food addiction," a compulsive eating pattern defined using symptoms parallel to substance use disorders. Impulsivity, a multidimensional construct robustly linked to drug addiction, has been increasingly examined as an obesity determinant, but with mixed findings. This study sought to clarify relations between three major domains of impulsivity (i.e., impulsive personality traits, discounting of delayed rewards, and behavioral inhibition) in both obesity and food addiction. Based on the association between impulsivity and compulsive drug use, the general hypothesis was that the impulsivity-food addiction relation would be stronger than and responsible for the impulsivity-obesity relation. Using a cross-sectional dimensional design, participants (N = 181; 32% obese) completed a biometric assessment, the Yale Food Addiction Scale (YFAS), the UPPS-P Impulsive Behavior Scales, a Go/NoGo task, and measures of monetary delay discounting. Results revealed significantly higher prevalence of food addiction among obese participants and stronger zero-order associations between impulsivity indices and YFAS compared to obesity. Two aspects of impulsivity were independently significantly associated with food addiction: (a) a composite of Positive and Negative Urgency, reflecting proneness to act impulsively during intense mood states, and (b) steep discounting of delayed rewards. Furthermore, the results supported food addiction as a mediator connecting both urgency and delay discounting with obesity. These findings provide further evidence linking impulsivity to food addiction and obesity, and suggest that food addiction may be a candidate etiological pathway to obesity for individuals exhibiting elevations in these domains. Copyright © 2017 Elsevier Ltd. All rights reserved.

Heavy metals in liquid pig manure in light of bacterial antimicrobial resistance

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hoelzel, Christina S., E-mail: Christina.Hoelzel@wzw.tum.de; Mueller, Christa; Harms, Katrin S.

Heavy metals are regularly found in liquid pig manure, and might interact with bacterial antimicrobial resistance. Concentrations of heavy metals were determined by atomic spectroscopic methods in 305 pig manure samples and were connected to the phenotypic resistance of Escherichia coli (n=613) against 29 antimicrobial drugs. Concentrations of heavy metals (/kg dry matter) were 0.08-5.30 mg cadmium, 1.1-32.0 mg chrome, 22.4-3387.6 mg copper, <2.0-26.7 mg lead, <0.01-0.11 mg mercury, 3.1-97.3 mg nickel and 93.0-8239.0 mg zinc. Associated with the detection of copper and zinc, resistance rates against {beta}-lactams were significantly elevated. By contrast, the presence of mercury was significantly associatedmore » with low antimicrobial resistance rates of Escherichia coli against {beta}-lactams, aminoglycosides and other antibiotics. Effects of subinhibitory concentrations of mercury on bacterial resistance against penicillins, cephalosporins, aminoglycosides and doxycycline were also demonstrated in a laboratory trial. Antimicrobial resistance in the porcine microflora might be increased by copper and zinc. By contrast, the occurrence of mercury in the environment might, due to co-toxicity, act counter-selective against antimicrobial resistant strains.« less

Detrimental effect of temperature increase on the fitness of an amphibian ( Lissotriton helveticus)

NASA Astrophysics Data System (ADS)

Galloy, Valérie; Denoël, Mathieu

2010-03-01

Increases of global temperatures have resulted in measurable shifts in the distribution, phenology and survival of some plant and animal species. However, the mechanisms showing links between global warming and biodiversity declines remain unclear. The aim of this study was to examine whether a key parameter of fitness, i.e. offspring number, could be affected by a temperature increase. To this end, we compared egg-laying traits at naturally occurring temperatures (14 °C, 18 °C and 22 °C) in palmate newts, Lissotriton helveticus. Our study suggests that water temperature increase has a negative effect on the fecundity of female newts. Females lay half as many eggs at high temperatures as they do at low temperatures, which results in a lower number of hatchlings. This study shows that global warming would affect amphibian populations. It complements other studies in pointing out that changes in phenology may not be driven only by warmer earlier temperatures but also by counter-selection during late-breeding, particularly in long-term breeders such as newts. More experimental studies should be carried out to understand the complex consequences of global warming and the proximate mechanisms of amphibian decline.

Utilization of a ts-sacB selection system for the generation of a Mycobacterium avium serovar-8 specific glycopeptidolipid allelic exchange mutant

PubMed Central

Irani, Vida R; Lee, Sun-Hwa; Eckstein, Torsten M; Inamine, Julia M; Belisle, John T; Maslow, Joel N

2004-01-01

Background Mycobacterium avium are ubiquitous environmental organisms and a cause of disseminated infection in patients with end-stage AIDS. The glycopeptidolipids (GPL) of M. avium are proposed to participate in the pathogenesis of this organism, however, establishment of a clear role for GPL in disease production has been limited by the inability to genetically manipulate M. avium. Methods To be able to study the role of the GPL in M. avium pathogenesis, a ts-sacB selection system, not previously used in M. avium, was employed as a means to achieve homologous recombination for the rhamnosyltransferase (rtfA) gene of a pathogenic serovar 8 strain of M. avium to prevent addition of serovar-specific sugars to rhamnose of the fatty acyl-peptide backbone of GPL. The genotype of the resultant rtfA mutant was confirmed by polymerase chain reaction and southern hybridization. Disruption in the proximal sugar of the haptenic oligosaccharide resulted in the loss of serovar specific GPL with no change in the pattern of non-serovar specific GPL moieties as shown by thin layer chromatography and gas chromatography/mass spectrometry. Complementation of wild type (wt) rtfA in trans through an integrative plasmid restored serovar-8 specific GPL expression identical to wt serovar 8 parent strain. Results In this study, we affirm our results that rtfA encodes an enzyme responsible for the transfer of Rha to 6d-Tal and provide evidence of a second allelic exchange mutagenesis system suitable for M. avium. Conclusion We report the second allelic exchange system for M. avium utilizing ts-sacB as double-negative and xylE as positive counter-selection markers, respectively. This system of allelic exchange would be especially useful for M. avium strains that demonstrate significant isoniazid (INH) resistance despite transformation with katG. Through the construction of mutants in GPL or other mycobacterial components, their roles in M. avium pathogenesis, biosynthesis, or drug resistance can be studied in a consistent manner. PMID:15458565

D{sub H} element reading frame selection is influenced by an Ig heavy chain transgene, but not by bcl-2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tarlinton, D.; Strasser, A.; McLean, M.

1995-04-01

Mouse B cell precursors containing Ig D{sub H}J{sub H} junctions in one particular reading frame are selectively lost during B cell development. In this register, arbitrarily referred to as reading frame 2, D{sub H}J{sub H} junctions give rise to an open reading frame starting upstream of the D{sub H} element and including the D{sub H}J{sub H}-peptide fused to the constant region of IgM. Expression of this protein, called D{mu}, has been strongly implicated in the loss of B cell precursors containing reading frame 2 D{sub H}J{sub H} junctions. In an attempt to elucidate the means of D{mu} counterselection, we havemore » examined the reading frame distribution of D{sub H}J{sub H} junctions in peripheral B cells from mice transgenic for either the human bcl-2 oncogene or for a functionally rearranged Ig {mu} heavy chain. In bcl-2 transgenic mice, reading frame 2 accounted for < 5% of the D{sub H}J{sub H} junctions in peripheral B cells, a value not significantly different from controls. Reading frames 1 and 3 were equally represented among the remaining junctions. By contrast, the reading frame distribution of endogenous D{sub H}J{sub H} junctions in splenic B cells from Ig {mu} heavy chain transgenic mice showed no evidence of bias against D{mu} encoding D{sub H}J{sub H} junctions. Reading frames 2 and 3 accounted for 27% and 30% of the sequenced D{sub H}J{sub H} junctions, respectively, and the remaining 43% were reading frame 1. Thus although the presence of BCL-2 cannot prevent the selective loss of reading frame 2 D{sub H}J{sub H} B cells, a functional {mu} heavy chain can. These results suggest that D{mu}-expressing B cell precursors may be selectively lost because of the premature and inappropriate cessation of heavy chain gene rearrangement rather than because of the induction of an apoptotic process which can be blocked by BCL-2. 42 refs., 4 figs., 4 tabs.« less

Examination of the validity and reliability of the French version of the Brief Self-Control Scale

PubMed Central

Brevers, Damien; Foucart, Jennifer; Verbanck, Paul; Turel, Ofir

2017-01-01

This study aims to develop and to validate a French version of the Brief Self-Control Scale (BSCS; Tangney et al., 2004). This instrument is usually applied as a unidimensional self-report measure for assessing trait self-control, which captures one’s dispositional ability to resist short-term temptation in order to reach more valuable long-term goals. Data were collected from two independent samples of French-speaking individuals (n1 = 287; n2 = 160). Results indicated that the French version of the BSCS can be treated as unidimensional, like the original questionnaire. Data also showed consistent acceptable reliability and reasonable test-retest stability. Acceptable external validity of constructs was supported by relationships with self-reported measures of impulsivity (UPPS), including urgency, lack of premeditation, and lack of perseverance. Overall, the findings suggest that the average score of the French version of the BSCS is a viable option for assessing trait self-control in French speaking populations. PMID:29200467

Self-Control Capacity as a Predictor of Borderline Personality Disorder Features, Problematic Drinking, and Their Co-Occurrence

PubMed Central

Johnson, Benjamin N.; Ashe, Melinda L.; Wilson, Stephen J.

2017-01-01

Borderline personality disorder (BPD) and alcohol use disorder (AUD) share impulsivity as an etiological factor. However, impulsivity is ill-defined, often overlapping with self-control capacity. This study attempts to disentangle these constructs and their associations with alcohol use and BPD. Undergraduates (N = 192) completed the Five Factor Model Rating Form, which generated two dimensional scales of BPD, the Self-Control Scale, the UPPS-P (self-reported impulsivity), and the Stop-signal and delay discounting tasks (laboratory-measured impulsivity). Self-control appeared as a major predictor of BPD features and drinking, explaining as much or more variance in outcome than impulsivity. Co-occurrence of elevated BPD features and problem drinking was also best explained by self-control. Laboratory measures of impulsivity were not correlated with BPD scales or alcohol use. Self-regulatory capacity may be an important but overlooked factor in BPD and alcohol use and should be considered alongside impulsivity in future research. PMID:27064849

The Theory of Planned Behavior and E-cig Use: Impulsive Personality, E-cig Attitudes, and E-cig Use.

PubMed

Hershberger, Alexandra; Connors, Miranda; Um, Miji; Cyders, Melissa A

2018-04-01

The current paper applied the Theory of Planned Behavior (TPB; Ajzen & Fishbein, 1988) to understand how impulsive personality traits and attitudes concerning e-cig use relate to the likelihood of electronic cigarette (e-cig) use. Seven hundred and fourteen participants (Mean age = 34.04, SD = 10.89, 48.6% female) completed cross-sectional measures of e-cig use attitudes (CEAC) and the Short UPPS-P Impulsive Behavior Scale. A structural path analysis suggested that urgency and deficits in conscientiousness were significantly related to e-cig attitudes (CFI = 0.99, TLI = 0.99, RMSEA = 0.02; urgency: β = 0.32, p = .001; deficits in conscientiousness: β = -0.48, p < .001). E-cig attitude scores were significantly higher for e-cig users than non-users, β = 0.85, p < .001. There was no significant direct path from impulsive personality traits to e-cig use. Findings provide initial support for a model in which impulsive traits are related to e-cig use through positive e-cig attitudes.

Examination of the validity and reliability of the French version of the Brief Self-Control Scale.

PubMed

Brevers, Damien; Foucart, Jennifer; Verbanck, Paul; Turel, Ofir

2017-10-01

This study aims to develop and to validate a French version of the Brief Self-Control Scale (BSCS; Tangney et al., 2004). This instrument is usually applied as a unidimensional self-report measure for assessing trait self-control, which captures one's dispositional ability to resist short-term temptation in order to reach more valuable long-term goals. Data were collected from two independent samples of French-speaking individuals ( n 1 = 287; n 2 = 160). Results indicated that the French version of the BSCS can be treated as unidimensional, like the original questionnaire. Data also showed consistent acceptable reliability and reasonable test-retest stability. Acceptable external validity of constructs was supported by relationships with self-reported measures of impulsivity (UPPS), including urgency, lack of premeditation, and lack of perseverance. Overall, the findings suggest that the average score of the French version of the BSCS is a viable option for assessing trait self-control in French speaking populations.

Impulsivity in Multiplayer Online Battle Arena Gamers: Preliminary Results on Experimental and Self-Report Measures.

PubMed

Nuyens, Filip; Deleuze, Jory; Maurage, Pierre; Griffiths, Mark D; Kuss, Daria J; Billieux, Joël

2016-06-01

Background and aims Multiplayer Online Battle Arena (MOBA) games have become the most popular type of video games played worldwide, superseding the playing of Massively Multiplayer Online Role-Playing Games and First-Person Shooter games. However, empirical studies focusing on the use and abuse of MOBA games are still very limited, particularly regarding impulsivity, which is an indicator of addictive states but has not yet been explored in MOBA games. In this context, the objective of the present study is to explore the associations between impulsivity and symptoms of addictive use of MOBA games in a sample of highly involved League of Legends (LoL, currently the most popular MOBA game) gamers. Methods Thirty-six LoL gamers were recruited and completed both experimental (Single Key Impulsivity Paradigm) and self-reported impulsivity assessments (s-UPPS-P Impulsive Behavior Scale, Barratt Impulsiveness Scale), in addition to an assessment of problematic video game use (Problematic Online Gaming Questionnaire). Results Results showed links between impulsivity-related constructs and signs of excessive MOBA game involvement. Findings indicated that impaired ability to postpone rewards in an experimental laboratory task was strongly related to problematic patterns of MOBA game involvement. Although less consistent, several associations were also found between self-reported impulsivity traits and signs of excessive MOBA game involvement. Conclusions Despite these results are preliminary and based upon a small (self-selected) sample, the present study highlights potential psychological factors related to the addictive use of MOBA games.

Impulsivity in Multiplayer Online Battle Arena Gamers: Preliminary Results on Experimental and Self-Report Measures

PubMed Central

Nuyens, Filip; Deleuze, Jory; Maurage, Pierre; Griffiths, Mark D.; Kuss, Daria J.; Billieux, Joël

2016-01-01

Background and aims Multiplayer Online Battle Arena (MOBA) games have become the most popular type of video games played worldwide, superseding the playing of Massively Multiplayer Online Role-Playing Games and First-Person Shooter games. However, empirical studies focusing on the use and abuse of MOBA games are still very limited, particularly regarding impulsivity, which is an indicator of addictive states but has not yet been explored in MOBA games. In this context, the objective of the present study is to explore the associations between impulsivity and symptoms of addictive use of MOBA games in a sample of highly involved League of Legends (LoL, currently the most popular MOBA game) gamers. Methods Thirty-six LoL gamers were recruited and completed both experimental (Single Key Impulsivity Paradigm) and self-reported impulsivity assessments (s-UPPS-P Impulsive Behavior Scale, Barratt Impulsiveness Scale), in addition to an assessment of problematic video game use (Problematic Online Gaming Questionnaire). Results Results showed links between impulsivity-related constructs and signs of excessive MOBA game involvement. Findings indicated that impaired ability to postpone rewards in an experimental laboratory task was strongly related to problematic patterns of MOBA game involvement. Although less consistent, several associations were also found between self-reported impulsivity traits and signs of excessive MOBA game involvement. Conclusions Despite these results are preliminary and based upon a small (self-selected) sample, the present study highlights potential psychological factors related to the addictive use of MOBA games. PMID:27156376

Selection, Identification, and Binding Mechanism Studies of an ssDNA Aptamer Targeted to Different Stages of E. coli O157:H7.

PubMed

Zou, Ying; Duan, Nuo; Wu, Shijia; Shen, Mofei; Wang, Zhouping

2018-06-06

Enterohemorrhagic Escherichia coli O157:H7 ( E. coli O157:H7) is known as an important food-borne pathogen related to public health. In this study, aptamers which could bind to different stages of E. coli O157:H7 (adjustment phase, log phase, and stationary phase) with high affinity and specificity were obtained by the whole cell-SELEX method through 14 selection rounds including three counter-selection rounds. Altogether, 32 sequences were obtained, and nine families were classified to select the optimal aptamer. To analyze affinity and specificity by flow cytometer, an ssDNA aptamer named Apt-5 was picked out as the optimal aptamer that recognizes different stages of E. coli O157:H7 specifically with the K d value of 9.04 ± 2.80 nM. In addition, in order to study the binding mechanism, target bacteria were treated by proteinase K and trypsin, indicating that the specific binding site is not protein on the cell membrane. Furthermore, when we treated E. coli O157:H7 with EDTA, the result showed that the binding site might be lipopolysaccharide (LPS) on the outer membrane of E. coli O157:H7.

Transient overexpression of DNA adenine methylase enables efficient and mobile genome engineering with reduced off-target effects

PubMed Central

Lennen, Rebecca M.; Nilsson Wallin, Annika I.; Pedersen, Margit; Bonde, Mads; Luo, Hao; Herrgård, Markus J.; Sommer, Morten O. A.

2016-01-01

Homologous recombination of single-stranded oligonucleotides is a highly efficient process for introducing precise mutations into the genome of E. coli and other organisms when mismatch repair (MMR) is disabled. This can result in the rapid accumulation of off-target mutations that can mask desired phenotypes, especially when selections need to be employed following the generation of combinatorial libraries. While the use of inducible mutator phenotypes or other MMR evasion tactics have proven useful, reported methods either require non-mobile genetic modifications or costly oligonucleotides that also result in reduced efficiencies of replacement. Therefore a new system was developed, Transient Mutator Multiplex Automated Genome Engineering (TM-MAGE), that solves problems encountered in other methods for oligonucleotide-mediated recombination. TM-MAGE enables nearly equivalent efficiencies of allelic replacement to the use of strains with fully disabled MMR and with an approximately 12- to 33-fold lower off-target mutation rate. Furthermore, growth temperatures are not restricted and a version of the plasmid can be readily removed by sucrose counterselection. TM-MAGE was used to combinatorially reconstruct mutations found in evolved salt-tolerant strains, enabling the identification of causative mutations and isolation of strains with up to 75% increases in growth rate and greatly reduced lag times in 0.6 M NaCl. PMID:26496947

Exogenous attention can be counter-selective: onset cues disrupt sensitivity to color changes.

PubMed

Müller-Plath, Gisela; Klöckner, Nils

2014-03-01

In peripheral spatial cueing paradigms, exogenous attentional capture is commonly observed after salient onset cues or with cues contingent on target characteristics. We proposed that exogenously captured attention disrupts the selectivity to target features. We tested this by experimentally emulating the everyday observation that in a viewing situation in which the observer is monitoring a stationary display fort change to occur, the onset of a salient stimulus (onset cue) or a change in a stationary stimulus similar to the expected one (contingent cue) has a distracting effect. As predicted, we found that both types of cues reduced the target detection sensitivity but enhanced the bias to respond in a go-nogo-paradigm. With the onset cue, the sensitivity loss was more pronounced at the side of the cue, whereas the contingent cue affected both sides likewise. Moreover, the effects of the onset cue interacted with the task difficulty: the more selectivity a task required the more immune it was against disruption, but the more likely was a response. We concluded that onset capture disrupts selective attention by adding noise to the processing of the target location. The effects of contingent capture could be explained with cue-target confounding. Finally, we suggest a new model of attentional capture in which exogenous and endogenous components interact in a dynamic way.

Phenotype-limited distributions: short-billed birds move away during times that prey bury deeply

PubMed Central

Duijns, Sjoerd; van Gils, Jan A.; Smart, Jennifer; Piersma, Theunis

2015-01-01

In our seasonal world, animals face a variety of environmental conditions in the course of the year. To cope with such seasonality, animals may be phenotypically flexible, but some phenotypic traits are fixed. If fixed phenotypic traits are functionally linked to resource use, then animals should redistribute in response to seasonally changing resources, leading to a ‘phenotype-limited’ distribution. Here, we examine this possibility for a shorebird, the bar-tailed godwit (Limosa lapponica; a long-billed and sexually dimorphic shorebird), that has to reach buried prey with a probing bill of fixed length. The main prey of female bar-tailed godwits is buried deeper in winter than in summer. Using sightings of individually marked females, we found that in winter only longer-billed individuals remained in the Dutch Wadden Sea, while the shorter-billed individuals moved away to an estuary with a more benign climate such as the Wash. Although longer-billed individuals have the widest range of options in winter and could therefore be selected for, counterselection may occur during the breeding season on the tundra, where surface-living prey may be captured more easily with shorter bills. Phenotype-limited distributions could be a widespread phenomenon and, when associated with assortative migration and mating, it may act as a precursor of phenotypic evolution. PMID:26543585

Phenotype-limited distributions: short-billed birds move away during times that prey bury deeply.

PubMed

Duijns, Sjoerd; van Gils, Jan A; Smart, Jennifer; Piersma, Theunis

2015-06-01

In our seasonal world, animals face a variety of environmental conditions in the course of the year. To cope with such seasonality, animals may be phenotypically flexible, but some phenotypic traits are fixed. If fixed phenotypic traits are functionally linked to resource use, then animals should redistribute in response to seasonally changing resources, leading to a 'phenotype-limited' distribution. Here, we examine this possibility for a shorebird, the bar-tailed godwit (Limosa lapponica; a long-billed and sexually dimorphic shorebird), that has to reach buried prey with a probing bill of fixed length. The main prey of female bar-tailed godwits is buried deeper in winter than in summer. Using sightings of individually marked females, we found that in winter only longer-billed individuals remained in the Dutch Wadden Sea, while the shorter-billed individuals moved away to an estuary with a more benign climate such as the Wash. Although longer-billed individuals have the widest range of options in winter and could therefore be selected for, counterselection may occur during the breeding season on the tundra, where surface-living prey may be captured more easily with shorter bills. Phenotype-limited distributions could be a widespread phenomenon and, when associated with assortative migration and mating, it may act as a precursor of phenotypic evolution.

Rethinking impulsivity in suicide.

PubMed

Klonsky, E David; May, Alexis

2010-12-01

Elevated impulsivity is thought to facilitate the transition from suicidal thoughts to suicidal behavior. Therefore, impulsivity should distinguish those who have attempted suicide (attempters) from those who have only considered suicide (ideators-only). This hypothesis was examined in three large nonclinical samples: (1) 2,011 military recruits, (2) 1,296 college students, and (3) 399 high school students. In sample 1, contrary to traditional models of suicide risk, a unidimensional measure of impulsivity failed to distinguish attempters from ideators-only. In samples 2 and 3, which were administered a multidimensional measure of impulsivity (i.e., the UPPS impulsive behavior scale; Whiteside & Lynam, 2001), different impulsivity-related traits characterized attempters and ideators-only. Whereas both attempters and ideators-only exhibited high urgency (the tendency to act impulsive in the face of negative emotions), only attempters exhibited poor premeditation (a diminished ability to think through the consequences of one's actions). Neither attempters nor ideators-only exhibited high sensation seeking or lack of perseverance. Future research should continue to distinguish impulsivity-related traits that predict suicide ideation from those that predict suicide attempts, and models of suicide risk should be revised accordingly.

Posttraumatic Stress Disorder's Underlying Dimensions and Their Relation With Impulsivity Facets.

PubMed

Contractor, Ateka A; Armour, Cherie; Forbes, David; Elhai, Jon D

2016-01-01

Research indicates a significant relationship between posttraumatic stress disorder (PTSD) and impulsivity (Kotler, Julian, Efront, and Amir, J Nerv Ment Dis 189:162-167, 2001; Ledgerwood and Petry, J Trauma Stress 19:411-416, 2006). The present study assessed relations between PTSD symptom clusters and impulsivity subscales in an effort to assess the specific impulsivity component most related to PTSD's alterations in arousal/reactivity and alterations in mood/cognitions symptoms. In the current study, the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, and the UPPS Impulsivity Scale were administered to a sample of 412 nonclinical subjects with a trauma history. Results indicated that PTSD's alterations in arousal/reactivity and mood/cognition factors were most related to impulsivity's sensation-seeking tendency compared with other impulsivity components. Results highlight the importance of assessing and addressing (1) sensation-seeking tendencies and (2) urges to act impulsively when experiencing negative affect in trauma treatment. Furthermore, it is possible that sensation-seeking tendencies are primarily driving the comorbidity between PTSD and certain impulsive behaviors.

cis-Prenyltransferase: New Insights into Protein Glycosylation, Rubber Synthesis, and Human Diseases.

PubMed

Grabińska, Kariona A; Park, Eon Joo; Sessa, William C

2016-08-26

cis-Prenyltransferases (cis-PTs) constitute a large family of enzymes conserved during evolution and present in all domains of life. cis-PTs catalyze consecutive condensation reactions of allylic diphosphate acceptor with isopentenyl diphosphate (IPP) in the cis (Z) configuration to generate linear polyprenyl diphosphate. The chain lengths of isoprenoid carbon skeletons vary widely from neryl pyrophosphate (C10) to natural rubber (C>10,000). The homo-dimeric bacterial enzyme, undecaprenyl diphosphate synthase (UPPS), has been structurally and mechanistically characterized in great detail and serves as a model for understanding the mode of action of eukaryotic cis-PTs. However, recent experiments have revealed that mammals, fungal, and long-chain plant cis-PTs are heteromeric enzymes composed of two distantly related subunits. In this review, the classification, function, and evolution of cis-PTs will be discussed with a special emphasis on the role of the newly described NgBR/Nus1 subunit and its plants' orthologs as essential, structural components of the cis-PTs activity. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Impulsivity Dimensions and Risky Sex Behaviors in an At-Risk Young Adult Sample.

PubMed

Curry, Inga; Luk, Jeremy W; Trim, Ryan S; Hopfer, Christian J; Hewitt, John K; Stallings, Michael C; Brown, Sandra A; Wall, Tamara L

2018-02-01

Impulsivity is a personality-based risk factor that has been well studied in relation to risky sexual behavior. Recent conceptualizations of impulsivity have proposed multidimensional facets comprised of premeditation, perseverance, sensation seeking, negative urgency, and positive urgency (UPPS-P model). Prior studies have found that these facets are associated with risky sexual behavior in adolescent and college student samples, but no prior studies have evaluated them in clinical samples. The current study examined how impulsivity-related traits related to two different risky sexual behaviors in a clinical sample of at-risk young adults who had both conduct disorder and substance use disorder symptoms as adolescents (n = 529). Lack of premeditation was also tested as a moderator of the relationship between facets of impulsivity and both risky sex outcomes. Results demonstrated that sensation seeking, negative urgency, and positive urgency were correlated with risky sex behaviors. Additionally, multiple regression analyses indicated that sensation seeking was uniquely associated with the number of sexual partners in the past 5 years, whereas positive urgency was uniquely associated with unprotected sex while under the influence. Finally, a significant interaction between lack of premeditation and negative urgency suggests that at-risk young adults with both high negative urgency and lack of premeditation were the likeliest to have the most sexual partners in the past 5 years. This study adds to the current understanding of the relationship between reward- and affect-driven facets of impulsivity and risky sexual behaviors and may lend utility to the development of interventions for at-risk populations.

White matter microstructure and impulsivity in methamphetamine dependence with and without a history of psychosis.

PubMed

Uhlmann, Anne; Fouche, Jean-Paul; Lederer, Katharina; Meintjes, Ernesta M; Wilson, Don; Stein, Dan J

2016-06-01

Methamphetamine (MA) use may lead to white matter injury and to a range of behavioral problems and psychiatric disorders, including psychosis. The present study sought to assess white matter microstructural impairment as well as impulsive behavior in MA dependence and MA-associated psychosis (MAP). Thirty patients with a history of MAP, 39 participants with MA dependence and 40 healthy controls underwent diffusion tensor imaging (DTI). Participants also completed the UPPS-P impulsive behavior questionnaire. We applied tract-based spatial statistics (TBSS) to investigate group differences in mean diffusivity (MD), fractional anisotropy (FA), axial (λ‖ ) and radial diffusivity (λ⊥ ), and their association with impulsivity scores and psychotic symptoms. The MAP group displayed widespread higher MD, λ‖ and λ⊥ levels compared to both controls and the MA group, and lower FA in extensive white matter areas relative to controls. MD levels correlated positively with negative psychotic symptoms in MAP. No significant DTI group differences were found between the MA group and controls. Both clinical groups showed high levels of impulsivity, and this dysfunction was associated with DTI measures in frontal white matter tracts. MAP patients show distinct patterns of impaired white matter integrity of global nature relative to controls and the MA group. Future work to investigate the precise nature and timing of alterations in MAP is needed. The results are further suggestive of frontal white matter pathology playing a role in impulsivity in MA dependence and MAP. Hum Brain Mapp 37:2055-2067, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

A Foreground Masking Strategy for [C II] Intensity Mapping Experiments Using Galaxies Selected by Stellar Mass and Redshift

NASA Astrophysics Data System (ADS)

Sun, G.; Moncelsi, L.; Viero, M. P.; Silva, M. B.; Bock, J.; Bradford, C. M.; Chang, T.-C.; Cheng, Y.-T.; Cooray, A. R.; Crites, A.; Hailey-Dunsheath, S.; Uzgil, B.; Hunacek, J. R.; Zemcov, M.

2018-04-01

Intensity mapping provides a unique means to probe the epoch of reionization (EoR), when the neutral intergalactic medium was ionized by energetic photons emitted from the first galaxies. The [C II] 158 μm fine-structure line is typically one of the brightest emission lines of star-forming galaxies and thus a promising tracer of the global EoR star formation activity. However, [C II] intensity maps at 6 ≲ z ≲ 8 are contaminated by interloping CO rotational line emission (3 ≤ J upp ≤ 6) from lower-redshift galaxies. Here we present a strategy to remove the foreground contamination in upcoming [C II] intensity mapping experiments, guided by a model of CO emission from foreground galaxies. The model is based on empirical measurements of the mean and scatter of the total infrared luminosities of galaxies at z < 3 and with stellar masses {M}* > {10}8 {M}ȯ selected in the K-band from the COSMOS/UltraVISTA survey, which can be converted to CO line strengths. For a mock field of the Tomographic Ionized-carbon Mapping Experiment, we find that masking out the “voxels” (spectral–spatial elements) containing foreground galaxies identified using an optimized CO flux threshold results in a z-dependent criterion {m}{{K}}AB}≲ 22 (or {M}* ≳ {10}9 {M}ȯ ) at z < 1 and makes a [C II]/COtot power ratio of ≳10 at k = 0.1 h/Mpc achievable, at the cost of a moderate ≲8% loss of total survey volume.

The mediating role of anger in the relationship between PTSD symptoms and impulsivity.

PubMed

Contractor, Ateka A; Armour, Cherie; Wang, Xin; Forbes, David; Elhai, Jon D

2015-03-01

Research indicates a significant relationship between posttraumatic stress disorder (PTSD) and anger (Olatunji, Ciesielski, & Tolin, 2010; Orth & Wieland, 2006). Individuals may seek urgent coping to deal with the distress of anger, which is a mobilizing and action-oriented emotion (Novaco & Chemtob, 2002); possibly in the form of impulsive actions consistent with impulsivity's association with anger (Milligan & Waller, 2001; Whiteside & Lynam, 2001). This could be 1 of the explanations for the relationship between PTSD and impulsivity (Kotler, Julian, Efront, & Amir, 2001; Ledgerwood & Petry, 2006). The present study assessed the mediating role of anger between PTSD (overall scores and subscales of arousal and negative alterations in mood/cognitions) and impulsivity, using gender as a covariate of impulsivity. The PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5), Dimensions of Anger Reaction scale-5, and the UPPS Impulsivity Scale were administered to a sample of 244 undergraduate students with a trauma history. Results based on 1000 bootstrapped samples indicated significant direct effects of PTSD (overall and 2 subscales) on anger, of anger on impulsivity, and of PTSD (overall and 2 subscales) on impulsivity. Further, anger significantly mediated the relationship between PTSD (overall and 2 subscales) and impulsivity, consistent with the hypothesized models. Results suggest that impulsivity aims at coping with distressing anger, possibly explaining the presence of substance usage, and other impulsive behaviors in people with PTSD. Further, anger probably serves as a mobilizing and action-oriented emotion coupled with PTSD symptoms. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

Effects of Shield1 on the viral replication of varicella-zoster virus containing FKBP-tagged ORF4 and 48

PubMed Central

Li, Shuying; Liu, Zhanjun; Li, Ji; Liu, Aihua; Zhu, Lihua; Yu, Kui; Zhang, Ke

2018-01-01

The present study aimed to explore the effects of a stabilizing ligand, Shield-1, on the replication of recombinant varicella-zoster virus (VZV) containing FK506 binding protein (FKPB) tags in essential open reading frames (ORF) 4 and 48. A specific galactokinase (galK) selection method was conducted, following the addition of galK labels to VZV ORF4 and 48, using a SW102 VZV bacterial artificial chromosome (BAC) system. Subsequently, recombinant VZV containing FKPB tags in ORF4 and 48 was constructed by counterselection and homologous recombination. Recombinant viral plasmids containing FKPB-tagged VZV ORF4 and 48 were extracted and transfected into human acute retinal pigment epithelial ARPE-19 cells. The results demonstrated that the FKPB-tagged viral protein was rapidly degraded by proteases in recombinant virus-infected ARPE-19 cells. In addition, the recombinant VZVORF4-FKBP-ORF48-FKBP virus could not grow if a synthetic ligand of FKBP, Shield1, was not added to the ARPE-19 cell culture medium; however, the degradation of FKPB-tagged viral protein was prevented if Shield1 was added to the ARPE-19 cell culture medium, thereby allowing viral replication in ARPE-19 cells. These results indicated that Shield1 may regulate replication of recombinant VZVORF4-FKBP-ORF48-FKBP following transfection into human epithelial cells. PMID:29115621

Female Choice Undermines the Emergence of Strong Sexual Isolation between Locally Adapted Populations of Atlantic Mollies (Poecilia mexicana)

PubMed Central

Zimmer, Claudia; Bierbach, David; Arias-Rodriguez, Lenin; Plath, Martin

2018-01-01

Divergent selection between ecologically dissimilar habitats promotes local adaptation, which can lead to reproductive isolation (RI). Populations in the Poecilia mexicana species complex have independently adapted to toxic hydrogen sulfide and show varying degrees of RI. Here, we examined the variation in the mate choice component of prezygotic RI. Mate choice tests across drainages (with stimulus males from another drainage) suggest that specific features of the males coupled with a general female preference for yellow color patterns explain the observed variation. Analyses of male body coloration identified the intensity of yellow fin coloration as a strong candidate to explain this pattern, and common-garden rearing suggested heritable population differences. Male sexual ornamentation apparently evolved differently across sulfide-adapted populations, for example because of differences in natural counterselection via predation. The ubiquitous preference for yellow color ornaments in poeciliid females likely undermines the emergence of strong RI, as female discrimination in favor of own males becomes weaker when yellow fin coloration in the respective sulfide ecotype increases. Our study illustrates the complexity of the (partly non-parallel) pathways to divergence among replicated ecological gradients. We suggest that future work should identify the genomic loci involved in the pattern reported here, making use of the increasing genomic and transcriptomic datasets available for our study system. PMID:29724050

Effects of the proposed California WaterFix North Delta Diversion on survival of juvenile Chinook salmon (Oncorhynchus tshawytscha) in the Sacramento-San Joaquin River Delta, northern California

USGS Publications Warehouse

Perry, Russell W.; Pope, Adam C.

2018-05-11

The California Department of Water Resources and Bureau of Reclamation propose new water intake facilities on the Sacramento River in northern California that would convey some of the water for export to areas south of the Sacramento-San Joaquin River Delta (hereinafter referred to as the Delta) through tunnels rather than through the Delta. The collection of water intakes, tunnels, pumping facilities, associated structures, and proposed operations are collectively referred to as California WaterFix. The water intake facilities, hereinafter referred to as the North Delta Diversion (NDD), are proposed to be located on the Sacramento River downstream of the city of Sacramento and upstream of the first major river junction where Sutter Slough branches from the Sacramento River. The NDD can divert a maximum discharge of 9,000 cubic feet per second (ft3 /s) from the Sacramento River, which reduces the amount of Sacramento River inflow into the Delta. In this report, we conduct four analyses to investigate the effect of the NDD and its proposed operation on survival of juvenile Chinook salmon (Oncorhynchus tshawytscha). All analyses used the results of a Bayesian survival model that allowed us to simulate travel time, migration routing, and survival of juvenile Chinook salmon migrating through the Delta in response to NDD operations, which affected both inflows to the Delta and operation of the Delta Cross Channel (DCC). For the first analysis, we evaluated the effect of the NDD bypass rules on salmon survival. The NDD bypass rules are a set of operational rule curves designed to provide adaptive levels of fish protection by defining allowable diversion rates as a function of (1) Sacramento River discharge as measured at Freeport, and (2) time of year when endangered runs requiring the most protection are present. We determined that all bypass rule curves except constant low-level pumping (maximum diversion of 900 ft3 /s) could cause a sizeable decrease in survival by as much as 6–10 percentage points. The maximum decrease in survival occurred at an intermediate Sacramento River flow of about 20,000–30,000 ft3 /s. Diversion rates increased rapidly as Sacramento River flows increased from 20,000 ft3 /s to 30,000 ft3 /s, until a maximum diversion rate was reached at 9,000 ft3 /s. Because through-Delta survival increases sharply over this range of Sacramento River flow before beginning to level off with further flow increases, increasing diversion rates over this flow range causes a large decrease in survival relative to no diversion.  For the second analysis, we applied the survival model to 82 years of daily simulated flows under the Proposed Action (PA) and No Action Alternative (NAA). The PA includes operation of the Central Valley Project/State Water Project with implementation of the NDD and its operations prescribed by the NDD bypass rules, whereas the NAA assumes system operations without implementation of the NDD. We also evaluated a “Level 1” (L1) scenario, which was similar to the PA scenario but applied the most protective bypass rule known as Level 1 post-pulse operations. We noted a high probability that survival under the PA scenario was lower than under the NAA scenario, and that travel time was longer under PA relative to NAA in most simulation years. However, the largest survival differences between the PA and NAA scenarios occurred during October–November and May–June. Although bypass rules are less restrictive during these periods, we determined that more frequent use of the DCC under PA led to the largest differences in survival between the two scenarios. Additionally, we noted no difference in median survival decreases between the PA and L1 scenarios, although in some years the L1 scenario had a lower survival decrease than the PA scenario. For the third analysis, we proposed a quantitative approach for developing NDD rule curves (that is, prescribed diversion flows for given inflows) by using the survival model to identify diversion rates that meet a criterion of a having a small probability of exceeding a given decrease in survival. We examined diversion rates that led to a 10% chance of exceeding a given decrease in survival for a range of absolute and relative decreases in survival. To maintain a given constant level of protection across the range of river flows, our analysis indicated that diversions had to increase at a much slower rate with respect to Sacramento River flow relative to the rule curves defined in the NDD bypass table. Additionally, we determined that diversion rates could be higher than under the bypass table rule curves at river flows less than 20,000 ft3 /s, but diversions had to be less than defined by NDD bypass rules at higher flows. For the fourth analysis, we simulated the effect of “real-time operations” on salmon survival, where bypass flow rates were determined by the presence of juvenile salmon entering the Delta, as indicated by juvenile salmon catch in a rotary screw trap upstream of the Delta. For this analysis, we evaluated NDD operations as defined by the L1 scenario and an additional scenario (Unlimited Pulse Protection [UPP]) that provided protection to an unlimited number of fish pulses. This analysis indicated that the highest catches occurred during flow pulses when daily survival was high, which caused annual survival to be weighted towards periods of high daily survival, resulting in a high annual survival. We determined that the mean annual survival decreased by 1–4 percentage points, and annual survival decreases were more frequently smaller for the UPP scenario. Additionally, because the UPP scenario protected an unlimited number of fish pulses, decreases in daily survival under the UPP scenario were less than under the L1 scenario.

Combined evaluation of personality, risk and coping in MS patients: A step towards individualized treatment choice - The PeRiCoMS-Study I.

PubMed

Bsteh, G; Monz, E; Zamarian, L; Hagspiel, S; Hegen, H; Auer, M; Wurth, S; Di Pauli, F; Deisenhammer, F; Berger, T

2017-05-15

Multiple sclerosis (MS) is a chronic inflammatory neurological disease requiring disease-modifying treatment (DMT). To provide patients with the optimal individual therapeutic option, treatment recommendations should be based not only on individual disease course and DMT specific benefit-risk estimates, but also on patient's individual characteristics such as personality, risk attitude and coping strategies. However, these characteristics are difficult to objectify in clinical routine practice without the support of appropriate evaluation instruments. To identify and to assemble an objective test battery measuring personality, risk attitude and coping strategies in MS patients. A comprehensive literature search was performed to obtain all questionnaires assessing personality, risk attitude and coping strategies. Availability in German language, validation in a published normative collective and a reliability of >0.70 were required for our purposes. Based on these criteria, we chose the Big-Five-Personality Test, UPPS Impulsive Behaviour Scale, Domain-Specific Risk-Taking scale (DOSPERT), Brief-COPE and Stress & Coping Inventory (SCI). Results were compared to published normative controls of the respective questionnaires. Out of 22 MS patients (7 males, 15 females) participating in this study, 19 (86.4%) completed all questionnaires. The median completion time was 45min (min-max range: 25-60min). The median scores of the MS group were within the average range of published control samples in all questionnaires. We report that traits of personality, risk attitude and coping strategies can be effectively and feasibly tested in MS patients by the instruments used in our exploratory study. There were no differences between MS patients and healthy controls, thus enabling assessment without being influenced by the diagnosis of MS. After validation in a larger cohort the "PeRiCoMS"-battery will be useful as another step towards a more individualized shared-decision-making in every day routine practice. Copyright © 2017 Elsevier B.V. All rights reserved.

UPSS and G2

NASA Technical Reports Server (NTRS)

Dito, Scott J.

2014-01-01

The Universal Propellant Servicing System (UPSS) is a dedicated mobile launcher propellant delivery method that will minimize danger and complexity in order to allow vehicles to be serviced and ultimately launched from a variety of locations previously not seen fit for space launch. The UPPS/G2 project is the development of a model, simulation, and ultimately a working application that will control and monitor the cryogenic fluid delivery to the rocket for testing purposes. To accomplish this, the project is using the programming language/environment Gensym G2. The environment is an all-inclusive application that allows development, testing, modeling, and finally operation of the unique application through graphical and programmatic methods. We have learned G2 through classes and trial-and-error, and are now in the process of building the application that will soon be able to be tested on apparatuses here at Kennedy Space Center, and eventually on the actual unit. The UPSS will bring near-autonomous control of launches to those that need it, as well it will be a great addition to NASA and KSC's operational viability and the opportunity to bring space launches to parts of the world, and in time constraints, once not thought possible.

The role of urgency in maladaptive behaviors.

PubMed

Anestis, Michael D; Selby, Edward A; Joiner, Thomas E

2007-12-01

Prior work on maladaptive behaviors has cited impulsivity as a risk factor. The concept of impulsivity, however, fails to address the potential role of negative affect in such behaviors. The UPPS Impulsive Behavior Scale addresses this weakness by dividing impulsivity into four subscales: Urgency, Sensation Seeking, (lack of) Premeditation, and (lack of) Perseverance. We predicted that urgency, defined as the tendency, specifically in the face of negative affect, to act quickly and without planning, would predict elevations on three maladaptive behaviors--excessive reassurance seeking, drinking to cope, and bulimic symptoms as measured by the Eating Disorder Inventory--in both cross-sectional and longitudinal analyses in an undergraduate sample (N=70). Participants were assessed at two time points, 3-4 weeks apart. Urgency significantly predicted all three outcome variables cross-sectionally at both Time 1 and Time 2. Time 1 urgency significantly predicted Time 2 excessive reassurance seeking. Changes in urgency from Time 1 to Time 2 predicted changes in all three outcome variables. Results indicate a clear cross-sectional relationship between urgency and certain maladaptive behaviors. Additionally, some form of longitudinal relationship may exist between these variables, although the use of residual change scores precluded distinction between true change and change due to error.

Adaptation to the Spanish population of the Substance Use Risk Profile Scale (SURPS) and psychometric properties.

PubMed

Fernández-Calderón, Fermín; Díaz-Batanero, Carmen; Rojas-Tejada, Antonio J; Castellanos-Ryan, Natalie; Lozano-Rojas, Óscar M

2017-07-14

The identification of different personality risk profiles for substance misuse is useful in preventing substance-related problems. This study aims to test the psychometric properties of a new version of the Substance Use Risk Profile Scale (SURPS) for Spanish college students. Cross-sectional study with 455 undergraduate students from four Spanish universities. A new version of the SURPS, adapted to the Spanish population, was administered with the Beck Hopelessness Scale, the UPPS-P Impulsive Behavior Scale, the State-Trait Anxiety Inventory (STAI) and the Alcohol Use Disorders Identification Test (AUDIT). Internal consistency reliability ranged between 0.652 and 0.806 for the four SURPS subscales, while reliability estimated by split-half coefficients varied from 0.686 to 0.829. The estimated test-retest reliability ranged between 0.733 and 0.868. The expected four-factor structure of the original scale was replicated. As evidence of convergent validity, we found that the SURPS subscales were significantly associated with other conceptually-relevant personality scales and significantly associated with alcohol use measures in theoretically-expected ways. This SURPS version may be a useful instrument for measuring personality traits related to vulnerability to substance use and misuse when targeting personality with preventive interventions.

How is impulsivity related to depression in adolescence? Evidence from a French validation of the cognitive emotion regulation questionnaire.

PubMed

d'Acremont, Mathieu; Van der Linden, Martial

2007-04-01

The aim of this study was to validate a French version of the Cognitive Emotion Regulation Questionnaire (CERQ; Garnefski, N., Kraaij, V., & Spinhoven, P., 2001. Negative life events, cognitive emotion regulation and emotional problems. Personality and Individual Differences, 30, 1311-1327) and to explore its relationships with impulsivity and depression. Teenagers from a junior secondary (n=107, 13-16 years) and a secondary school (n=110, 15-19 years) completed the CERQ, which assesses regulation strategies in response to negative events. The secondary school adolescents also completed the UPPS Impulsive Behavior Scale (Whiteside, S. P., & Lynam, D. R., 2001. The five factor model and impulsivity: Using a structural model of personality to understand impulsivity. Personality and Individual Differences, 30, 669-689) and the Reynolds Adolescent Depression Scale (Reynolds, W. M., 1987. Reynolds Adolescent Depression Scale: Professional manual. Odessa, FL: Psychological Assessment Resources). Factor analysis for the CERQ confirmed the presence of the nine original regulation strategies. In the secondary school students, impulsivity was related to depression. A path analysis revealed that regulation strategies mediated this relationship. The role of emotion regulation in the development of adolescent psychopathology is discussed.

Psychometric properties of the Barratt Impulsiveness Scale in patients with gambling disorders, hypersexuality, and methamphetamine dependence.

PubMed

Reid, Rory C; Cyders, Melissa A; Moghaddam, Jacquelene F; Fong, Timothy W

2014-11-01

Although the Barratt Impulsiveness Scale (BIS; Patton, Stanford, & Barratt, 1995) is a widely-used self-report measure of impulsivity, there have been numerous questions about the invariance of the factor structure across clinical populations (Haden & Shiva, 2008, 2009; Ireland & Archer, 2008). The goal of this article is to examine the factor structure of the BIS among a sample consisting of three populations exhibiting addictive behaviors and impulsivity: pathological gamblers, hypersexual patients, and individuals seeking treatment for methamphetamine dependence to determine if modification to the existing factors might improve the psychometric properties of the BIS. The current study found that the factor structure of the BIS does not replicate in this sample and instead produces a 12-item three-factor solution consisting of motor-impulsiveness (5 items), non-planning impulsiveness (3 items), and immediacy impulsiveness (4 items). The clinical utility of the BIS in this population is questionable. The authors suggest future studies to investigate comparisons with this modified version of the BIS and other impulsivity scales such as the UPPS-P Impulsive Behavior Scale in clinical populations when assessing disposition toward rash action. Copyright © 2013. Published by Elsevier Ltd.

Investigating the moderating role of emotional awareness in the association between urgency and binge eating.

PubMed

Manjrekar, Eishita; Berenbaum, Howard; Bhayani, Natasha

2015-04-01

Binge eating has been found to be associated with urgency (the tendency to act impulsively in response to negative affect) and emotional awareness (i.e., attention to emotions, clarity of emotions). The present study tested the hypothesis that the relation between binge eating and urgency would be moderated by emotional awareness, over and above negative affect. Participants were 249 female college students. Items from the Trait Meta Mood Scale (TMMS), the Urgency subscale of the UPPS Impulsive Behavior Scale, and the Bulimia (B) subscale of the Eating Disorders Inventory (EDI-3) were administered. As predicted, emotional awareness moderated the link between urgency and binge eating. Both Urgency×Attention to emotions and Urgency×Clarity of emotions significantly predicted binge eating scores, even after taking into account negative affect. Consistent with past research, higher levels of urgency were associated with higher levels of binge eating, even after taking negative affect into account. However, the associations were particularly strong among individuals with low levels of attention to emotions and low levels of clarity of emotions. The findings from this study have implications for future research examining binge eating. Copyright © 2015 Elsevier Ltd. All rights reserved.

Impulsivity and risk for prescription opioid misuse in a chronic pain patient sample.

PubMed

Vest, Noel; Reynolds, Caleb J; Tragesser, Sarah L

2016-09-01

Misuse of, and addiction to, prescription opioid pain relievers is a growing concern, in both non-clinical samples and chronic pain patients receiving opioid analgesic therapy. Research is needed to identify which patients may be more prone to misuse or dependence on opioids in a chronic pain treatment setting. Based on literature showing the role of impulsivity in substance use disorders generally, we predicted that impulsivity may also be important to understanding which individuals may be at risk for opioid misuse when opioids are prescribed for pain. The present study examined associations between impulsivity facets and measures of prescription opioid misuse and symptoms. Four facets of impulsivity were examined: urgency, sensation seeking, lack of premeditation, and lack of perseverance. 143 patients receiving treatment for chronic pain at a regional pain clinic completed a series of questionnaires including the UPPS and measures of opioid risk and misuse. Consistent with predictions, urgency was associated with risk for future misuse (β=0.246, p<0.05), current misuse (β=0.253, p<0.01), and symptoms of current opioid use disorder (OUD; β=0.206, p<0.05). Sensation seeking was also associated with current misuse (β=0.279, p<0.01). These results suggest that identifying facets of impulsivity is important to understanding and assessing for risk of prescription opioid misuse in the context of chronic pain treatment. These data indicate that patients who react impulsively to negative mood states and cravings may be especially prone to developing aberrant use patterns when taking prescription opioids. This is the first known study to identify the role of urgency in predicting risk for OUDs in chronic pain patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

Brain structural correlates of reward sensitivity and impulsivity in adolescents with normal and excess weight.

PubMed

Moreno-López, Laura; Soriano-Mas, Carles; Delgado-Rico, Elena; Rio-Valle, Jacqueline S; Verdejo-García, Antonio

2012-01-01

Neuroscience evidence suggests that adolescent obesity is linked to brain dysfunctions associated with enhanced reward and somatosensory processing and reduced impulse control during food processing. Comparatively less is known about the role of more stable brain structural measures and their link to personality traits and neuropsychological factors on the presentation of adolescent obesity. Here we aimed to investigate regional brain anatomy in adolescents with excess weight vs. lean controls. We also aimed to contrast the associations between brain structure and personality and cognitive measures in both groups. Fifty-two adolescents (16 with normal weight and 36 with excess weight) were scanned using magnetic resonance imaging and completed the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (SPSRQ), the UPPS-P scale, and the Stroop task. Voxel-based morphometry (VBM) was used to assess possible between-group differences in regional gray matter (GM) and to measure the putative differences in the way reward and punishment sensitivity, impulsivity and inhibitory control relate to regional GM volumes, which were analyzed using both region of interest (ROI) and whole brain analyses. The ROIs included areas involved in reward/somatosensory processing (striatum, somatosensory cortices) and motivation/impulse control (hippocampus, prefrontal cortex). Excess weight adolescents showed increased GM volume in the right hippocampus. Voxel-wise volumes of the second somatosensory cortex (SII) were correlated with reward sensitivity and positive urgency in lean controls, but this association was missed in excess weight adolescents. Moreover, Stroop performance correlated with dorsolateral prefrontal cortex volumes in controls but not in excess weight adolescents. Adolescents with excess weight have structural abnormalities in brain regions associated with somatosensory processing and motivation.

Fitness costs and stability of Cry1Fa resistance in Brazilian populations of Spodoptera frugiperda.

PubMed

Santos-Amaya, Oscar F; Tavares, Clébson S; Rodrigues, João Victor C; Campos, Silverio O; Guedes, Raul Narciso C; Alves, Analiza P; Pereira, Eliseu José G

2017-01-01

The presence of fitness costs of resistance to Bacillus thuringiensis (Bt) insecticidal proteins in insect populations may delay or even reverse the local selection of insect resistance to Bt transgenic crops, and deserves rigorous investigation. Here we assessed the fitness costs associated with Cry1Fa resistance in two strains of fall armyworm, Spodoptera frugiperda (Lepidoptera: Noctuidae), derived from field collections in different Brazilian regions and further selected in the laboratory for high levels of resistance to Cry1Fa using leaves of TC1507 corn. Fitness components were compared using paired resistant and susceptible strains with similar genetic backgrounds and F 1 generations from reciprocal crosses, all of them reared on non-transgenic corn leaves. No apparent life history costs in the larval stage were observed in the Bt-resistant strains. Moreover, the resistance remained stable for seven generations in the absence of selection, with no decrease in the proportion of resistant individuals. Larval respiration rates were also similar between resistant and susceptible homozygotes, and heterozygotes displayed respiration rates and demographic performance equal or superior to those of susceptible homozygotes. In combination, these results indicate the lack of strong fitness costs associated with resistance to Cry1Fa in the fall armyworm strains studied. These findings suggest that Cry1Fa resistance in S. frugiperda populations is unlikely to be counterselected in Cry1Fa-free environments. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

Improving the measurement of semantic similarity by combining gene ontology and co-functional network: a random walk based approach.

PubMed

Peng, Jiajie; Zhang, Xuanshuo; Hui, Weiwei; Lu, Junya; Li, Qianqian; Liu, Shuhui; Shang, Xuequn

2018-03-19

Gene Ontology (GO) is one of the most popular bioinformatics resources. In the past decade, Gene Ontology-based gene semantic similarity has been effectively used to model gene-to-gene interactions in multiple research areas. However, most existing semantic similarity approaches rely only on GO annotations and structure, or incorporate only local interactions in the co-functional network. This may lead to inaccurate GO-based similarity resulting from the incomplete GO topology structure and gene annotations. We present NETSIM2, a new network-based method that allows researchers to measure GO-based gene functional similarities by considering the global structure of the co-functional network with a random walk with restart (RWR)-based method, and by selecting the significant term pairs to decrease the noise information. Based on the EC number (Enzyme Commission)-based groups of yeast and Arabidopsis, evaluation test shows that NETSIM2 can enhance the accuracy of Gene Ontology-based gene functional similarity. Using NETSIM2 as an example, we found that the accuracy of semantic similarities can be significantly improved after effectively incorporating the global gene-to-gene interactions in the co-functional network, especially on the species that gene annotations in GO are far from complete.

A PLSPM-Based Test Statistic for Detecting Gene-Gene Co-Association in Genome-Wide Association Study with Case-Control Design

PubMed Central

Zhang, Xiaoshuai; Yang, Xiaowei; Yuan, Zhongshang; Liu, Yanxun; Li, Fangyu; Peng, Bin; Zhu, Dianwen; Zhao, Jinghua; Xue, Fuzhong

2013-01-01

For genome-wide association data analysis, two genes in any pathway, two SNPs in the two linked gene regions respectively or in the two linked exons respectively within one gene are often correlated with each other. We therefore proposed the concept of gene-gene co-association, which refers to the effects not only due to the traditional interaction under nearly independent condition but the correlation between two genes. Furthermore, we constructed a novel statistic for detecting gene-gene co-association based on Partial Least Squares Path Modeling (PLSPM). Through simulation, the relationship between traditional interaction and co-association was highlighted under three different types of co-association. Both simulation and real data analysis demonstrated that the proposed PLSPM-based statistic has better performance than single SNP-based logistic model, PCA-based logistic model, and other gene-based methods. PMID:23620809

A PLSPM-based test statistic for detecting gene-gene co-association in genome-wide association study with case-control design.

PubMed

Zhang, Xiaoshuai; Yang, Xiaowei; Yuan, Zhongshang; Liu, Yanxun; Li, Fangyu; Peng, Bin; Zhu, Dianwen; Zhao, Jinghua; Xue, Fuzhong

2013-01-01

For genome-wide association data analysis, two genes in any pathway, two SNPs in the two linked gene regions respectively or in the two linked exons respectively within one gene are often correlated with each other. We therefore proposed the concept of gene-gene co-association, which refers to the effects not only due to the traditional interaction under nearly independent condition but the correlation between two genes. Furthermore, we constructed a novel statistic for detecting gene-gene co-association based on Partial Least Squares Path Modeling (PLSPM). Through simulation, the relationship between traditional interaction and co-association was highlighted under three different types of co-association. Both simulation and real data analysis demonstrated that the proposed PLSPM-based statistic has better performance than single SNP-based logistic model, PCA-based logistic model, and other gene-based methods.

Oligo/Polynucleotide-Based Gene Modification: Strategies and Therapeutic Potential

PubMed Central

Sargent, R. Geoffrey; Kim, Soya

2011-01-01

Oligonucleotide- and polynucleotide-based gene modification strategies were developed as an alternative to transgene-based and classical gene targeting-based gene therapy approaches for treatment of genetic disorders. Unlike the transgene-based strategies, oligo/polynucleotide gene targeting approaches maintain gene integrity and the relationship between the protein coding and gene-specific regulatory sequences. Oligo/polynucleotide-based gene modification also has several advantages over classical vector-based homologous recombination approaches. These include essentially complete homology to the target sequence and the potential to rapidly engineer patient-specific oligo/polynucleotide gene modification reagents. Several oligo/polynucleotide-based approaches have been shown to successfully mediate sequence-specific modification of genomic DNA in mammalian cells. The strategies involve the use of polynucleotide small DNA fragments, triplex-forming oligonucleotides, and single-stranded oligodeoxynucleotides to mediate homologous exchange. The primary focus of this review will be on the mechanistic aspects of the small fragment homologous replacement, triplex-forming oligonucleotide-mediated, and single-stranded oligodeoxynucleotide-mediated gene modification strategies as it relates to their therapeutic potential. PMID:21417933

Affective decision-making predictive of Chinese adolescent drinking behaviors

PubMed Central

XIAO, LIN; BECHARA, ANTOINE; GRENARD, L. JERRY; STACY, W. ALAN; PALMER, PAULA; WEI, YONGLAN; JIA, YONG; FU, XIAOLU; JOHNSON, C. ANDERSON

2013-01-01

The goal of the current investigation was to address whether affective decision making would serve as a unique neuropsychological marker to predict drinking behaviors among adolescents. We conducted a longitudinal study of 181 Chinese adolescents in Chengdu city, China. In their 10th grade (ages 15–16), these adolescents were tested for their affective decision-making ability using the Iowa Gambling Task (IGT) and working memory capacity using the Self-Ordered Pointing Test. Self-report questionnaires were used to assess academic performance and drinking behaviors. At 1-year follow-up, questionnaires were completed to assess drinking behaviors, and the UPPS Impulsive Behavior Scale was used to examine four dimensions of impulsivity: urgency, lack of premeditation, lack of perseverance, and sensation seeking. Results indicated that those adolescents who progressed to binge drinking or exhibited consistent binge drinking not only performed poorly on the IGT but also scored significantly higher in urgency compared to those who never or occasionally drank. Moreover, better IGT scores predicted fewer drinking problems and fewer drinks 1 year later after controlling for demographic variables, the previous drinking behaviors, working memory, and impulsivity. These findings suggest that deficits in affective decision making may be important independent determinants of compulsive drinking and potentially addictive behavior in adolescents. PMID:19573273

Interrelationships among impulsive personality traits, food addiction, and Body Mass Index

PubMed Central

Murphy, Cara M.; Stojek, Monika K.; MacKillop, James

2016-01-01

Objective Impulsive personality traits have been robustly associated with alcohol and drug misuse, but have received little attention in the context of food addiction. The goal of the current study was to examine the interrelationships between impulsive personality traits, food addiction, and Body Mass Index (BMI), including indirect pathways of influence. Method Participants (N = 233) completed the Yale Food Addiction Scale (YFAS) to assess patterns of addictive consumption of food, the UPPS-P Impulsivity Scale to assess impulsive personality traits, and provided weight and height to generate BMI. Results Significant positive associations were found between facets of impulsivity, food addiction symptoms, and BMI. Impulsivity was found to be indirectly associated with BMI by way of associations with addictive consumption of food. In particular, an inclination toward behaving irrationally while experiencing negative mood states (Negative Urgency) and low levels of task persistence (lack of Perseverance) were significantly associated with food addiction directly and that relationship was responsible for their relationship to BMI. Conclusions Dispositional impulsivity, routinely associated with high-risk behaviors including addictive consumption of alcohol and drugs, may be an important risk factor when considering tendency to engage in addictive consumption of food. Monitoring food addiction symptoms early may help reduce the likelihood that compulsive food consumption patterns result in weight gain and obesity. Methodological considerations are discussed. PMID:24511618

Dysfunctional decision-making in pathological gambling: pattern specificity and the role of impulsivity.

PubMed

Kräplin, Anja; Dshemuchadse, Maja; Behrendt, Silke; Scherbaum, Stefan; Goschke, Thomas; Bühringer, Gerhard

2014-03-30

Dysfunctional decision-making in individuals with pathological gambling (PGs) may result from dominating reward-driven processes, indicated by higher impulsivity. In the current study we examined (1) if PGs show specific decision-making impairments related to dominating reward-driven processes rather than to strategic planning deficits and (2) whether these impairments are related to impulsivity. Nineteen PGs according to DSM-IV and 19 matched control subjects undertook the Cambridge Gambling Task (CGT) to assess decision-making. The delay discounting paradigm (DDP) as well as the UPPS Impulsive Behavior Scale (measuring urgency, premeditation, perseverance and sensation seeking) were administered as multidimensional measures of impulsivity. Results revealed that (1) PGs exhibited higher risk seeking and an immediate reward focus in the CGT and, in contrast, comparable strategic planning to the control group. (2) Decision-making impairments were related to more severe delay discounting and, specifically, to increased urgency and less premeditation. Our findings suggest (1) the necessity to disentangle decision-making components in order to improve etiological models of PGs, and (2) that urgency and premeditation are specifically related to disadvantageous decision-making and should be tackled in intervention strategies focusing on emotion tolerance and control strategies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Psychological predictors of problematic involvement in massively multiplayer online role-playing games: illustration in a sample of male cybercafé players.

PubMed

Billieux, Joël; Chanal, Julien; Khazaal, Yasser; Rochat, Lucien; Gay, Philippe; Zullino, Daniele; Van der Linden, Martial

2011-01-01

Massively Multiplayer Online Role-Playing Games (MMORPGs) are video games in which a large number of players interact with one another in a persistent virtual world. MMORPGs can become problematic and result in negative outcomes in daily living (e.g. loss of control on gaming behaviors, compromised social and individual quality of life). The aim of the present study is to investigate psychological predictors of problematic involvement in MMORPGs. Fifty-four males who played MMORPGs regularly were recruited in cybercafés and screened using the UPPS Impulsive Behavior Scale (which assesses 4 facets of impulsivity) and the Motivation to Play Online Questionnaire (which assesses personal motives to play online). Negative consequences due to excessive time spent on the Internet were assessed with the Internet Addiction Test. Multiple regression analysis showed that problematic use of MMORPGs is significantly predicted by: (1) high urgency (b = 0.45), and (2) a motivation to play for immersion (b = 0.35). This study showed that, for certain individuals (who are characterized by a proneness to act rashly in emotional contexts and motivated to play to be immersed in a virtual world), involvement in MMORPGs can become problematic and engender tangible negative consequences in daily life. Copyright © 2011 S. Karger AG, Basel.

Neuroticism and Negative Urgency in Problematic Alcohol Use: A Pilot Study.

PubMed

Papachristou, Harilaos; Nederkoorn, Chantal; Jansen, Anita

2016-09-18

Problematic alcohol use is common among university students and personality might account for individual differences in developing this maladaptive behavior. Two personality dispositions implicated in problematic alcohol use are negative urgency and neuroticism. However, the relationship of these traits to problematic alcohol use is unclear. In college students high neuroticism is not directly linked to problematic alcohol use. On the other hand, the experience of emotional distress in people high in neuroticism could impair the capacity for impulse control. Loss of impulse control under conditions of negative affect could trigger impulsive drinking and problematic alcohol use in the long run. We investigated this idea by testing whether negative urgency mediates the relationship of neuroticism to problematic alcohol use. Participants were 60 undergraduate university students who completed the Urgency subscale of the Urgency, (lack of) Premeditation, (lack of) Perseverance, Sensation Seeking, and Positive Urgency Impulsive Behaviour scale (UPPS-P), the Alcohol Use Disorders Identification Test (AUDIT), and the Neuroticism subscale of the Eysenck Personality Questionnaire Revised short form (EPQ-RSS). The results confirmed our hypothesis as we found an indirect effect of negative urgency on the relationship between neuroticism and problematic alcohol use. It appears that it is not distress but the tendency to act rashly when distressed that is important in developing problematic alcohol drinking in university students.

Spatial-temporal evolution of self-organized loop-patterns on a water surface and a diffuse discharge in the gap

NASA Astrophysics Data System (ADS)

Li, Xuechen; Geng, Jinling; Jia, Pengying; Zhang, Panpan; Zhang, Qi; Li, Yaru

2017-11-01

Excited by an alternating current voltage, a patterned discharge and a diffuse discharge are generated in a needle to liquid configuration. Using an intensified charge-coupled device (ICCD), temporal evolution of the discharge between the two electrodes is investigated for the diffuse mode and the patterned mode, respectively. For the diffuse mode, the positive discharge is in a glow regime, and the negative discharge is in a Townsend discharge regime. For the patterned mode, the discharge always belongs to the Townsend discharge regime. Moreover, in the patterned mode, various patterns including the single loop, single loop with the surrounding corona, triple loops, and concentric loops with a central spot are observed on the water surface with the increasing positive peak-value of the applied voltage (Upp). Temporally resolved images of the loop-patterns are captured on the water surface. From the electrical measurements and the ICCD imaging, it is found that the loop pattern emerges after the discharge bridges the two electrodes. Then, it begins to evolve and finally degenerates with the decrease in the discharge current. The pattern does not disappear until the discharge quenches. Formation of the loop-patterns is attributed to the role of negative ions.

Impulsivity in men with prescription of benzodiazepines and methadone in prison.

PubMed

Moreno-Ramos, Luis; Fernández-Serrano, María José; Pérez-García, Miguel; Verdejo-García, Antonio

2016-06-14

Benzodiazepines and methadone use has been associated with various neuropsychological impairments. However, to the best of our knowledge, no studies have been carried out on the effect of these substances (either separately or combined) on impulsive personality, including studies in prisoners. The aim of this study is to examine the impulsive personality of a sample of 134 male prisoners using the Sensitivity to Punishment and Sensitivity to Reward Questionnaire (Torrubia, Avila, Molto, & Caseras, 2001) and the UPPS-P Scale (Cyders et al., 2007). Some of these were methadone users, methadone and benzodiazepines users, polydrug users in abstinence and non-dependent drug users. The results showed that drug users have greater sensitivity to reward, positive urgency, negative urgency and sensation seeking than non-dependent users. Methadone users showed more sensitivity to punishment and lack of perseverance with respect to other users. No differences were found between methadone+benzodiazepines users and other groups. The secondary aim is to examine which impulsive personality dimensions are related to the two motivational systems proposed by Gray (BIS-BAS) using exploratory factor analysis. Results showed two different components. One component was defined by the subscales sensitivity to reinforcement, positive urgency, negative urgency and sensation seeking. The second component was defined by the subscales sensitivity to punishment, lack of perseverance and lack of premeditation.

Behavioural ratings of self-regulatory mechanisms and driving behaviour after an acquired brain injury.

PubMed

Rike, Per-Ola; Ulleberg, Pål; Schultheis, Maria T; Lundqvist, Anna; Schanke, Anne-Kristine

2014-01-01

To explore whether measurements of self-regulatory mechanisms and cognition predict driving behaviour after an acquired brain injury (ABI). Consecutive follow-up study. At baseline participants included 77 persons with stroke and 32 persons with a traumatic brain injury (TBI), all of whom completed a multidisciplinary driving assessment (MDA). A follow-up cohort of 34 persons that succeeded the MDA was included. Baseline measurements: Neuropsychological tests and measurements of self-regulatory mechanisms (BRIEF-A and UPPS Impulsive Behaviour Scale), driving behaviour (DBQ) and pre-injury driving characteristics (mileage, compensatory driving strategies and accident rates). Follow-up measurements: Post-injury driving characteristics were collected by mailed questionnaires from the participants who succeeded the MDA. A MDA, which included a medical examination, neuropsychological testing and an on-road driving test, was considered in the decision for or against granting a driver's license. Self-regulatory mechanisms and driving behaviour were examined for research purposes only. At baseline, self-regulatory mechanisms were significantly associated to aberrant driving behaviour, but not with neuropsychological data or with the outcome of the on-road driving test. Aspects of self-regulation were associated to driving behaviour at follow-up. It is recommended that self-regulatory measurements should regularly be considered in the driving assessments after ABI.

Interrelationships among impulsive personality traits, food addiction, and Body Mass Index.

PubMed

Murphy, Cara M; Stojek, Monika K; MacKillop, James

2014-02-01

Impulsive personality traits have been robustly associated with alcohol and drug misuse, but have received little attention in the context of food addiction. The goal of the current study was to examine the interrelationships between impulsive personality traits, food addiction, and Body Mass Index (BMI), including indirect pathways of influence. Participants (N = 233) completed the Yale Food Addiction Scale (YFAS) to assess patterns of addictive consumption of food, the upps-p impulsivity scale to assess impulsive personality traits, and provided weight and height to generate BMI. Significant positive associations were found between facets of impulsivity, food addiction symptoms, and BMI. Impulsivity was found to be indirectly associated with BMI by way of associations with addictive consumption of food. In particular, an inclination toward behaving irrationally while experiencing negative mood states (Negative Urgency) and low levels of task persistence (lack of Perseverance) were significantly associated with food addiction directly and that relationship was responsible for their relationship to BMI. Dispositional impulsivity, routinely associated with high-risk behaviors including addictive consumption of alcohol and drugs, may be an important risk factor when considering tendency to engage in addictive consumption of food. Monitoring food addiction symptoms early may help reduce the likelihood that compulsive food consumption patterns result in weight gain and obesity. Methodological considerations are discussed.

Observations on the function of the female urethra: II: Relation between maximum urethral closure pressure at rest and the degree of urethral incompetence.

PubMed

Schick, Erik; Bertrand, Pierre E; Jolivet-Tremblay, Martine; Dupont, Charles; Tessier, Jocelyne

2004-01-01

To study the relation between maximum urethral closure pressure (MUCP) at rest and the degree of urethral incompetence in the female. Two hundred fifty five patients aged 20 years or older, with stable bladders on multichannel urodynamics, without known neurological pathology, and with no previous history of pelvic or anti-incontinence surgery were included in the study. Resting urethral pressure profile (UPP) and the grade of urethral incompetence was registered. Mean age of the group was 45.6+/-12.7 years; mean MUCP was 62.7+/-28.5 cm of water. There was a statistically significant difference in the MUCP when the different grades of urethral incompetence were compared to each other, the higher grades being associated with a lower maximal closure pressure. This study demonstrates that there is a highly significant relationship between MUCP and between all grades of urethral incompetence. This supports previous observations that MUCP decreases when abdominal leak point pressure (ALPP) is low and that this might be secondary to some mechanical failure in the pressure transmission from the abdominal cavity to the urethra. Studies should never compare continent to incontinent cohorts without considering their ALPP because in doing so they are comparing groups that are functionally heterogeneous. Copyright 2003 Wiley-Liss, Inc.

Which dimensions of impulsivity are related to problematic practice of physical exercise?

PubMed

Kotbagi, Gayatri; Morvan, Yannick; Romo, Lucia; Kern, Laurence

2017-06-01

Background and aims Problematic practice of physical exercise (PPPE) has been suggested to be a behavioral addiction. Impulsivity represents a core dimension of behavioral addictions. However, little is known about impulsivity facets in PPPE. The aim of this study was to investigate the role of impulsivity facets in PPPE. Methods A total of 684 students (between 18 and 25 years) took part in this study and filled up a battery of questionnaire, which consisted of following measures - Global Physical Activity Questionnaire, Exercise Dependence Scale - Revised, and the UPPS Impulsive Behavior Scale. Multiple regression analyses were utilized to investigate the predictive role of each impulsivity facet in PPPE. Results Age, the total level of physical activity per day, sex (male), negative urgency, and sensation seeking were found to be significant predictors of PPPE. A categorical analysis of PPPE revealed that negative urgency, positive urgency, and sensation seeking were significantly higher in the dependent category of PPPE. Discussion and conclusions Associations to negative urgency and sensation seeking might indicate that PPPE serves to regulate or alleviate negative affect or aversive emotional states. Thus, PPPE could be conceptualized as a short-term coping strategy dedicated to relieving negative affective states, like other maladaptive behaviors such as binge eating, binge drinking, or compulsive buying.

Coalmines as Underground Pumped Storage Power Plants (UPP) - A Contribution to a Sustainable Energy Supply?

NASA Astrophysics Data System (ADS)

Luick, H.; Niemann, A.; Perau, E.; Schreiber, U.

2012-04-01

In Europe, electrical power generation from renewable energy sources rose by about 50% in the last 20 years. In Germany, renewable electricity is mainly provided by wind power and photovoltaic. Energy output depends on weather conditions like wind speed or solar radiation and may therefore vary considerably. Rapid fluctuations in power generation already require regulation of conventional power plants by the distribution network operators to stabilize and ensure grid frequency and overall system stability. In order to avoid future blackouts caused by intermittent energy sources, it is necessary to increase the storage capacity for electric power. Theoretically, there are many technologies for storing energy, like accumulators, hydrogen storage systems, biomethane facilities (hydrocarbon synthesis) or compressed air storage. Only a few technologies combine sufficient capacity, fast response, high efficiency, low storage loss and long-term application experience. A pumped storage power plant (PSPP) is a state of the art technology which combines all of these aspects. Energy is stored in form of potential energy by pumping water to an upper reservoir in times of energy surplus or low energy costs. In times of insufficient power supply or high energy costs, the water is released through turbines to produce electric energy. The efficiency of state-of-the-art systems is about 70-80%. The total head (geodetic height between upper and lower reservoirs) and the storage capacity of the reservoirs as given in a mountainous terrain, determine the energy storage capacity of a PSPP. An alternative is the use of man-made geodetic height differences as given in ore, coal or open cast lignite mines. In these cases, the lower reservoir of the plant is located in the drifts or at the bottom of the mine. Energieforschungszentrum Niedersachsen (EFZN) has already explored the installation of a PSPP in abandoned ore mines in the Harz-region/Germany (Beck 2011). In 2011/2012 a basic research project, funded by Mercator Research Center Ruhr has been performed to investigate the field of application of coal mines for underground pumped storage plants (UPP). In further research, in co-operation with the Ruhrkohle AG coal mines in the Ruhr Area will be investigated (Niemann, 2011). The coal mine "Prosper-Haniel" is located in the northern part of the Ruhr Area and shafts have a maximum depth of 1,159 m. It will be closed in 2018. In principal two different designs had been investigated (Luick 2011). The first is a closed system in which water circulates isolated from surrounding groundwater in drifts and shafts supported by casings. The second one is an open system, with a varying groundwater table at a defined depth. Problems resulting from this are the stability of the surrounding rock, its porosity and fissurization, composition of mine waters, the necessity of new drifts and shafts or the upgrading of old ones. In addition, the configuration and arrangement of turbines, pumps and ventilation shafts play an important role. The presentation gives an outline towards problems and challenges which have to be solved in order to establish an innovative contribution for future energy storage.

Development of a DNA Aptamer for Screening Neisseria meningitidis Serogroup B by Cell SELEX

PubMed Central

Mirzakhani, Kimia; Gargari, Seyed Latif Mousavi; Rasooli, Iraj; Rasoulinejad, Samaneh

2018-01-01

Background: Artificial oligonucleotides like DNA or RNA aptamers can be used as biodiagnostic alternatives for antibodies to detect pathogens. Comparing to antibodies, artificial oligonucleotides are produced easily at lower costs and are more stable. Neisseria meningitidis, the causative agent of meningitis, is responsible for about 1% of infections in an epidemic period. Specific DNA aptamers that bind to N. meningitidis serogroup B were identified by whole-cell Systemic Evolution of Ligands by EXponential Enrichment (SELEX). Methods: The SELEX begins with a library of labeled ssDNA molecules. After six rounds of selection and two rounds of counter-selection, 60 clones were obtained, of which the binding efficiency of 21 aptamers to the aforementioned bacterium was tested by flow cytometry. Results: The aptamers K3 and K4 showed the highest affinity to N. meningitidis serogroup B and no affinity to N. meningitidis serogroups Y, A, and C, or to other meningitis causing bacteria. The dissociation constant (Kd value) for K3 and K4 were calculated as 28.3 ± 8.9 pM and 39.1 ± 8.6 pM, respectively. K3 aptamer with the lowest Kd was chosen as the main aptamer. K3 could detect N. meningitidis in patients’ cerebrospinal fluid (CSF) samples and in CSF from healthy volunteers inoculated with N. meningitidis serogroup B (ATCC 13090) at 200 and 100 CFU ml-1, respectively. Conclusion: The findings suggest the application of the developed aptamer in specific detection of N. meningitidis serogroup B amongst a group of meningitis causing bacteria.

Persistence of Agrobacterium tumefaciens in transformed conifers.

PubMed

Charity, Julia A; Klimaszewska, Krystyna

2005-01-01

Previous studies have shown that the widely used plant transformation vector Agrobacterium tumefaciens can persist in genetically engineered plants in vitro and in transgenic greenhouse-grown plants, despite the use of counter-selective antibiotics. However, little is known regarding Agrobacterium persistence in tree species. To understand the kinetics of A. tumefaciens decline and persistence in transformation experiments, we assayed for the presence of A. tumefaciens in spruce and pine embryogenic tissue for up to 10 weeks post-transformation. The A. tumefaciens populations declined rapidly in the first five days post-cocultivation but generally declined more slowly in pine, relative to spruce. No bacteria were detected in spruce embryogenic tissue beyond four weeks after cocultivation, however in pine there were -100 colony forming units per g tissue at 10 weeks post-cocultivation. We present evidence that the detection limit for PCR using virD2 primers to detect A. tumefaciens in a background of pine needle DNA was approximately 10(9)-10(10) A. tumefaciens cells per g of tissue. We also assayed for A. tumefaciens in transgenic pine and spruce embryogenic tissue and from needles, branches, stems and roots of transformed plants, up to four years post-inoculation. Occasionally A. tumefaciens was detected in embryogenic tissue up to 12 months post-inoculation. A. tumefaciens was never detected in cultured embryogenic tissue more than twelve months after inoculation, nor in developing somatic embryos or germinating plantlets, nor any of the parts of greenhouse-grown plants. From these data we conclude that if A. tumefaciens persists in transgenic conifers, it does so beneath our ability to detect it.

A powerful score-based test statistic for detecting gene-gene co-association.

PubMed

Xu, Jing; Yuan, Zhongshang; Ji, Jiadong; Zhang, Xiaoshuai; Li, Hongkai; Wu, Xuesen; Xue, Fuzhong; Liu, Yanxun

2016-01-29

The genetic variants identified by Genome-wide association study (GWAS) can only account for a small proportion of the total heritability for complex disease. The existence of gene-gene joint effects which contains the main effects and their co-association is one of the possible explanations for the "missing heritability" problems. Gene-gene co-association refers to the extent to which the joint effects of two genes differ from the main effects, not only due to the traditional interaction under nearly independent condition but the correlation between genes. Generally, genes tend to work collaboratively within specific pathway or network contributing to the disease and the specific disease-associated locus will often be highly correlated (e.g. single nucleotide polymorphisms (SNPs) in linkage disequilibrium). Therefore, we proposed a novel score-based statistic (SBS) as a gene-based method for detecting gene-gene co-association. Various simulations illustrate that, under different sample sizes, marginal effects of causal SNPs and co-association levels, the proposed SBS has the better performance than other existed methods including single SNP-based and principle component analysis (PCA)-based logistic regression model, the statistics based on canonical correlations (CCU), kernel canonical correlation analysis (KCCU), partial least squares path modeling (PLSPM) and delta-square (δ (2)) statistic. The real data analysis of rheumatoid arthritis (RA) further confirmed its advantages in practice. SBS is a powerful and efficient gene-based method for detecting gene-gene co-association.

THE HERSCHEL COMPREHENSIVE (U)LIRG EMISSION SURVEY (HERCULES): CO LADDERS, FINE STRUCTURE LINES, AND NEUTRAL GAS COOLING

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rosenberg, M. J. F.; Van der Werf, P. P.; Israel, F. P.

2015-03-10

(Ultra) luminous infrared galaxies ((U)LIRGs) are objects characterized by their extreme infrared (8-1000 μm) luminosities (L {sub LIRG} > 10{sup 11} L {sub ☉} and L {sub ULIRG} > 10{sup 12} L {sub ☉}). The Herschel Comprehensive ULIRG Emission Survey (PI: van der Werf) presents a representative flux-limited sample of 29 (U)LIRGs that spans the full luminosity range of these objects (10{sup 11} L {sub ☉} ≤ L {sub IR} ≤ 10{sup 13} L {sub ☉}). With the Herschel Space Observatory, we observe [C II] 157 μm, [O I] 63 μm, and [O I] 145 μm line emission with Photodetector Array Cameramore » and Spectrometer, CO J = 4-3 through J = 13-12, [C I] 370 μm, and [C I] 609 μm with SPIRE, and low-J CO transitions with ground-based telescopes. The CO ladders of the sample are separated into three classes based on their excitation level. In 13 of the galaxies, the [O I] 63 μm emission line is self absorbed. Comparing the CO excitation to the InfraRed Astronomical Satellite 60/100 μm ratio and to far infrared luminosity, we find that the CO excitation is more correlated to the far infrared colors. We present cooling budgets for the galaxies and find fine-structure line flux deficits in the [C II], [Si II], [O I], and [C I] lines in the objects with the highest far IR fluxes, but do not observe this for CO 4 ≤ J {sub upp} ≤ 13. In order to study the heating of the molecular gas, we present a combination of three diagnostic quantities to help determine the dominant heating source. Using the CO excitation, the CO J = 1-0 linewidth, and the active galactic nucleus (AGN) contribution, we conclude that galaxies with large CO linewidths always have high-excitation CO ladders, and often low AGN contributions, suggesting that mechanical heating is important.« less

Statistics on gene-based laser speckles with a small number of scatterers: implications for the detection of polymorphism in the Chlamydia trachomatis omp1 gene

NASA Astrophysics Data System (ADS)

Ulyanov, Sergey S.; Ulianova, Onega V.; Zaytsev, Sergey S.; Saltykov, Yury V.; Feodorova, Valentina A.

2018-04-01

The transformation mechanism for a nucleotide sequence of the Chlamydia trachomatis gene into a speckle pattern has been considered. The first and second-order statistics of gene-based speckles have been analyzed. It has been demonstrated that gene-based speckles do not obey Gaussian statistics and belong to the class of speckles with a small number of scatterers. It has been shown that gene polymorphism can be easily detected through analysis of the statistical characteristics of gene-based speckles.

A Critical Look at Entropy-Based Gene-Gene Interaction Measures.

PubMed

Lee, Woojoo; Sjölander, Arvid; Pawitan, Yudi

2016-07-01

Several entropy-based measures for detecting gene-gene interaction have been proposed recently. It has been argued that the entropy-based measures are preferred because entropy can better capture the nonlinear relationships between genotypes and traits, so they can be useful to detect gene-gene interactions for complex diseases. These suggested measures look reasonable at intuitive level, but so far there has been no detailed characterization of the interactions captured by them. Here we study analytically the properties of some entropy-based measures for detecting gene-gene interactions in detail. The relationship between interactions captured by the entropy-based measures and those of logistic regression models is clarified. In general we find that the entropy-based measures can suffer from a lack of specificity in terms of target parameters, i.e., they can detect uninteresting signals as interactions. Numerical studies are carried out to confirm theoretical findings. © 2016 WILEY PERIODICALS, INC.

LEGO: a novel method for gene set over-representation analysis by incorporating network-based gene weights

PubMed Central

Dong, Xinran; Hao, Yun; Wang, Xiao; Tian, Weidong

2016-01-01

Pathway or gene set over-representation analysis (ORA) has become a routine task in functional genomics studies. However, currently widely used ORA tools employ statistical methods such as Fisher’s exact test that reduce a pathway into a list of genes, ignoring the constitutive functional non-equivalent roles of genes and the complex gene-gene interactions. Here, we develop a novel method named LEGO (functional Link Enrichment of Gene Ontology or gene sets) that takes into consideration these two types of information by incorporating network-based gene weights in ORA analysis. In three benchmarks, LEGO achieves better performance than Fisher and three other network-based methods. To further evaluate LEGO’s usefulness, we compare LEGO with five gene expression-based and three pathway topology-based methods using a benchmark of 34 disease gene expression datasets compiled by a recent publication, and show that LEGO is among the top-ranked methods in terms of both sensitivity and prioritization for detecting target KEGG pathways. In addition, we develop a cluster-and-filter approach to reduce the redundancy among the enriched gene sets, making the results more interpretable to biologists. Finally, we apply LEGO to two lists of autism genes, and identify relevant gene sets to autism that could not be found by Fisher. PMID:26750448

LEGO: a novel method for gene set over-representation analysis by incorporating network-based gene weights.

PubMed

Dong, Xinran; Hao, Yun; Wang, Xiao; Tian, Weidong

2016-01-11

Pathway or gene set over-representation analysis (ORA) has become a routine task in functional genomics studies. However, currently widely used ORA tools employ statistical methods such as Fisher's exact test that reduce a pathway into a list of genes, ignoring the constitutive functional non-equivalent roles of genes and the complex gene-gene interactions. Here, we develop a novel method named LEGO (functional Link Enrichment of Gene Ontology or gene sets) that takes into consideration these two types of information by incorporating network-based gene weights in ORA analysis. In three benchmarks, LEGO achieves better performance than Fisher and three other network-based methods. To further evaluate LEGO's usefulness, we compare LEGO with five gene expression-based and three pathway topology-based methods using a benchmark of 34 disease gene expression datasets compiled by a recent publication, and show that LEGO is among the top-ranked methods in terms of both sensitivity and prioritization for detecting target KEGG pathways. In addition, we develop a cluster-and-filter approach to reduce the redundancy among the enriched gene sets, making the results more interpretable to biologists. Finally, we apply LEGO to two lists of autism genes, and identify relevant gene sets to autism that could not be found by Fisher.

Evaluation of Gene-Based Family-Based Methods to Detect Novel Genes Associated With Familial Late Onset Alzheimer Disease

PubMed Central

Fernández, Maria V.; Budde, John; Del-Aguila, Jorge L.; Ibañez, Laura; Deming, Yuetiva; Harari, Oscar; Norton, Joanne; Morris, John C.; Goate, Alison M.; Cruchaga, Carlos

2018-01-01

Gene-based tests to study the combined effect of rare variants on a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially studies of complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We examined the performance of several collapsing, variance-component, and transmission disequilibrium tests across eight different software packages and 22 models utilizing a cohort of 285 families (N = 1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the tested phenotype and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B, a GWAS candidate gene for sporadic AD, along with six novel genes (CHRD, CLCN2, HDLBP, CPAMD8, NLRP9, and MAS1L) as candidate genes for familial LOAD. PMID:29670507

Evaluation of Gene-Based Family-Based Methods to Detect Novel Genes Associated With Familial Late Onset Alzheimer Disease.

PubMed

Fernández, Maria V; Budde, John; Del-Aguila, Jorge L; Ibañez, Laura; Deming, Yuetiva; Harari, Oscar; Norton, Joanne; Morris, John C; Goate, Alison M; Cruchaga, Carlos

2018-01-01

Gene-based tests to study the combined effect of rare variants on a particular phenotype have been widely developed for case-control studies, but their evolution and adaptation for family-based studies, especially studies of complex incomplete families, has been slower. In this study, we have performed a practical examination of all the latest gene-based methods available for family-based study designs using both simulated and real datasets. We examined the performance of several collapsing, variance-component, and transmission disequilibrium tests across eight different software packages and 22 models utilizing a cohort of 285 families ( N = 1,235) with late-onset Alzheimer disease (LOAD). After a thorough examination of each of these tests, we propose a methodological approach to identify, with high confidence, genes associated with the tested phenotype and we provide recommendations to select the best software and model for family-based gene-based analyses. Additionally, in our dataset, we identified PTK2B , a GWAS candidate gene for sporadic AD, along with six novel genes ( CHRD, CLCN2, HDLBP, CPAMD8, NLRP9 , and MAS1L ) as candidate genes for familial LOAD.

Analysis of bHLH coding genes using gene co-expression network approach.

PubMed

Srivastava, Swati; Sanchita; Singh, Garima; Singh, Noopur; Srivastava, Gaurava; Sharma, Ashok

2016-07-01

Network analysis provides a powerful framework for the interpretation of data. It uses novel reference network-based metrices for module evolution. These could be used to identify module of highly connected genes showing variation in co-expression network. In this study, a co-expression network-based approach was used for analyzing the genes from microarray data. Our approach consists of a simple but robust rank-based network construction. The publicly available gene expression data of Solanum tuberosum under cold and heat stresses were considered to create and analyze a gene co-expression network. The analysis provide highly co-expressed module of bHLH coding genes based on correlation values. Our approach was to analyze the variation of genes expression, according to the time period of stress through co-expression network approach. As the result, the seed genes were identified showing multiple connections with other genes in the same cluster. Seed genes were found to be vary in different time periods of stress. These analyzed seed genes may be utilized further as marker genes for developing the stress tolerant plant species.

A computational approach to candidate gene prioritization for X-linked mental retardation using annotation-based binary filtering and motif-based linear discriminatory analysis

PubMed Central

2011-01-01

Background Several computational candidate gene selection and prioritization methods have recently been developed. These in silico selection and prioritization techniques are usually based on two central approaches - the examination of similarities to known disease genes and/or the evaluation of functional annotation of genes. Each of these approaches has its own caveats. Here we employ a previously described method of candidate gene prioritization based mainly on gene annotation, in accompaniment with a technique based on the evaluation of pertinent sequence motifs or signatures, in an attempt to refine the gene prioritization approach. We apply this approach to X-linked mental retardation (XLMR), a group of heterogeneous disorders for which some of the underlying genetics is known. Results The gene annotation-based binary filtering method yielded a ranked list of putative XLMR candidate genes with good plausibility of being associated with the development of mental retardation. In parallel, a motif finding approach based on linear discriminatory analysis (LDA) was employed to identify short sequence patterns that may discriminate XLMR from non-XLMR genes. High rates (>80%) of correct classification was achieved, suggesting that the identification of these motifs effectively captures genomic signals associated with XLMR vs. non-XLMR genes. The computational tools developed for the motif-based LDA is integrated into the freely available genomic analysis portal Galaxy (http://main.g2.bx.psu.edu/). Nine genes (APLN, ZC4H2, MAGED4, MAGED4B, RAP2C, FAM156A, FAM156B, TBL1X, and UXT) were highlighted as highly-ranked XLMR methods. Conclusions The combination of gene annotation information and sequence motif-orientated computational candidate gene prediction methods highlight an added benefit in generating a list of plausible candidate genes, as has been demonstrated for XLMR. Reviewers: This article was reviewed by Dr Barbara Bardoni (nominated by Prof Juergen Brosius); Prof Neil Smalheiser and Dr Dustin Holloway (nominated by Prof Charles DeLisi). PMID:21668950

Development of Biodegradable Polycation-Based Inhalable Dry Gene Powders by Spray Freeze Drying

PubMed Central

Okuda, Tomoyuki; Suzuki, Yumiko; Kobayashi, Yuko; Ishii, Takehiko; Uchida, Satoshi; Itaka, Keiji; Kataoka, Kazunori; Okamoto, Hirokazu

2015-01-01

In this study, two types of biodegradable polycation (PAsp(DET) homopolymer and PEG-PAsp(DET) copolymer) were applied as vectors for inhalable dry gene powders prepared by spray freeze drying (SFD). The prepared dry gene powders had spherical and porous structures with a 5~10-μm diameter, and the integrity of plasmid DNA could be maintained during powder production. Furthermore, it was clarified that PEG-PAsp(DET)-based dry gene powder could more sufficiently maintain both the physicochemical properties and in vitro gene transfection efficiencies of polyplexes reconstituted after powder production than PAsp(DET)-based dry gene powder. From an in vitro inhalation study using an Andersen cascade impactor, it was demonstrated that the addition of l-leucine could markedly improve the inhalation performance of dry powders prepared by SFD. Following pulmonary delivery to mice, both PAsp(DET)- and PEG-PAsp(DET)-based dry gene powders could achieve higher gene transfection efficiencies in the lungs compared with a chitosan-based dry gene powder previously reported by us. PMID:26343708

A Cancer Gene Selection Algorithm Based on the K-S Test and CFS.

PubMed

Su, Qiang; Wang, Yina; Jiang, Xiaobing; Chen, Fuxue; Lu, Wen-Cong

2017-01-01

To address the challenging problem of selecting distinguished genes from cancer gene expression datasets, this paper presents a gene subset selection algorithm based on the Kolmogorov-Smirnov (K-S) test and correlation-based feature selection (CFS) principles. The algorithm selects distinguished genes first using the K-S test, and then, it uses CFS to select genes from those selected by the K-S test. We adopted support vector machines (SVM) as the classification tool and used the criteria of accuracy to evaluate the performance of the classifiers on the selected gene subsets. This approach compared the proposed gene subset selection algorithm with the K-S test, CFS, minimum-redundancy maximum-relevancy (mRMR), and ReliefF algorithms. The average experimental results of the aforementioned gene selection algorithms for 5 gene expression datasets demonstrate that, based on accuracy, the performance of the new K-S and CFS-based algorithm is better than those of the K-S test, CFS, mRMR, and ReliefF algorithms. The experimental results show that the K-S test-CFS gene selection algorithm is a very effective and promising approach compared to the K-S test, CFS, mRMR, and ReliefF algorithms.

Framework for reanalysis of publicly available Affymetrix® GeneChip® data sets based on functional regions of interest.

PubMed

Saka, Ernur; Harrison, Benjamin J; West, Kirk; Petruska, Jeffrey C; Rouchka, Eric C

2017-12-06

Since the introduction of microarrays in 1995, researchers world-wide have used both commercial and custom-designed microarrays for understanding differential expression of transcribed genes. Public databases such as ArrayExpress and the Gene Expression Omnibus (GEO) have made millions of samples readily available. One main drawback to microarray data analysis involves the selection of probes to represent a specific transcript of interest, particularly in light of the fact that transcript-specific knowledge (notably alternative splicing) is dynamic in nature. We therefore developed a framework for reannotating and reassigning probe groups for Affymetrix® GeneChip® technology based on functional regions of interest. This framework addresses three issues of Affymetrix® GeneChip® data analyses: removing nonspecific probes, updating probe target mapping based on the latest genome knowledge and grouping probes into gene, transcript and region-based (UTR, individual exon, CDS) probe sets. Updated gene and transcript probe sets provide more specific analysis results based on current genomic and transcriptomic knowledge. The framework selects unique probes, aligns them to gene annotations and generates a custom Chip Description File (CDF). The analysis reveals only 87% of the Affymetrix® GeneChip® HG-U133 Plus 2 probes uniquely align to the current hg38 human assembly without mismatches. We also tested new mappings on the publicly available data series using rat and human data from GSE48611 and GSE72551 obtained from GEO, and illustrate that functional grouping allows for the subtle detection of regions of interest likely to have phenotypical consequences. Through reanalysis of the publicly available data series GSE48611 and GSE72551, we profiled the contribution of UTR and CDS regions to the gene expression levels globally. The comparison between region and gene based results indicated that the detected expressed genes by gene-based and region-based CDFs show high consistency and regions based results allows us to detection of changes in transcript formation.

Prioritizing Genes Related to Nicotine Addiction Via a Multi-source-Based Approach.

PubMed

Liu, Xinhua; Liu, Meng; Li, Xia; Zhang, Lihua; Fan, Rui; Wang, Ju

2015-08-01

Nicotine has a broad impact on both the central and peripheral nervous systems. Over the past decades, an increasing number of genes potentially involved in nicotine addiction have been identified by different technical approaches. However, the molecular mechanisms underlying nicotine addiction remain largely unknown. Under such situation, prioritizing the candidate genes for further investigation is becoming increasingly important. In this study, we presented a multi-source-based gene prioritization approach for nicotine addiction by utilizing the vast amounts of information generated from for nicotine addiction study during the past years. In this approach, we first collected and curated genes from studies in four categories, i.e., genetic association analysis, genetic linkage analysis, high-throughput gene/protein expression analysis, and literature search of single gene/protein-based studies. Based on these resources, the genes were scored and a weight value was determined for each category. Finally, the genes were ranked by their combined scores, and 220 genes were selected as the prioritized nicotine addiction-related genes. Evaluation suggested the prioritized genes were promising targets for further analysis and replication study.

A prospective study of the influence of the UPPS model of impulsivity on the co-occurrence of bulimic symptoms and non-suicidal self-injury.

PubMed

Peterson, Claire M; Fischer, Sarah

2012-12-01

Individuals with bulimia nervosa (BN) often report co-morbid symptoms of non suicidal self-injury (NSSI). This study examined the influence of (lack of) perseverance, (lack of) premeditation, sensation seeking, and negative urgency (the tendency to act rashly when experiencing negative affect) on these two behavior patterns. We hypothesized that negative urgency influences vulnerability to multiple maladaptive behavior patterns, thus influencing the co-occurrence of NSSI and BN symptoms. 489 young adult women completed baseline assessments, and 209 completed an eight month follow-up assessment. Structural equation modeling was used to examine the influence of four personality pathways to impulsive behavior simultaneously on both behaviors at baseline, and the incremental predictive utility of traits on both behaviors at eight month follow up. Additionally, we examined the influence of NSSI at baseline on symptoms of BN at follow up, and symptoms of BN at baseline on NSSI at follow up. Negative urgency accounted for significant variance in NSSI and eating pathology. Baseline (lack of) perseverance contributed significantly to binge eating frequency at follow-up, when accounting for baseline symptoms. NSSI at baseline was associated with increased purging at follow-up. Individual differences in impulsivity appear to influence both NSSI and eating pathology. Copyright © 2012 Elsevier Ltd. All rights reserved.

Impulsive Personality and Alcohol Use: Bidirectional Relations Over One Year

PubMed Central

Kaiser, Alison; Bonsu, Jacqueline A.; Charnigo, Richard J.; Milich, Richard; Lynam, Donald R.

2016-01-01

Objective: Impulsive personality traits have been found to be robust predictors of substance use and problems in both cross-sectional and longitudinal research. Studies examining the relations of substance use and impulsive personality over time indicate a bidirectional relation, where substance use is also predictive of increases in later impulsive personality. The present study sought to build on these findings by examining the bidirectional relations among the different impulsive personality traits assessed by the UPPS-P Impulsive Behavior Scale, with an interest in urgency (the tendency to act rashly when experiencing strong affect). Method: Participants were 525 first-year college students (48.0% male, 81.1% White), who completed self-report measures assessing personality traits and a structured interview assessing past and current substance use. Data collection took place at two different time points: the first occurred during the participants’ first year of college, and the second occurred approximately 1 year later. Bidirectional relations were examined using structural equation modeling. Results: Time 1 (T1) positive urgency predicted higher levels of alcohol use at Time 2 (T2), whereas T1 lack of perseverance predicted lower levels of alcohol use at T2. T1 alcohol use predicted higher levels of positive urgency, negative urgency, sensation seeking, and lack of premeditation at T2. Conclusions: Findings provide greater resolution in characterizing the bidirectional relation between impulsive personality traits and substance use. PMID:27172580

[Comparison of efficacy of heel ulcer prevention between classic padded bandage and polyurethane heel in a medium-stay hospital: randomized controlled trial].

PubMed

Ferrer Solà, Marta; Espaulella Panicot, Joan; Altimires Roset, Jacint; Ylla-Català Borè, Elisenda; Moreno Susi, María

2013-01-01

The aim of the study is to determine the incidence of heel pressure ulcers (UPPT) and to compare the two systems for UPPT prevention: classic padded bandage and polyurethane heel. Prospective intervention study in a medium-long hospital stay of all people admitted that had no UPPT but had a risk of UPPT according to the Braden Scale or clinical judgment. The patients were randomized to prevention with classic padded bandage or polyurethane heel. The outcome variable was the incidence of UPPT for each study group, which was recorded every 15 days or when there were clinical changes. Of the 940 patients evaluated, 409 with a mean age of 80.5 years and 59.1% women,were included in the study. Of these, 78% had Barthel score ≤30; 28.6% dementia; delirium 37.6%; 27.6% diabetes; and 19.6% other UPP. The overall incidence was 2.9% UPPT; 2.49% in the classic padded bandage and 3.37% in the polyurethane heel group (p=0.82). No statistically significant differences were observed between the group with the classical dressing and the group with the polyurethane heel dressing. The use of multiple measures to prevent UPPT achieved a low incidence of these. Copyright © 2011 SEGG. Published by Elsevier Espana. All rights reserved.

Blunted feedback processing during risk-taking in adolescents with features of problematic Internet use.

PubMed

Yau, Yvonne H C; Potenza, Marc N; Mayes, Linda C; Crowley, Michael J

2015-06-01

While the conceptualization of problematic Internet use (PIU) as a "behavioral addiction" resembling substance-use disorders is debated, the neurobiological underpinnings of PIU remain understudied. This study examined whether adolescents displaying features of PIU (at-risk PIU; ARPIU) are more impulsive and exhibit blunted responding in the neural mechanisms underlying feedback processing and outcome evaluation during risk-taking. Event-related potentials (ERPs) elicited by positive (i.e. reward) and negative (i.e. loss) feedback were recorded during performance on a modified version of the Balloon Analogue Risk Task (BART) among ARPIU (n=39) and non-ARPIU subjects (n=27). Compared to non-ARPIU, ARPIU adolescents displayed higher levels of urgency and lack of perseverance on the UPPS Impulsive Behavior Scale. Although no between-group difference in BART performance was observed, ERPs demonstrated overall decreased sensitivity to feedback in ARPIU compared to non-ARPIU adolescents, as indexed by blunted feedback-related negativity (FRN) and P300 amplitudes to both negative and positive feedback. The present study provides evidence for feedback processing during risk-taking as a neural correlate of ARPIU. Given recent concerns regarding the growing prevalence of PIU as a health concern, future work should examine the extent to which feedback processing may represent a risk factor for PIU, a consequence of PIU, or possibly both. Copyright © 2015 Elsevier Ltd. All rights reserved.

Measurement of stellar occultations

NASA Astrophysics Data System (ADS)

Eberle, Andreas

2008-09-01

Whenever an asteroid occults a star, we have the opportunity to study that asteroid in great detail. As frequently shown in the past, amateur astronomers1 have the necessary equipment to measure such events successfully2. Combined with the dense net of amateur observatories and online coordination tools3 for movable stations, they can create fine grids to detect even small bodies. The analysis of these events gives us the possibility to receive high precision astrometry data, to determine the asteroids size and shape (and therefore its albedo), and even to collect information on the star itself.4 While usually a set of several light curves is required to do so, a single recording5 of (10734) Wieck's occultation of HIP 22157 on 2008 Feb 08 was sufficient to retrieve the necessary data6. 1 Observation campaigns are organized by the International Occultation Timing Association (IOTA), http://www.iota-es.de/ 2 for results see e.g. euraster.net by E. Frappa, http://www.euraster.net/ 3 Occult Watcher by H. Pavlov, http://www.hristopavlov.net/OccultWatcher/OccultWatcher.html 4 see K. Miyashita's analysis of the observation of the occultation of TYC 1886-01206-1 by Kalliope and Linus, http://www005.upp.so-net.ne.jp/k miyash/occ02/kalliope/doublestar en.html 5 recording obtained by H. Michels, MPC Station Code 240 6 using Limovie by K. Miyashita

Mutated-leptin gene transfer induces increases in body weight by electroporation and hydrodynamics-based gene delivery in mice.

PubMed

Xiang, Lan; Murai, Atsushi; Muramatsu, Tatsuo

2005-12-01

To investigate whether in vivo gene transfer causes leptin-antagonistic effects on food intake, animal body weight and fat tissue weight, the R128Q mutated-leptin gene, an R to Q substitution at position 128 of mouse leptin, was transferred into mouse liver and leg muscle by electroporation and hydrodynamics-based gene delivery. Mutated-leptin gene transfer by electroporation caused significant increases in body weight at 5 days and after (5.4% increase relative to control; p<0.05). Hydrodynamics-based gene delivery of the mutated-leptin gene also caused an increase in body weight (3.0% increase relative to control; p<0.05). Mutated-leptin gene transfer by electroporation significantly increased the tissue weight of epididymal white fat and neuropeptide Y mRNA expression in the hypothalamus compared with those of the control group 3 weeks after gene transfer (p<0.05). These results suggest that mutated-leptin gene transfer successfully produced leptin-antagonistic effects by modulating the central regulator of energy homeostasis. Also, the extent of leptin-antagonistic effects by electroporation was much higher than hydrodynamics-based gene delivery, with at least single gene transfer.

A random set scoring model for prioritization of disease candidate genes using protein complexes and data-mining of GeneRIF, OMIM and PubMed records.

PubMed

Jiang, Li; Edwards, Stefan M; Thomsen, Bo; Workman, Christopher T; Guldbrandtsen, Bernt; Sørensen, Peter

2014-09-24

Prioritizing genetic variants is a challenge because disease susceptibility loci are often located in genes of unknown function or the relationship with the corresponding phenotype is unclear. A global data-mining exercise on the biomedical literature can establish the phenotypic profile of genes with respect to their connection to disease phenotypes. The importance of protein-protein interaction networks in the genetic heterogeneity of common diseases or complex traits is becoming increasingly recognized. Thus, the development of a network-based approach combined with phenotypic profiling would be useful for disease gene prioritization. We developed a random-set scoring model and implemented it to quantify phenotype relevance in a network-based disease gene-prioritization approach. We validated our approach based on different gene phenotypic profiles, which were generated from PubMed abstracts, OMIM, and GeneRIF records. We also investigated the validity of several vocabulary filters and different likelihood thresholds for predicted protein-protein interactions in terms of their effect on the network-based gene-prioritization approach, which relies on text-mining of the phenotype data. Our method demonstrated good precision and sensitivity compared with those of two alternative complex-based prioritization approaches. We then conducted a global ranking of all human genes according to their relevance to a range of human diseases. The resulting accurate ranking of known causal genes supported the reliability of our approach. Moreover, these data suggest many promising novel candidate genes for human disorders that have a complex mode of inheritance. We have implemented and validated a network-based approach to prioritize genes for human diseases based on their phenotypic profile. We have devised a powerful and transparent tool to identify and rank candidate genes. Our global gene prioritization provides a unique resource for the biological interpretation of data from genome-wide association studies, and will help in the understanding of how the associated genetic variants influence disease or quantitative phenotypes.

Machine Learning–Based Differential Network Analysis: A Study of Stress-Responsive Transcriptomes in Arabidopsis[W

PubMed Central

Ma, Chuang; Xin, Mingming; Feldmann, Kenneth A.; Wang, Xiangfeng

2014-01-01

Machine learning (ML) is an intelligent data mining technique that builds a prediction model based on the learning of prior knowledge to recognize patterns in large-scale data sets. We present an ML-based methodology for transcriptome analysis via comparison of gene coexpression networks, implemented as an R package called machine learning–based differential network analysis (mlDNA) and apply this method to reanalyze a set of abiotic stress expression data in Arabidopsis thaliana. The mlDNA first used a ML-based filtering process to remove nonexpressed, constitutively expressed, or non-stress-responsive “noninformative” genes prior to network construction, through learning the patterns of 32 expression characteristics of known stress-related genes. The retained “informative” genes were subsequently analyzed by ML-based network comparison to predict candidate stress-related genes showing expression and network differences between control and stress networks, based on 33 network topological characteristics. Comparative evaluation of the network-centric and gene-centric analytic methods showed that mlDNA substantially outperformed traditional statistical testing–based differential expression analysis at identifying stress-related genes, with markedly improved prediction accuracy. To experimentally validate the mlDNA predictions, we selected 89 candidates out of the 1784 predicted salt stress–related genes with available SALK T-DNA mutagenesis lines for phenotypic screening and identified two previously unreported genes, mutants of which showed salt-sensitive phenotypes. PMID:24520154

Genic insights from integrated human proteomics in GeneCards.

PubMed

Fishilevich, Simon; Zimmerman, Shahar; Kohn, Asher; Iny Stein, Tsippi; Olender, Tsviya; Kolker, Eugene; Safran, Marilyn; Lancet, Doron

2016-01-01

GeneCards is a one-stop shop for searchable human gene annotations (http://www.genecards.org/). Data are automatically mined from ∼120 sources and presented in an integrated web card for every human gene. We report the application of recent advances in proteomics to enhance gene annotation and classification in GeneCards. First, we constructed the Human Integrated Protein Expression Database (HIPED), a unified database of protein abundance in human tissues, based on the publically available mass spectrometry (MS)-based proteomics sources ProteomicsDB, Multi-Omics Profiling Expression Database, Protein Abundance Across Organisms and The MaxQuant DataBase. The integrated database, residing within GeneCards, compares favourably with its individual sources, covering nearly 90% of human protein-coding genes. For gene annotation and comparisons, we first defined a protein expression vector for each gene, based on normalized abundances in 69 normal human tissues. This vector is portrayed in the GeneCards expression section as a bar graph, allowing visual inspection and comparison. These data are juxtaposed with transcriptome bar graphs. Using the protein expression vectors, we further defined a pairwise metric that helps assess expression-based pairwise proximity. This new metric for finding functional partners complements eight others, including sharing of pathways, gene ontology (GO) terms and domains, implemented in the GeneCards Suite. In parallel, we calculated proteome-based differential expression, highlighting a subset of tissues that overexpress a gene and subserving gene classification. This textual annotation allows users of VarElect, the suite's next-generation phenotyper, to more effectively discover causative disease variants. Finally, we define the protein-RNA expression ratio and correlation as yet another attribute of every gene in each tissue, adding further annotative information. The results constitute a significant enhancement of several GeneCards sections and help promote and organize the genome-wide structural and functional knowledge of the human proteome. Database URL:http://www.genecards.org/. © The Author(s) 2016. Published by Oxford University Press.

The Orphan Disease Networks

PubMed Central

Zhang, Minlu; Zhu, Cheng; Jacomy, Alexis; Lu, Long J.; Jegga, Anil G.

2011-01-01

The low prevalence rate of orphan diseases (OD) requires special combined efforts to improve diagnosis, prevention, and discovery of novel therapeutic strategies. To identify and investigate relationships based on shared genes or shared functional features, we have conducted a bioinformatic-based global analysis of all orphan diseases with known disease-causing mutant genes. Starting with a bipartite network of known OD and OD-causing mutant genes and using the human protein interactome, we first construct and topologically analyze three networks: the orphan disease network, the orphan disease-causing mutant gene network, and the orphan disease-causing mutant gene interactome. Our results demonstrate that in contrast to the common disease-causing mutant genes that are predominantly nonessential, a majority of orphan disease-causing mutant genes are essential. In confirmation of this finding, we found that OD-causing mutant genes are topologically important in the protein interactome and are ubiquitously expressed. Additionally, functional enrichment analysis of those genes in which mutations cause ODs shows that a majority result in premature death or are lethal in the orthologous mouse gene knockout models. To address the limitations of traditional gene-based disease networks, we also construct and analyze OD networks on the basis of shared enriched features (biological processes, cellular components, pathways, phenotypes, and literature citations). Analyzing these functionally-linked OD networks, we identified several additional OD-OD relations that are both phenotypically similar and phenotypically diverse. Surprisingly, we observed that the wiring of the gene-based and other feature-based OD networks are largely different; this suggests that the relationship between ODs cannot be fully captured by the gene-based network alone. PMID:21664998

Genes with minimal phylogenetic information are problematic for coalescent analyses when gene tree estimation is biased.

PubMed

Xi, Zhenxiang; Liu, Liang; Davis, Charles C

2015-11-01

The development and application of coalescent methods are undergoing rapid changes. One little explored area that bears on the application of gene-tree-based coalescent methods to species tree estimation is gene informativeness. Here, we investigate the accuracy of these coalescent methods when genes have minimal phylogenetic information, including the implementation of the multilocus bootstrap approach. Using simulated DNA sequences, we demonstrate that genes with minimal phylogenetic information can produce unreliable gene trees (i.e., high error in gene tree estimation), which may in turn reduce the accuracy of species tree estimation using gene-tree-based coalescent methods. We demonstrate that this problem can be alleviated by sampling more genes, as is commonly done in large-scale phylogenomic analyses. This applies even when these genes are minimally informative. If gene tree estimation is biased, however, gene-tree-based coalescent analyses will produce inconsistent results, which cannot be remedied by increasing the number of genes. In this case, it is not the gene-tree-based coalescent methods that are flawed, but rather the input data (i.e., estimated gene trees). Along these lines, the commonly used program PhyML has a tendency to infer one particular bifurcating topology even though it is best represented as a polytomy. We additionally corroborate these findings by analyzing the 183-locus mammal data set assembled by McCormack et al. (2012) using ultra-conserved elements (UCEs) and flanking DNA. Lastly, we demonstrate that when employing the multilocus bootstrap approach on this 183-locus data set, there is no strong conflict between species trees estimated from concatenation and gene-tree-based coalescent analyses, as has been previously suggested by Gatesy and Springer (2014). Copyright © 2015 Elsevier Inc. All rights reserved.

Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10.

PubMed

Doyle-Cooper, Colleen; Hudson, Krystalyn E; Cooper, Anthony B; Ota, Takayuki; Skog, Patrick; Dawson, Phillip E; Zwick, Michael B; Schief, William R; Burton, Dennis R; Nemazee, David

2013-09-15

A major goal of HIV research is to develop vaccines reproducibly eliciting broadly neutralizing Abs (bNAbs); however, this has proved to be challenging. One suggested explanation for this difficulty is that epitopes seen by bNAbs mimic self, leading to immune tolerance. We generated knock-in mice expressing bNAb 4E10, which recognizes the membrane proximal external region of gp41. Unlike b12 knock-in mice, described in the companion article (Ota et al. 2013. J. Immunol. 191: 3179-3185), 4E10HL mice were found to undergo profound negative selection of B cells, indicating that 4E10 is, to a physiologically significant extent, autoreactive. Negative selection occurred by various mechanisms, including receptor editing, clonal deletion, and receptor downregulation. Despite significant deletion, small amounts of IgM and IgG anti-gp41 were found in the sera of 4E10HL mice. On a Rag1⁻/⁻ background, 4E10HL mice had virtually no serum Ig of any kind. These results are consistent with a model in which B cells with 4E10 specificity are counterselected, raising the question of how 4E10 was generated in the patient from whom it was isolated. This represents the second example of a membrane proximal external region-directed bNAb that is apparently autoreactive in a physiological setting. The relative conservation in HIV of the 4E10 epitope might reflect the fact that it is under less intense immunological selection as a result of B cell self-tolerance. The safety and desirability of targeting this epitope by a vaccine is discussed in light of the newly described bNAb 10E8.

The interplay of UV and cutaneous papillomavirus infection in skin cancer development

PubMed Central

Stephan, Sonja; Braspenning-Wesch, Ilona; Mikulec, Julita; Niebler, Martina; Gröne, Hermann-Josef; Flechtenmacher, Christa; Akgül, Baki

2017-01-01

Cutaneous human papillomaviruses (HPVs) are considered as cofactors for non-melanoma skin cancer (NMSC) development, especially in association with UVB. Extensively studied transgenic mouse models failed to mimic all aspects of virus-host interactions starting from primary infection to the appearance of a tumor. Using the natural model Mastomys coucha, which reflects the human situation in many aspects, we provide the first evidence that only UVB and Mastomys natalensis papillomavirus (MnPV) infection strongly promote NMSC formation. Using UVB exposures that correspond to UV indices of different geographical regions, irradiated animals developed either well-differentiated keratinizing squamous cell carcinomas (SCCs), still supporting productive infections with high viral loads and transcriptional activity, or poorly differentiated non-keratinizing SCCs almost lacking MnPV DNA and in turn, early and late viral transcription. Intriguingly, animals with the latter phenotype, however, still showed strong seropositivity, clearly verifying a preceding MnPV infection. Of note, the mere presence of MnPV could induce γH2AX foci, indicating that viral infection without prior UVB exposure can already perturb genome stability of the host cell. Moreover, as shown both under in vitro and in vivo conditions, MnPV E6/E7 expression also attenuates the excision repair of cyclobutane pyrimidine dimers upon UVB irradiation, suggesting a viral impact on the DNA damage response. While mutations of Ras family members (e.g. Hras, Kras, and Nras) were absent, the majority of SCCs harbored—like in humans—Trp53 mutations especially at two hot-spots in the DNA-binding domain, resulting in a loss of function that favored tumor dedifferentiation, counter-selective for viral maintenance. Such a constellation provides a reasonable explanation for making continuous viral presence dispensable during skin carcinogenesis as observed in patients with NMSC. PMID:29190285

Exploring the role of peptides in polymer-based gene delivery.

PubMed

Sun, Yanping; Yang, Zhen; Wang, Chunxi; Yang, Tianzhi; Cai, Cuifang; Zhao, Xiaoyun; Yang, Li; Ding, Pingtian

2017-09-15

Polymers are widely studied as non-viral gene vectors because of their strong DNA binding ability, capacity to carry large payload, flexibility of chemical modifications, low immunogenicity, and facile processes for manufacturing. However, high cytotoxicity and low transfection efficiency substantially restrict their application in clinical trials. Incorporating functional peptides is a promising approach to address these issues. Peptides demonstrate various functions in polymer-based gene delivery systems, such as targeting to specific cells, breaching membrane barriers, facilitating DNA condensation and release, and lowering cytotoxicity. In this review, we systematically summarize the role of peptides in polymer-based gene delivery, and elaborate how to rationally design polymer-peptide based gene delivery vectors. Polymers are widely studied as non-viral gene vectors, but suffer from high cytotoxicity and low transfection efficiency. Incorporating short, bioactive peptides into polymer-based gene delivery systems can address this issue. Peptides demonstrate various functions in polymer-based gene delivery systems, such as targeting to specific cells, breaching membrane barriers, facilitating DNA condensation and release, and lowering cytotoxicity. In this review, we highlight the peptides' roles in polymer-based gene delivery, and elaborate how to utilize various functional peptides to enhance the transfection efficiency of polymers. The optimized peptide-polymer vectors should be able to alter their structures and functions according to biological microenvironments and utilize inherent intracellular pathways of cells, and consequently overcome the barriers during gene delivery to enhance transfection efficiency. Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

ConGEMs: Condensed Gene Co-Expression Module Discovery Through Rule-Based Clustering and Its Application to Carcinogenesis.

PubMed

Mallik, Saurav; Zhao, Zhongming

2017-12-28

For transcriptomic analysis, there are numerous microarray-based genomic data, especially those generated for cancer research. The typical analysis measures the difference between a cancer sample-group and a matched control group for each transcript or gene. Association rule mining is used to discover interesting item sets through rule-based methodology. Thus, it has advantages to find causal effect relationships between the transcripts. In this work, we introduce two new rule-based similarity measures-weighted rank-based Jaccard and Cosine measures-and then propose a novel computational framework to detect condensed gene co-expression modules ( C o n G E M s) through the association rule-based learning system and the weighted similarity scores. In practice, the list of evolved condensed markers that consists of both singular and complex markers in nature depends on the corresponding condensed gene sets in either antecedent or consequent of the rules of the resultant modules. In our evaluation, these markers could be supported by literature evidence, KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway and Gene Ontology annotations. Specifically, we preliminarily identified differentially expressed genes using an empirical Bayes test. A recently developed algorithm-RANWAR-was then utilized to determine the association rules from these genes. Based on that, we computed the integrated similarity scores of these rule-based similarity measures between each rule-pair, and the resultant scores were used for clustering to identify the co-expressed rule-modules. We applied our method to a gene expression dataset for lung squamous cell carcinoma and a genome methylation dataset for uterine cervical carcinogenesis. Our proposed module discovery method produced better results than the traditional gene-module discovery measures. In summary, our proposed rule-based method is useful for exploring biomarker modules from transcriptomic data.

Recent progresses in gene delivery-based bone tissue engineering.

PubMed

Lu, Chia-Hsin; Chang, Yu-Han; Lin, Shih-Yeh; Li, Kuei-Chang; Hu, Yu-Chen

2013-12-01

Gene therapy has converged with bone engineering over the past decade, by which a variety of therapeutic genes have been delivered to stimulate bone repair. These genes can be administered via in vivo or ex vivo approach using either viral or nonviral vectors. This article reviews the fundamental aspects and recent progresses in the gene therapy-based bone engineering, with emphasis on the new genes, viral vectors and gene delivery approaches. © 2013.

Prioritization of candidate disease genes by topological similarity between disease and protein diffusion profiles.

PubMed

Zhu, Jie; Qin, Yufang; Liu, Taigang; Wang, Jun; Zheng, Xiaoqi

2013-01-01

Identification of gene-phenotype relationships is a fundamental challenge in human health clinic. Based on the observation that genes causing the same or similar phenotypes tend to correlate with each other in the protein-protein interaction network, a lot of network-based approaches were proposed based on different underlying models. A recent comparative study showed that diffusion-based methods achieve the state-of-the-art predictive performance. In this paper, a new diffusion-based method was proposed to prioritize candidate disease genes. Diffusion profile of a disease was defined as the stationary distribution of candidate genes given a random walk with restart where similarities between phenotypes are incorporated. Then, candidate disease genes are prioritized by comparing their diffusion profiles with that of the disease. Finally, the effectiveness of our method was demonstrated through the leave-one-out cross-validation against control genes from artificial linkage intervals and randomly chosen genes. Comparative study showed that our method achieves improved performance compared to some classical diffusion-based methods. To further illustrate our method, we used our algorithm to predict new causing genes of 16 multifactorial diseases including Prostate cancer and Alzheimer's disease, and the top predictions were in good consistent with literature reports. Our study indicates that integration of multiple information sources, especially the phenotype similarity profile data, and introduction of global similarity measure between disease and gene diffusion profiles are helpful for prioritizing candidate disease genes. Programs and data are available upon request.

Tensor decomposition-based and principal-component-analysis-based unsupervised feature extraction applied to the gene expression and methylation profiles in the brains of social insects with multiple castes.

PubMed

Taguchi, Y-H

2018-05-08

Even though coexistence of multiple phenotypes sharing the same genomic background is interesting, it remains incompletely understood. Epigenomic profiles may represent key factors, with unknown contributions to the development of multiple phenotypes, and social-insect castes are a good model for elucidation of the underlying mechanisms. Nonetheless, previous studies have failed to identify genes associated with aberrant gene expression and methylation profiles because of the lack of suitable methodology that can address this problem properly. A recently proposed principal component analysis (PCA)-based and tensor decomposition (TD)-based unsupervised feature extraction (FE) can solve this problem because these two approaches can deal with gene expression and methylation profiles even when a small number of samples is available. PCA-based and TD-based unsupervised FE methods were applied to the analysis of gene expression and methylation profiles in the brains of two social insects, Polistes canadensis and Dinoponera quadriceps. Genes associated with differential expression and methylation between castes were identified, and analysis of enrichment of Gene Ontology terms confirmed reliability of the obtained sets of genes from the biological standpoint. Biologically relevant genes, shown to be associated with significant differential gene expression and methylation between castes, were identified here for the first time. The identification of these genes may help understand the mechanisms underlying epigenetic control of development of multiple phenotypes under the same genomic conditions.

HGPEC: a Cytoscape app for prediction of novel disease-gene and disease-disease associations and evidence collection based on a random walk on heterogeneous network.

PubMed

Le, Duc-Hau; Pham, Van-Huy

2017-06-15

Finding gene-disease and disease-disease associations play important roles in the biomedical area and many prioritization methods have been proposed for this goal. Among them, approaches based on a heterogeneous network of genes and diseases are considered state-of-the-art ones, which achieve high prediction performance and can be used for diseases with/without known molecular basis. Here, we developed a Cytoscape app, namely HGPEC, based on a random walk with restart algorithm on a heterogeneous network of genes and diseases. This app can prioritize candidate genes and diseases by employing a heterogeneous network consisting of a network of genes/proteins and a phenotypic disease similarity network. Based on the rankings, novel disease-gene and disease-disease associations can be identified. These associations can be supported with network- and rank-based visualization as well as evidences and annotations from biomedical data. A case study on prediction of novel breast cancer-associated genes and diseases shows the abilities of HGPEC. In addition, we showed prominence in the performance of HGPEC compared to other tools for prioritization of candidate disease genes. Taken together, our app is expected to effectively predict novel disease-gene and disease-disease associations and support network- and rank-based visualization as well as biomedical evidences for such the associations.

ARNetMiT R Package: association rules based gene co-expression networks of miRNA targets.

PubMed

Özgür Cingiz, M; Biricik, G; Diri, B

2017-03-31

miRNAs are key regulators that bind to target genes to suppress their gene expression level. The relations between miRNA-target genes enable users to derive co-expressed genes that may be involved in similar biological processes and functions in cells. We hypothesize that target genes of miRNAs are co-expressed, when they are regulated by multiple miRNAs. With the usage of these co-expressed genes, we can theoretically construct co-expression networks (GCNs) related to 152 diseases. In this study, we introduce ARNetMiT that utilize a hash based association rule algorithm in a novel way to infer the GCNs on miRNA-target genes data. We also present R package of ARNetMiT, which infers and visualizes GCNs of diseases that are selected by users. Our approach assumes miRNAs as transactions and target genes as their items. Support and confidence values are used to prune association rules on miRNA-target genes data to construct support based GCNs (sGCNs) along with support and confidence based GCNs (scGCNs). We use overlap analysis and the topological features for the performance analysis of GCNs. We also infer GCNs with popular GNI algorithms for comparison with the GCNs of ARNetMiT. Overlap analysis results show that ARNetMiT outperforms the compared GNI algorithms. We see that using high confidence values in scGCNs increase the ratio of the overlapped gene-gene interactions between the compared methods. According to the evaluation of the topological features of ARNetMiT based GCNs, the degrees of nodes have power-law distribution. The hub genes discovered by ARNetMiT based GCNs are consistent with the literature.

Finding minimum gene subsets with heuristic breadth-first search algorithm for robust tumor classification

PubMed Central

2012-01-01

Background Previous studies on tumor classification based on gene expression profiles suggest that gene selection plays a key role in improving the classification performance. Moreover, finding important tumor-related genes with the highest accuracy is a very important task because these genes might serve as tumor biomarkers, which is of great benefit to not only tumor molecular diagnosis but also drug development. Results This paper proposes a novel gene selection method with rich biomedical meaning based on Heuristic Breadth-first Search Algorithm (HBSA) to find as many optimal gene subsets as possible. Due to the curse of dimensionality, this type of method could suffer from over-fitting and selection bias problems. To address these potential problems, a HBSA-based ensemble classifier is constructed using majority voting strategy from individual classifiers constructed by the selected gene subsets, and a novel HBSA-based gene ranking method is designed to find important tumor-related genes by measuring the significance of genes using their occurrence frequencies in the selected gene subsets. The experimental results on nine tumor datasets including three pairs of cross-platform datasets indicate that the proposed method can not only obtain better generalization performance but also find many important tumor-related genes. Conclusions It is found that the frequencies of the selected genes follow a power-law distribution, indicating that only a few top-ranked genes can be used as potential diagnosis biomarkers. Moreover, the top-ranked genes leading to very high prediction accuracy are closely related to specific tumor subtype and even hub genes. Compared with other related methods, the proposed method can achieve higher prediction accuracy with fewer genes. Moreover, they are further justified by analyzing the top-ranked genes in the context of individual gene function, biological pathway, and protein-protein interaction network. PMID:22830977

Identification of novel risk genes associated with type 1 diabetes mellitus using a genome-wide gene-based association analysis.

PubMed

Qiu, Ying-Hua; Deng, Fei-Yan; Li, Min-Jing; Lei, Shu-Feng

2014-11-01

Type 1 diabetes mellitus is a serious disorder characterized by destruction of pancreatic β-cells, culminating in absolute insulin deficiency. Genetic factors contribute to the susceptibility of type 1 diabetes mellitus. The aim of the present study was to identify more susceptibility genes of type 1 diabetes mellitus. We carried out an initial gene-based genome-wide association study in a total of 4,075 type 1 diabetes mellitus cases and 2,604 controls by using the Gene-based Association Test using Extended Simes procedure. Furthermore, we carried out replication studies, differential expression analysis and functional annotation clustering analysis to support the significance of the identified susceptibility genes. We identified 452 genes associated with type 1 diabetes mellitus, even after adapting the genome-wide threshold for significance (P < 9.05E-04). Among these genes, 171 were newly identified for type 1 diabetes mellitus, which were ignored in single-nucleotide polymorphism-based association analysis and were not previously reported. We found that 53 genes have supportive evidence from replication studies and/or differential expression studies. In particular, seven genes including four non-human leukocyte antigen (HLA) genes (RASIP1, STRN4, BCAR1 and MYL2) are replicated in at least one independent population and also differentially expressed in peripheral blood mononuclear cells or monocytes. Furthermore, the associated genes tend to enrich in immune-related pathways or Gene Ontology project terms. The present results suggest the high power of gene-based association analysis in detecting disease-susceptibility genes. Our findings provide more insights into the genetic basis of type 1 diabetes mellitus.

Chloroplast genes transferred to the nuclear plant genome have adjusted to nuclear base composition and codon usage.

PubMed Central

Oliver, J L; Marín, A; Martínez-Zapater, J M

1990-01-01

During plant evolution, some plastid genes have been moved to the nuclear genome. These transferred genes are now correctly expressed in the nucleus, their products being transported into the chloroplast. We compared the base compositions, the distributions of some dinucleotides and codon usages of transferred, nuclear and chloroplast genes in two dicots and two monocots plant species. Our results indicate that transferred genes have adjusted to nuclear base composition and codon usage, being now more similar to the nuclear genes than to the chloroplast ones in every species analyzed. PMID:2308837

Gene network biological validity based on gene-gene interaction relevance.

PubMed

Gómez-Vela, Francisco; Díaz-Díaz, Norberto

2014-01-01

In recent years, gene networks have become one of the most useful tools for modeling biological processes. Many inference gene network algorithms have been developed as techniques for extracting knowledge from gene expression data. Ensuring the reliability of the inferred gene relationships is a crucial task in any study in order to prove that the algorithms used are precise. Usually, this validation process can be carried out using prior biological knowledge. The metabolic pathways stored in KEGG are one of the most widely used knowledgeable sources for analyzing relationships between genes. This paper introduces a new methodology, GeneNetVal, to assess the biological validity of gene networks based on the relevance of the gene-gene interactions stored in KEGG metabolic pathways. Hence, a complete KEGG pathway conversion into a gene association network and a new matching distance based on gene-gene interaction relevance are proposed. The performance of GeneNetVal was established with three different experiments. Firstly, our proposal is tested in a comparative ROC analysis. Secondly, a randomness study is presented to show the behavior of GeneNetVal when the noise is increased in the input network. Finally, the ability of GeneNetVal to detect biological functionality of the network is shown.

Simple Monitoring of Gene Targeting Efficiency in Human Somatic Cell Lines Using the PIGA Gene

PubMed Central

Karnan, Sivasundaram; Konishi, Yuko; Ota, Akinobu; Takahashi, Miyuki; Damdindorj, Lkhagvasuren; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2012-01-01

Gene targeting in most of human somatic cell lines has been labor-intensive because of low homologous recombination efficiency. The development of an experimental system that permits a facile evaluation of gene targeting efficiency in human somatic cell lines is the first step towards the improvement of this technology and its application to a broad range of cell lines. In this study, we utilized phosphatidylinositol glycan anchor biosynthesis class A (PIGA), a gene essential for the synthesis of glycosylphosphatidyl inositol (GPI) anchors, as a reporter of gene targeting events in human somatic cell lines. Targeted disruption of PIGA was quantitatively detected with FLAER, a reagent that specifically binds to GPI anchors. Using this PIGA-based reporter system, we successfully detected adeno-associated virus (AAV)-mediated gene targeting events both with and without promoter-trap enrichment of gene-targeted cell population. The PIGA-based reporter system was also capable of reproducing previous findings that an AAV-mediated gene targeting achieves a remarkably higher ratio of homologous versus random integration (H/R ratio) of targeting vectors than a plasmid-mediated gene targeting. The PIGA-based system also detected an approximately 2-fold increase in the H/R ratio achieved by a small negative selection cassette introduced at the end of the AAV-based targeting vector with a promoter-trap system. Thus, our PIGA-based system is useful for monitoring AAV-mediated gene targeting and will assist in improving gene targeting technology in human somatic cell lines. PMID:23056640

A cluster of culture positive gonococcal infections but with false negative cppB gene based PCR.

PubMed

Lum, G; Freeman, K; Nguyen, N L; Limnios, E A; Tabrizi, S N; Carter, I; Chambers, I W; Whiley, D M; Sloots, T P; Garland, S M; Tapsall, J W

2005-10-01

To describe the prevalence and characteristics of isolates of Neisseria gonorrhoeae grown from urine samples that produced negative results with nucleic acid amplification assays (NAA) targeting the cppB gene. An initial cluster of culture positive, but cppB gene based NAA negative, gonococcal infections was recognised. Urine samples and suspensions of gonococci isolated over 9 months in the Northern Territory of Australia were examined using cppB gene based and other non-cppB gene based NAA. The gonococcal isolates were phenotyped by determining the auxotype/serovar (A/S) class and genotyped by pulsed field gel electrophoresis (PFGE). 14 (9.8%) of 143 gonococci isolated were of A/S class Pro(-/)Brpyut, indistinguishable on PFGE and negative in cppB gene based, but not other, NAA. This cluster represents a temporal and geographic expansion of a gonococcal subtype lacking the cppB gene with consequent loss of sensitivity of NAA dependent on amplification of this target. Gonococci lacking the cppB gene have in the past been more commonly associated with the PAU-/PCU- auxotype, a gonococcal subtype hitherto infrequently encountered in Australia. NAA based on the cppB gene as a target may produce false positive as well as false negative NAA. This suggests that unless there is continuing comparison with culture to show their utility, cppB gene based NAA should be regarded as suboptimal for use either as a diagnostic or supplemental assay for diagnosis of gonorrhoea, and NAA with alternative amplification targets should be substituted.

Evaluation of the efficacy of twelve mitochondrial protein-coding genes as barcodes for mollusk DNA barcoding.

PubMed

Yu, Hong; Kong, Lingfeng; Li, Qi

2016-01-01

In this study, we evaluated the efficacy of 12 mitochondrial protein-coding genes from 238 mitochondrial genomes of 140 molluscan species as potential DNA barcodes for mollusks. Three barcoding methods (distance, monophyly and character-based methods) were used in species identification. The species recovery rates based on genetic distances for the 12 genes ranged from 70.83 to 83.33%. There were no significant differences in intra- or interspecific variability among the 12 genes. The monophyly and character-based methods provided higher resolution than the distance-based method in species delimitation. Especially in closely related taxa, the character-based method showed some advantages. The results suggested that besides the standard COI barcode, other 11 mitochondrial protein-coding genes could also be potentially used as a molecular diagnostic for molluscan species discrimination. Our results also showed that the combination of mitochondrial genes did not enhance the efficacy for species identification and a single mitochondrial gene would be fully competent.

Two-Way Gene Interaction From Microarray Data Based on Correlation Methods.

PubMed

Alavi Majd, Hamid; Talebi, Atefeh; Gilany, Kambiz; Khayyer, Nasibeh

2016-06-01

Gene networks have generated a massive explosion in the development of high-throughput techniques for monitoring various aspects of gene activity. Networks offer a natural way to model interactions between genes, and extracting gene network information from high-throughput genomic data is an important and difficult task. The purpose of this study is to construct a two-way gene network based on parametric and nonparametric correlation coefficients. The first step in constructing a Gene Co-expression Network is to score all pairs of gene vectors. The second step is to select a score threshold and connect all gene pairs whose scores exceed this value. In the foundation-application study, we constructed two-way gene networks using nonparametric methods, such as Spearman's rank correlation coefficient and Blomqvist's measure, and compared them with Pearson's correlation coefficient. We surveyed six genes of venous thrombosis disease, made a matrix entry representing the score for the corresponding gene pair, and obtained two-way interactions using Pearson's correlation, Spearman's rank correlation, and Blomqvist's coefficient. Finally, these methods were compared with Cytoscape, based on BIND, and Gene Ontology, based on molecular function visual methods; R software version 3.2 and Bioconductor were used to perform these methods. Based on the Pearson and Spearman correlations, the results were the same and were confirmed by Cytoscape and GO visual methods; however, Blomqvist's coefficient was not confirmed by visual methods. Some results of the correlation coefficients are not the same with visualization. The reason may be due to the small number of data.

Differentially Coexpressed Disease Gene Identification Based on Gene Coexpression Network.

PubMed

Jiang, Xue; Zhang, Han; Quan, Xiongwen

2016-01-01

Screening disease-related genes by analyzing gene expression data has become a popular theme. Traditional disease-related gene selection methods always focus on identifying differentially expressed gene between case samples and a control group. These traditional methods may not fully consider the changes of interactions between genes at different cell states and the dynamic processes of gene expression levels during the disease progression. However, in order to understand the mechanism of disease, it is important to explore the dynamic changes of interactions between genes in biological networks at different cell states. In this study, we designed a novel framework to identify disease-related genes and developed a differentially coexpressed disease-related gene identification method based on gene coexpression network (DCGN) to screen differentially coexpressed genes. We firstly constructed phase-specific gene coexpression network using time-series gene expression data and defined the conception of differential coexpression of genes in coexpression network. Then, we designed two metrics to measure the value of gene differential coexpression according to the change of local topological structures between different phase-specific networks. Finally, we conducted meta-analysis of gene differential coexpression based on the rank-product method. Experimental results demonstrated the feasibility and effectiveness of DCGN and the superior performance of DCGN over other popular disease-related gene selection methods through real-world gene expression data sets.

GeneMesh: a web-based microarray analysis tool for relating differentially expressed genes to MeSH terms.

PubMed

Jani, Saurin D; Argraves, Gary L; Barth, Jeremy L; Argraves, W Scott

2010-04-01

An important objective of DNA microarray-based gene expression experimentation is determining inter-relationships that exist between differentially expressed genes and biological processes, molecular functions, cellular components, signaling pathways, physiologic processes and diseases. Here we describe GeneMesh, a web-based program that facilitates analysis of DNA microarray gene expression data. GeneMesh relates genes in a query set to categories available in the Medical Subject Headings (MeSH) hierarchical index. The interface enables hypothesis driven relational analysis to a specific MeSH subcategory (e.g., Cardiovascular System, Genetic Processes, Immune System Diseases etc.) or unbiased relational analysis to broader MeSH categories (e.g., Anatomy, Biological Sciences, Disease etc.). Genes found associated with a given MeSH category are dynamically linked to facilitate tabular and graphical depiction of Entrez Gene information, Gene Ontology information, KEGG metabolic pathway diagrams and intermolecular interaction information. Expression intensity values of groups of genes that cluster in relation to a given MeSH category, gene ontology or pathway can be displayed as heat maps of Z score-normalized values. GeneMesh operates on gene expression data derived from a number of commercial microarray platforms including Affymetrix, Agilent and Illumina. GeneMesh is a versatile web-based tool for testing and developing new hypotheses through relating genes in a query set (e.g., differentially expressed genes from a DNA microarray experiment) to descriptors making up the hierarchical structure of the National Library of Medicine controlled vocabulary thesaurus, MeSH. The system further enhances the discovery process by providing links between sets of genes associated with a given MeSH category to a rich set of html linked tabular and graphic information including Entrez Gene summaries, gene ontologies, intermolecular interactions, overlays of genes onto KEGG pathway diagrams and heatmaps of expression intensity values. GeneMesh is freely available online at http://proteogenomics.musc.edu/genemesh/.

Invasive Species Management on Military Lands: Clustered Regularly Interspaced Short Palindromic Repeat/ CRISPR associated protein 9 (CRISPR/Cas9) based Gene Drives

DTIC Science & Technology

2017-06-30

Clustered Regularly Interspaced Short Palindromic Repeat/ CRISPR -associated protein 9 ( CRISPR /Cas9)-based Gene Drives En vi ro nm en ta l L ab or at...Management on Military Lands Clustered Regularly Interspaced Short Palindromic Repeat/ CRISPR -associated protein 9 ( CRISPR /Cas9)-based Gene Drives Ping... CRISPR /Cas9-based Gene Drives for Invasive Species Management on Military Lands” ERDC/EL SR-17-2 ii Abstract Applications of genetic engineering

A hybrid network-based method for the detection of disease-related genes

NASA Astrophysics Data System (ADS)

Cui, Ying; Cai, Meng; Dai, Yang; Stanley, H. Eugene

2018-02-01

Detecting disease-related genes is crucial in disease diagnosis and drug design. The accepted view is that neighbors of a disease-causing gene in a molecular network tend to cause the same or similar diseases, and network-based methods have been recently developed to identify novel hereditary disease-genes in available biomedical networks. Despite the steady increase in the discovery of disease-associated genes, there is still a large fraction of disease genes that remains under the tip of the iceberg. In this paper we exploit the topological properties of the protein-protein interaction (PPI) network to detect disease-related genes. We compute, analyze, and compare the topological properties of disease genes with non-disease genes in PPI networks. We also design an improved random forest classifier based on these network topological features, and a cross-validation test confirms that our method performs better than previous similar studies.

The chemiluminescence based Ziplex automated workstation focus array reproduces ovarian cancer Affymetrix GeneChip expression profiles.

PubMed

Quinn, Michael C J; Wilson, Daniel J; Young, Fiona; Dempsey, Adam A; Arcand, Suzanna L; Birch, Ashley H; Wojnarowicz, Paulina M; Provencher, Diane; Mes-Masson, Anne-Marie; Englert, David; Tonin, Patricia N

2009-07-06

As gene expression signatures may serve as biomarkers, there is a need to develop technologies based on mRNA expression patterns that are adaptable for translational research. Xceed Molecular has recently developed a Ziplex technology, that can assay for gene expression of a discrete number of genes as a focused array. The present study has evaluated the reproducibility of the Ziplex system as applied to ovarian cancer research of genes shown to exhibit distinct expression profiles initially assessed by Affymetrix GeneChip analyses. The new chemiluminescence-based Ziplex gene expression array technology was evaluated for the expression of 93 genes selected based on their Affymetrix GeneChip profiles as applied to ovarian cancer research. Probe design was based on the Affymetrix target sequence that favors the 3' UTR of transcripts in order to maximize reproducibility across platforms. Gene expression analysis was performed using the Ziplex Automated Workstation. Statistical analyses were performed to evaluate reproducibility of both the magnitude of expression and differences between normal and tumor samples by correlation analyses, fold change differences and statistical significance testing. Expressions of 82 of 93 (88.2%) genes were highly correlated (p < 0.01) in a comparison of the two platforms. Overall, 75 of 93 (80.6%) genes exhibited consistent results in normal versus tumor tissue comparisons for both platforms (p < 0.001). The fold change differences were concordant for 87 of 93 (94%) genes, where there was agreement between the platforms regarding statistical significance for 71 (76%) of 87 genes. There was a strong agreement between the two platforms as shown by comparisons of log2 fold differences of gene expression between tumor versus normal samples (R = 0.93) and by Bland-Altman analysis, where greater than 90% of expression values fell within the 95% limits of agreement. Overall concordance of gene expression patterns based on correlations, statistical significance between tumor and normal ovary data, and fold changes was consistent between the Ziplex and Affymetrix platforms. The reproducibility and ease-of-use of the technology suggests that the Ziplex array is a suitable platform for translational research.

Polycation-based gene therapy: current knowledge and new perspectives.

PubMed

Tiera, Marcio J; Shi, Qin; Winnik, Françoise M; Fernandes, Julio C

2011-08-01

At present, gene transfection insufficient efficiency is a major drawback of non-viral gene therapy. The 2 main types of delivery systems deployed in gene therapy are based on viral or non-viral gene carriers. Several non-viral modalities can transfer foreign genetic material into the human body. To do so, polycation-based gene delivery methods must achieve sufficient efficiency in the transportation of therapeutic genes across various extracellular and intracellular barriers. These barriers include interactions with blood components, vascular endothelial cells and uptake by the reticuloendothelial system. Furthermore, the degradation of therapeutic DNA by serum nucleases is a potential obstacle for functional delivery to target cells. Cationic polymers constitute one of the most promising approaches to the use of viral vectors for gene therapy. A better understanding of the mechanisms by which DNA can escape from endosomes and traffic to enter the nucleus has triggered new strategies of synthesis and has revitalized research into new polycation-based systems. The objective of this review is to address the state of the art in gene therapy with synthetic and natural polycations and the latest advances to improve gene transfer efficiency in cells.

GO-based functional dissimilarity of gene sets.

PubMed

Díaz-Díaz, Norberto; Aguilar-Ruiz, Jesús S

2011-09-01

The Gene Ontology (GO) provides a controlled vocabulary for describing the functions of genes and can be used to evaluate the functional coherence of gene sets. Many functional coherence measures consider each pair of gene functions in a set and produce an output based on all pairwise distances. A single gene can encode multiple proteins that may differ in function. For each functionality, other proteins that exhibit the same activity may also participate. Therefore, an identification of the most common function for all of the genes involved in a biological process is important in evaluating the functional similarity of groups of genes and a quantification of functional coherence can helps to clarify the role of a group of genes working together. To implement this approach to functional assessment, we present GFD (GO-based Functional Dissimilarity), a novel dissimilarity measure for evaluating groups of genes based on the most relevant functions of the whole set. The measure assigns a numerical value to the gene set for each of the three GO sub-ontologies. Results show that GFD performs robustly when applied to gene set of known functionality (extracted from KEGG). It performs particularly well on randomly generated gene sets. An ROC analysis reveals that the performance of GFD in evaluating the functional dissimilarity of gene sets is very satisfactory. A comparative analysis against other functional measures, such as GS2 and those presented by Resnik and Wang, also demonstrates the robustness of GFD.

Inferring gene regression networks with model trees

PubMed Central

2010-01-01

Background Novel strategies are required in order to handle the huge amount of data produced by microarray technologies. To infer gene regulatory networks, the first step is to find direct regulatory relationships between genes building the so-called gene co-expression networks. They are typically generated using correlation statistics as pairwise similarity measures. Correlation-based methods are very useful in order to determine whether two genes have a strong global similarity but do not detect local similarities. Results We propose model trees as a method to identify gene interaction networks. While correlation-based methods analyze each pair of genes, in our approach we generate a single regression tree for each gene from the remaining genes. Finally, a graph from all the relationships among output and input genes is built taking into account whether the pair of genes is statistically significant. For this reason we apply a statistical procedure to control the false discovery rate. The performance of our approach, named REGNET, is experimentally tested on two well-known data sets: Saccharomyces Cerevisiae and E.coli data set. First, the biological coherence of the results are tested. Second the E.coli transcriptional network (in the Regulon database) is used as control to compare the results to that of a correlation-based method. This experiment shows that REGNET performs more accurately at detecting true gene associations than the Pearson and Spearman zeroth and first-order correlation-based methods. Conclusions REGNET generates gene association networks from gene expression data, and differs from correlation-based methods in that the relationship between one gene and others is calculated simultaneously. Model trees are very useful techniques to estimate the numerical values for the target genes by linear regression functions. They are very often more precise than linear regression models because they can add just different linear regressions to separate areas of the search space favoring to infer localized similarities over a more global similarity. Furthermore, experimental results show the good performance of REGNET. PMID:20950452

The construction of an EST database for Bombyx mori and its application

PubMed Central

Mita, Kazuei; Morimyo, Mitsuoki; Okano, Kazuhiro; Koike, Yoshiko; Nohata, Junko; Kawasaki, Hideki; Kadono-Okuda, Keiko; Yamamoto, Kimiko; Suzuki, Masataka G.; Shimada, Toru; Goldsmith, Marian R.; Maeda, Susumu

2003-01-01

To build a foundation for the complete genome analysis of Bombyx mori, we have constructed an EST database. Because gene expression patterns deeply depend on tissues as well as developmental stages, we analyzed many cDNA libraries prepared from various tissues and different developmental stages to cover the entire set of Bombyx genes. So far, the Bombyx EST database contains 35,000 ESTs from 36 cDNA libraries, which are grouped into ≈11,000 nonredundant ESTs with the average length of 1.25 kb. The comparison with FlyBase suggests that the present EST database, SilkBase, covers >55% of all genes of Bombyx. The fraction of library-specific ESTs in each cDNA library indicates that we have not yet reached saturation, showing the validity of our strategy for constructing an EST database to cover all genes. To tackle the coming saturation problem, we have checked two methods, subtraction and normalization, to increase coverage and decrease the number of housekeeping genes, resulting in a 5–11% increase of library-specific ESTs. The identification of a number of genes and comprehensive cloning of gene families have already emerged from the SilkBase search. Direct links of SilkBase with FlyBase and WormBase provide ready identification of candidate Lepidoptera-specific genes. PMID:14614147

Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder.

PubMed

Kilaru, V; Iyer, S V; Almli, L M; Stevens, J S; Lori, A; Jovanovic, T; Ely, T D; Bradley, B; Binder, E B; Koen, N; Stein, D J; Conneely, K N; Wingo, A P; Smith, A K; Ressler, K J

2016-05-24

Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD.

Genome-wide gene-based analysis suggests an association between Neuroligin 1 (NLGN1) and post-traumatic stress disorder

PubMed Central

Kilaru, V; Iyer, S V; Almli, L M; Stevens, J S; Lori, A; Jovanovic, T; Ely, T D; Bradley, B; Binder, E B; Koen, N; Stein, D J; Conneely, K N; Wingo, A P; Smith, A K; Ressler, K J

2016-01-01

Post-traumatic stress disorder (PTSD) develops in only some people following trauma exposure, but the mechanisms differentially explaining risk versus resilience remain largely unknown. PTSD is heritable but candidate gene studies and genome-wide association studies (GWAS) have identified only a modest number of genes that reliably contribute to PTSD. New gene-based methods may help identify additional genes that increase risk for PTSD development or severity. We applied gene-based testing to GWAS data from the Grady Trauma Project (GTP), a primarily African American cohort, and identified two genes (NLGN1 and ZNRD1-AS1) that associate with PTSD after multiple test correction. Although the top SNP from NLGN1 did not replicate, we observed gene-based replication of NLGN1 with PTSD in the Drakenstein Child Health Study (DCHS) cohort from Cape Town. NLGN1 has previously been associated with autism, and it encodes neuroligin 1, a protein involved in synaptogenesis, learning, and memory. Within the GTP dataset, a single nucleotide polymorphism (SNP), rs6779753, underlying the gene-based association, associated with the intermediate phenotypes of higher startle response and greater functional magnetic resonance imaging activation of the amygdala, orbitofrontal cortex, right thalamus and right fusiform gyrus in response to fearful faces. These findings support a contribution of the NLGN1 gene pathway to the neurobiological underpinnings of PTSD. PMID:27219346

InteGO2: A web tool for measuring and visualizing gene semantic similarities using Gene Ontology

DOE PAGES

Peng, Jiajie; Li, Hongxiang; Liu, Yongzhuang; ...

2016-08-31

Here, the Gene Ontology (GO) has been used in high-throughput omics research as a major bioinformatics resource. The hierarchical structure of GO provides users a convenient platform for biological information abstraction and hypothesis testing. Computational methods have been developed to identify functionally similar genes. However, none of the existing measurements take into account all the rich information in GO. Similarly, using these existing methods, web-based applications have been constructed to compute gene functional similarities, and to provide pure text-based outputs. Without a graphical visualization interface, it is difficult for result interpretation. As a result, we present InteGO2, a web toolmore » that allows researchers to calculate the GO-based gene semantic similarities using seven widely used GO-based similarity measurements. Also, we provide an integrative measurement that synergistically integrates all the individual measurements to improve the overall performance. Using HTML5 and cytoscape.js, we provide a graphical interface in InteGO2 to visualize the resulting gene functional association networks. In conclusion, InteGO2 is an easy-to-use HTML5 based web tool. With it, researchers can measure gene or gene product functional similarity conveniently, and visualize the network of functional interactions in a graphical interface.« less

InteGO2: a web tool for measuring and visualizing gene semantic similarities using Gene Ontology.

PubMed

Peng, Jiajie; Li, Hongxiang; Liu, Yongzhuang; Juan, Liran; Jiang, Qinghua; Wang, Yadong; Chen, Jin

2016-08-31

The Gene Ontology (GO) has been used in high-throughput omics research as a major bioinformatics resource. The hierarchical structure of GO provides users a convenient platform for biological information abstraction and hypothesis testing. Computational methods have been developed to identify functionally similar genes. However, none of the existing measurements take into account all the rich information in GO. Similarly, using these existing methods, web-based applications have been constructed to compute gene functional similarities, and to provide pure text-based outputs. Without a graphical visualization interface, it is difficult for result interpretation. We present InteGO2, a web tool that allows researchers to calculate the GO-based gene semantic similarities using seven widely used GO-based similarity measurements. Also, we provide an integrative measurement that synergistically integrates all the individual measurements to improve the overall performance. Using HTML5 and cytoscape.js, we provide a graphical interface in InteGO2 to visualize the resulting gene functional association networks. InteGO2 is an easy-to-use HTML5 based web tool. With it, researchers can measure gene or gene product functional similarity conveniently, and visualize the network of functional interactions in a graphical interface. InteGO2 can be accessed via http://mlg.hit.edu.cn:8089/ .

InteGO2: A web tool for measuring and visualizing gene semantic similarities using Gene Ontology

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peng, Jiajie; Li, Hongxiang; Liu, Yongzhuang

Here, the Gene Ontology (GO) has been used in high-throughput omics research as a major bioinformatics resource. The hierarchical structure of GO provides users a convenient platform for biological information abstraction and hypothesis testing. Computational methods have been developed to identify functionally similar genes. However, none of the existing measurements take into account all the rich information in GO. Similarly, using these existing methods, web-based applications have been constructed to compute gene functional similarities, and to provide pure text-based outputs. Without a graphical visualization interface, it is difficult for result interpretation. As a result, we present InteGO2, a web toolmore » that allows researchers to calculate the GO-based gene semantic similarities using seven widely used GO-based similarity measurements. Also, we provide an integrative measurement that synergistically integrates all the individual measurements to improve the overall performance. Using HTML5 and cytoscape.js, we provide a graphical interface in InteGO2 to visualize the resulting gene functional association networks. In conclusion, InteGO2 is an easy-to-use HTML5 based web tool. With it, researchers can measure gene or gene product functional similarity conveniently, and visualize the network of functional interactions in a graphical interface.« less

Prediction of operon-like gene clusters in the Arabidopsis thaliana genome based on co-expression analysis of neighboring genes.

PubMed

Wada, Masayoshi; Takahashi, Hiroki; Altaf-Ul-Amin, Md; Nakamura, Kensuke; Hirai, Masami Y; Ohta, Daisaku; Kanaya, Shigehiko

2012-07-15

Operon-like arrangements of genes occur in eukaryotes ranging from yeasts and filamentous fungi to nematodes, plants, and mammals. In plants, several examples of operon-like gene clusters involved in metabolic pathways have recently been characterized, e.g. the cyclic hydroxamic acid pathways in maize, the avenacin biosynthesis gene clusters in oat, the thalianol pathway in Arabidopsis thaliana, and the diterpenoid momilactone cluster in rice. Such operon-like gene clusters are defined by their co-regulation or neighboring positions within immediate vicinity of chromosomal regions. A comprehensive analysis of the expression of neighboring genes therefore accounts a crucial step to reveal the complete set of operon-like gene clusters within a genome. Genome-wide prediction of operon-like gene clusters should contribute to functional annotation efforts and provide novel insight into evolutionary aspects acquiring certain biological functions as well. We predicted co-expressed gene clusters by comparing the Pearson correlation coefficient of neighboring genes and randomly selected gene pairs, based on a statistical method that takes false discovery rate (FDR) into consideration for 1469 microarray gene expression datasets of A. thaliana. We estimated that A. thaliana contains 100 operon-like gene clusters in total. We predicted 34 statistically significant gene clusters consisting of 3 to 22 genes each, based on a stringent FDR threshold of 0.1. Functional relationships among genes in individual clusters were estimated by sequence similarity and functional annotation of genes. Duplicated gene pairs (determined based on BLAST with a cutoff of E<10(-5)) are included in 27 clusters. Five clusters are associated with metabolism, containing P450 genes restricted to the Brassica family and predicted to be involved in secondary metabolism. Operon-like clusters tend to include genes encoding bio-machinery associated with ribosomes, the ubiquitin/proteasome system, secondary metabolic pathways, lipid and fatty-acid metabolism, and the lipid transfer system. Copyright © 2012 Elsevier B.V. All rights reserved.

Water-soluble polymers bearing phosphorylcholine group and other zwitterionic groups for carrying DNA derivatives.

PubMed

Lin, Xiaojie; Ishihara, Kazuhiko

2014-01-01

Water-soluble polymers with equal positive and negative charges in the same monomer unit, such as the phosphorylcholine group and other zwitterionic groups, exhibit promising potential in gene delivery with appreciable transfection efficiency, compared with the traditional poly(ethylene glycol)-based polycation-gene complexes. These zwitterionic polymers with various architectural structures and properties have been synthesized by various polymerization methods, such as conventional radical polymerization, atom-transfer radical-polymerization, reversible addition-fragmentation chain-transfer polymerization, and nitroxide-mediated radical polymerization. These techniques have been used to efficiently facilitate gene therapy by fabrication of non-viral vectors with high cytocompatibility, large gene-carrying capacity, effective cell-membrane permeability, and in vivo gene-loading/releasing functionality. Zwitterionic polymer-based gene delivery vectors systems can be categorized into soluble-polymer/gene mixing, molecular self-assembly, and polymer-gene conjugation systems. This review describes the preparation and characterization of various zwitterionic polymer-based gene delivery vectors, specifically water-soluble phospholipid polymers for carrying gene derivatives.

Gene-Based Testing of Interactions in Association Studies of Quantitative Traits

PubMed Central

Ma, Li; Clark, Andrew G.; Keinan, Alon

2013-01-01

Various methods have been developed for identifying gene–gene interactions in genome-wide association studies (GWAS). However, most methods focus on individual markers as the testing unit, and the large number of such tests drastically erodes statistical power. In this study, we propose novel interaction tests of quantitative traits that are gene-based and that confer advantage in both statistical power and biological interpretation. The framework of gene-based gene–gene interaction (GGG) tests combine marker-based interaction tests between all pairs of markers in two genes to produce a gene-level test for interaction between the two. The tests are based on an analytical formula we derive for the correlation between marker-based interaction tests due to linkage disequilibrium. We propose four GGG tests that extend the following P value combining methods: minimum P value, extended Simes procedure, truncated tail strength, and truncated P value product. Extensive simulations point to correct type I error rates of all tests and show that the two truncated tests are more powerful than the other tests in cases of markers involved in the underlying interaction not being directly genotyped and in cases of multiple underlying interactions. We applied our tests to pairs of genes that exhibit a protein–protein interaction to test for gene-level interactions underlying lipid levels using genotype data from the Atherosclerosis Risk in Communities study. We identified five novel interactions that are not evident from marker-based interaction testing and successfully replicated one of these interactions, between SMAD3 and NEDD9, in an independent sample from the Multi-Ethnic Study of Atherosclerosis. We conclude that our GGG tests show improved power to identify gene-level interactions in existing, as well as emerging, association studies. PMID:23468652

Multi-label literature classification based on the Gene Ontology graph.

PubMed

Jin, Bo; Muller, Brian; Zhai, Chengxiang; Lu, Xinghua

2008-12-08

The Gene Ontology is a controlled vocabulary for representing knowledge related to genes and proteins in a computable form. The current effort of manually annotating proteins with the Gene Ontology is outpaced by the rate of accumulation of biomedical knowledge in literature, which urges the development of text mining approaches to facilitate the process by automatically extracting the Gene Ontology annotation from literature. The task is usually cast as a text classification problem, and contemporary methods are confronted with unbalanced training data and the difficulties associated with multi-label classification. In this research, we investigated the methods of enhancing automatic multi-label classification of biomedical literature by utilizing the structure of the Gene Ontology graph. We have studied three graph-based multi-label classification algorithms, including a novel stochastic algorithm and two top-down hierarchical classification methods for multi-label literature classification. We systematically evaluated and compared these graph-based classification algorithms to a conventional flat multi-label algorithm. The results indicate that, through utilizing the information from the structure of the Gene Ontology graph, the graph-based multi-label classification methods can significantly improve predictions of the Gene Ontology terms implied by the analyzed text. Furthermore, the graph-based multi-label classifiers are capable of suggesting Gene Ontology annotations (to curators) that are closely related to the true annotations even if they fail to predict the true ones directly. A software package implementing the studied algorithms is available for the research community. Through utilizing the information from the structure of the Gene Ontology graph, the graph-based multi-label classification methods have better potential than the conventional flat multi-label classification approach to facilitate protein annotation based on the literature.

Two-Way Gene Interaction From Microarray Data Based on Correlation Methods

PubMed Central

Alavi Majd, Hamid; Talebi, Atefeh; Gilany, Kambiz; Khayyer, Nasibeh

2016-01-01

Background Gene networks have generated a massive explosion in the development of high-throughput techniques for monitoring various aspects of gene activity. Networks offer a natural way to model interactions between genes, and extracting gene network information from high-throughput genomic data is an important and difficult task. Objectives The purpose of this study is to construct a two-way gene network based on parametric and nonparametric correlation coefficients. The first step in constructing a Gene Co-expression Network is to score all pairs of gene vectors. The second step is to select a score threshold and connect all gene pairs whose scores exceed this value. Materials and Methods In the foundation-application study, we constructed two-way gene networks using nonparametric methods, such as Spearman’s rank correlation coefficient and Blomqvist’s measure, and compared them with Pearson’s correlation coefficient. We surveyed six genes of venous thrombosis disease, made a matrix entry representing the score for the corresponding gene pair, and obtained two-way interactions using Pearson’s correlation, Spearman’s rank correlation, and Blomqvist’s coefficient. Finally, these methods were compared with Cytoscape, based on BIND, and Gene Ontology, based on molecular function visual methods; R software version 3.2 and Bioconductor were used to perform these methods. Results Based on the Pearson and Spearman correlations, the results were the same and were confirmed by Cytoscape and GO visual methods; however, Blomqvist’s coefficient was not confirmed by visual methods. Conclusions Some results of the correlation coefficients are not the same with visualization. The reason may be due to the small number of data. PMID:27621916

Transposon based functional characterization of soybean genes

USDA-ARS?s Scientific Manuscript database

Type II transposable elements that use cut and paste mechanism for jumping from one genomic region to another is ideal in tagging and cloning genes. Precise excision from an insertion site in a mutant gene leads to regaining the wild-type function. Thus, function of a gene can be established based o...

Statistical approach for selection of biologically informative genes.

PubMed

Das, Samarendra; Rai, Anil; Mishra, D C; Rai, Shesh N

2018-05-20

Selection of informative genes from high dimensional gene expression data has emerged as an important research area in genomics. Many gene selection techniques have been proposed so far are either based on relevancy or redundancy measure. Further, the performance of these techniques has been adjudged through post selection classification accuracy computed through a classifier using the selected genes. This performance metric may be statistically sound but may not be biologically relevant. A statistical approach, i.e. Boot-MRMR, was proposed based on a composite measure of maximum relevance and minimum redundancy, which is both statistically sound and biologically relevant for informative gene selection. For comparative evaluation of the proposed approach, we developed two biological sufficient criteria, i.e. Gene Set Enrichment with QTL (GSEQ) and biological similarity score based on Gene Ontology (GO). Further, a systematic and rigorous evaluation of the proposed technique with 12 existing gene selection techniques was carried out using five gene expression datasets. This evaluation was based on a broad spectrum of statistically sound (e.g. subject classification) and biological relevant (based on QTL and GO) criteria under a multiple criteria decision-making framework. The performance analysis showed that the proposed technique selects informative genes which are more biologically relevant. The proposed technique is also found to be quite competitive with the existing techniques with respect to subject classification and computational time. Our results also showed that under the multiple criteria decision-making setup, the proposed technique is best for informative gene selection over the available alternatives. Based on the proposed approach, an R Package, i.e. BootMRMR has been developed and available at https://cran.r-project.org/web/packages/BootMRMR. This study will provide a practical guide to select statistical techniques for selecting informative genes from high dimensional expression data for breeding and system biology studies. Published by Elsevier B.V.

Gene function prediction with gene interaction networks: a context graph kernel approach.

PubMed

Li, Xin; Chen, Hsinchun; Li, Jiexun; Zhang, Zhu

2010-01-01

Predicting gene functions is a challenge for biologists in the postgenomic era. Interactions among genes and their products compose networks that can be used to infer gene functions. Most previous studies adopt a linkage assumption, i.e., they assume that gene interactions indicate functional similarities between connected genes. In this study, we propose to use a gene's context graph, i.e., the gene interaction network associated with the focal gene, to infer its functions. In a kernel-based machine-learning framework, we design a context graph kernel to capture the information in context graphs. Our experimental study on a testbed of p53-related genes demonstrates the advantage of using indirect gene interactions and shows the empirical superiority of the proposed approach over linkage-assumption-based methods, such as the algorithm to minimize inconsistent connected genes and diffusion kernels.

Alternative options for DNA-based experimental therapy of β-thalassemia.

PubMed

Gambari, Roberto

2012-04-01

Beta-thalassemias are caused by more than 200 mutations of the β-globin gene, leading to low or absent production of adult hemoglobin. Achievements have been made with innovative therapeutic strategies for β-thalassemias, based on research conducted at the levels of gene structure, transcription, mRNA processing and protein synthesis. The objective of this review is to describe the development of therapeutic strategies employing viral and non-viral DNA-based approaches for treatment of β-thalassemia. Modification of β-globin gene expression in β-thalassemia cells has been achieved by gene therapy, correction of the mutated β-globin gene and RNA repair. In addition, cellular therapy has been proposed for β-thalassemia, including reprogramming of somatic cells to generate induced pluripotent stem cells to be genetically corrected. Based on the concept that increased production of fetal hemoglobin (HbF) is beneficial in β-thalassemia, DNA-based approaches to increase HbF production have been optimized, including treatment of target cells with lentiviral vectors carrying γ-globin genes. Finally, DNA-based targeting of α-globin gene expression has been applied to reduce the excess of α-globin production by β-thalassemia cells, one of the major causes of the clinical phenotype.

Gene function prediction based on Gene Ontology Hierarchy Preserving Hashing.

PubMed

Zhao, Yingwen; Fu, Guangyuan; Wang, Jun; Guo, Maozu; Yu, Guoxian

2018-02-23

Gene Ontology (GO) uses structured vocabularies (or terms) to describe the molecular functions, biological roles, and cellular locations of gene products in a hierarchical ontology. GO annotations associate genes with GO terms and indicate the given gene products carrying out the biological functions described by the relevant terms. However, predicting correct GO annotations for genes from a massive set of GO terms as defined by GO is a difficult challenge. To combat with this challenge, we introduce a Gene Ontology Hierarchy Preserving Hashing (HPHash) based semantic method for gene function prediction. HPHash firstly measures the taxonomic similarity between GO terms. It then uses a hierarchy preserving hashing technique to keep the hierarchical order between GO terms, and to optimize a series of hashing functions to encode massive GO terms via compact binary codes. After that, HPHash utilizes these hashing functions to project the gene-term association matrix into a low-dimensional one and performs semantic similarity based gene function prediction in the low-dimensional space. Experimental results on three model species (Homo sapiens, Mus musculus and Rattus norvegicus) for interspecies gene function prediction show that HPHash performs better than other related approaches and it is robust to the number of hash functions. In addition, we also take HPHash as a plugin for BLAST based gene function prediction. From the experimental results, HPHash again significantly improves the prediction performance. The codes of HPHash are available at: http://mlda.swu.edu.cn/codes.php?name=HPHash. Copyright © 2018 Elsevier Inc. All rights reserved.

Cis-regulatory element based targeted gene finding: genome-wide identification of abscisic acid- and abiotic stress-responsive genes in Arabidopsis thaliana.

PubMed

Zhang, Weixiong; Ruan, Jianhua; Ho, Tuan-Hua David; You, Youngsook; Yu, Taotao; Quatrano, Ralph S

2005-07-15

A fundamental problem of computational genomics is identifying the genes that respond to certain endogenous cues and environmental stimuli. This problem can be referred to as targeted gene finding. Since gene regulation is mainly determined by the binding of transcription factors and cis-regulatory DNA sequences, most existing gene annotation methods, which exploit the conservation of open reading frames, are not effective in finding target genes. A viable approach to targeted gene finding is to exploit the cis-regulatory elements that are known to be responsible for the transcription of target genes. Given such cis-elements, putative target genes whose promoters contain the elements can be identified. As a case study, we apply the above approach to predict the genes in model plant Arabidopsis thaliana which are inducible by a phytohormone, abscisic acid (ABA), and abiotic stress, such as drought, cold and salinity. We first construct and analyze two ABA specific cis-elements, ABA-responsive element (ABRE) and its coupling element (CE), in A.thaliana, based on their conservation in rice and other cereal plants. We then use the ABRE-CE module to identify putative ABA-responsive genes in A.thaliana. Based on RT-PCR verification and the results from literature, this method has an accuracy rate of 67.5% for the top 40 predictions. The cis-element based targeted gene finding approach is expected to be widely applicable since a large number of cis-elements in many species are available.

MiRNA-TF-gene network analysis through ranking of biomolecules for multi-informative uterine leiomyoma dataset.

PubMed

Mallik, Saurav; Maulik, Ujjwal

2015-10-01

Gene ranking is an important problem in bioinformatics. Here, we propose a new framework for ranking biomolecules (viz., miRNAs, transcription-factors/TFs and genes) in a multi-informative uterine leiomyoma dataset having both gene expression and methylation data using (statistical) eigenvector centrality based approach. At first, genes that are both differentially expressed and methylated, are identified using Limma statistical test. A network, comprising these genes, corresponding TFs from TRANSFAC and ITFP databases, and targeter miRNAs from miRWalk database, is then built. The biomolecules are then ranked based on eigenvector centrality. Our proposed method provides better average accuracy in hub gene and non-hub gene classifications than other methods. Furthermore, pre-ranked Gene set enrichment analysis is applied on the pathway database as well as GO-term databases of Molecular Signatures Database with providing a pre-ranked gene-list based on different centrality values for comparing among the ranking methods. Finally, top novel potential gene-markers for the uterine leiomyoma are provided. Copyright © 2015 Elsevier Inc. All rights reserved.

Development of New Candidate Gene and EST-Based Molecular Markers for Gossypium Species

PubMed Central

Buyyarapu, Ramesh; Kantety, Ramesh V.; Yu, John Z.; Saha, Sukumar; Sharma, Govind C.

2011-01-01

New source of molecular markers accelerate the efforts in improving cotton fiber traits and aid in developing high-density integrated genetic maps. We developed new markers based on candidate genes and G. arboreum EST sequences that were used for polymorphism detection followed by genetic and physical mapping. Nineteen gene-based markers were surveyed for polymorphism detection in 26 Gossypium species. Cluster analysis generated a phylogenetic tree with four major sub-clusters for 23 species while three species branched out individually. CAP method enhanced the rate of polymorphism of candidate gene-based markers between G. hirsutum and G. barbadense. Two hundred A-genome based SSR markers were designed after datamining of G. arboreum EST sequences (Mississippi Gossypium arboreum   EST-SSR: MGAES). Over 70% of MGAES markers successfully produced amplicons while 65 of them demonstrated polymorphism between the parents of G. hirsutum and G. barbadense RIL population and formed 14 linkage groups. Chromosomal localization of both candidate gene-based and MGAES markers was assisted by euploid and hypoaneuploid CS-B analysis. Gene-based and MGAES markers were highly informative as they were designed from candidate genes and fiber transcriptome with a potential to be integrated into the existing cotton genetic and physical maps. PMID:22315588

Characterization of the complete mitochondrial genome of the Grey-backed Shrike, Lanius tephronotus (Aves: Passeriformes): the first representative of the family Laniidae with a novel CAA stop codon at the end of cox2 gene.

PubMed

Qian, Chaoju; Yan, Xia; Guo, Zhichun; Wang, Yuanxiu; Li, Xixi; Yang, Jianke; Kan, Xianzhao

2013-08-01

The complete Grey-backed Shrike mitochondrial genome has been sequenced to be 16,820 bp in length, consisting of 37 encode genes: 13 protein-coding genes, 2 ribosomal RNA genes, and 22 transfer RNA genes. In addition, a single control region was also observed. Compared with other reported Passeriformes mtgenome sequences, three bases CAA were detected at the end of Lanius tephronotus cox2 gene with the downstream adjacent base T. The first base of CAA probably occurred C to U transcript editing event resulting in a normal stop codon UAA.

A Generalized Approach for Measuring Relationships Among Genes.

PubMed

Wang, Lijun; Ahsan, Md Asif; Chen, Ming

2017-07-21

Several methods for identifying relationships among pairs of genes have been developed. In this article, we present a generalized approach for measuring relationships between any pairs of genes, which is based on statistical prediction. We derive two particular versions of the generalized approach, least squares estimation (LSE) and nearest neighbors prediction (NNP). According to mathematical proof, LSE is equivalent to the methods based on correlation; and NNP is approximate to one popular method called the maximal information coefficient (MIC) according to the performances in simulations and real dataset. Moreover, the approach based on statistical prediction can be extended from two-genes relationships to multi-genes relationships. This application would help to identify relationships among multi-genes.

Co-expression network with protein-protein interaction and transcription regulation in malaria parasite Plasmodium falciparum.

PubMed

Yu, Fu-Dong; Yang, Shao-You; Li, Yuan-Yuan; Hu, Wei

2013-04-10

Malaria continues to be one of the most severe global infectious diseases, as a major threat to human health and economic development. Network-based biological analysis is a promising approach to uncover key genes and biological processes from a network viewpoint, which could not be recognized from individual gene-based signatures. We integrated gene co-expression profile with protein-protein interaction and transcriptional regulation information to construct a comprehensive gene co-expression network of Plasmodium falciparum. Based on this network, we identified 10 core modules by using ICE (Iterative Clique Enumeration) algorithm, which were essential for malaria parasite development in intraerythrocytic developmental cycle (IDC) stages. In each module, all genes were highly correlated probably due to co-regulation or formation of a protein complex. Some of these genes were recognized to be differentially coexpressed among three close-by IDC stages. The gene of prpf8 (PFD0265w) encoding pre-mRNA processing splicing factor 8 product was identified as DCGs (differentially co-expressed genes) among IDC stages, although this gene function was seldom reported in previous researches. Integrating the species-specific gene prediction and differential co-expression gene detection, we found some modules could perform species-specific functions according to some of genes in these modules were species-specific genes, like the module 10. Furthermore, in order to reveal the underlying mechanisms of the erythrocyte invasion by P. falciparum, Steiner Tree algorithm was employed to identify the invasion subnetwork from our gene co-expression network. The subnetwork-based analysis indicated that some important Plasmodium parasite specific genes could corporate with each other and be co-regulated during the parasite invasion process, which including a head-to-head gene pair of PfRH2a (PF13_0198) and PfRH2b (MAL13P1.176). This study based on gene co-expression network could shed new insights on the mechanisms of pathogenesis, even virulence and P. falciparum development. Crown Copyright © 2012. Published by Elsevier B.V. All rights reserved.

Reranking candidate gene models with cross-species comparison for improved gene prediction

PubMed Central

Liu, Qian; Crammer, Koby; Pereira, Fernando CN; Roos, David S

2008-01-01

Background Most gene finders score candidate gene models with state-based methods, typically HMMs, by combining local properties (coding potential, splice donor and acceptor patterns, etc). Competing models with similar state-based scores may be distinguishable with additional information. In particular, functional and comparative genomics datasets may help to select among competing models of comparable probability by exploiting features likely to be associated with the correct gene models, such as conserved exon/intron structure or protein sequence features. Results We have investigated the utility of a simple post-processing step for selecting among a set of alternative gene models, using global scoring rules to rerank competing models for more accurate prediction. For each gene locus, we first generate the K best candidate gene models using the gene finder Evigan, and then rerank these models using comparisons with putative orthologous genes from closely-related species. Candidate gene models with lower scores in the original gene finder may be selected if they exhibit strong similarity to probable orthologs in coding sequence, splice site location, or signal peptide occurrence. Experiments on Drosophila melanogaster demonstrate that reranking based on cross-species comparison outperforms the best gene models identified by Evigan alone, and also outperforms the comparative gene finders GeneWise and Augustus+. Conclusion Reranking gene models with cross-species comparison improves gene prediction accuracy. This straightforward method can be readily adapted to incorporate additional lines of evidence, as it requires only a ranked source of candidate gene models. PMID:18854050

A Nonlinear Model for Gene-Based Gene-Environment Interaction.

PubMed

Sa, Jian; Liu, Xu; He, Tao; Liu, Guifen; Cui, Yuehua

2016-06-04

A vast amount of literature has confirmed the role of gene-environment (G×E) interaction in the etiology of complex human diseases. Traditional methods are predominantly focused on the analysis of interaction between a single nucleotide polymorphism (SNP) and an environmental variable. Given that genes are the functional units, it is crucial to understand how gene effects (rather than single SNP effects) are influenced by an environmental variable to affect disease risk. Motivated by the increasing awareness of the power of gene-based association analysis over single variant based approach, in this work, we proposed a sparse principle component regression (sPCR) model to understand the gene-based G×E interaction effect on complex disease. We first extracted the sparse principal components for SNPs in a gene, then the effect of each principal component was modeled by a varying-coefficient (VC) model. The model can jointly model variants in a gene in which their effects are nonlinearly influenced by an environmental variable. In addition, the varying-coefficient sPCR (VC-sPCR) model has nice interpretation property since the sparsity on the principal component loadings can tell the relative importance of the corresponding SNPs in each component. We applied our method to a human birth weight dataset in Thai population. We analyzed 12,005 genes across 22 chromosomes and found one significant interaction effect using the Bonferroni correction method and one suggestive interaction. The model performance was further evaluated through simulation studies. Our model provides a system approach to evaluate gene-based G×E interaction.

pySAPC, a python package for sparse affinity propagation clustering: Application to odontogenesis whole genome time series gene-expression data.

PubMed

Cao, Huojun; Amendt, Brad A

2016-11-01

Developmental dental anomalies are common forms of congenital defects. The molecular mechanisms of dental anomalies are poorly understood. Systematic approaches such as clustering genes based on similar expression patterns could identify novel genes involved in dental anomalies and provide a framework for understanding molecular regulatory mechanisms of these genes during tooth development (odontogenesis). A python package (pySAPC) of sparse affinity propagation clustering algorithm for large datasets was developed. Whole genome pair-wise similarity was calculated based on expression pattern similarity based on 45 microarrays of several stages during odontogenesis. pySAPC identified 743 gene clusters based on expression pattern similarity during mouse tooth development. Three clusters are significantly enriched for genes associated with dental anomalies (with FDR <0.1). The three clusters of genes have distinct expression patterns during odontogenesis. Clustering genes based on similar expression profiles recovered several known regulatory relationships for genes involved in odontogenesis, as well as many novel genes that may be involved with the same genetic pathways as genes that have already been shown to contribute to dental defects. By using sparse similarity matrix, pySAPC use much less memory and CPU time compared with the original affinity propagation program that uses a full similarity matrix. This python package will be useful for many applications where dataset(s) are too large to use full similarity matrix. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. Copyright © 2016. Published by Elsevier B.V.

Gene therapy for cardiovascular disease: advances in vector development, targeting, and delivery for clinical translation.

PubMed

Rincon, Melvin Y; VandenDriessche, Thierry; Chuah, Marinee K

2015-10-01

Gene therapy is a promising modality for the treatment of inherited and acquired cardiovascular diseases. The identification of the molecular pathways involved in the pathophysiology of heart failure and other associated cardiac diseases led to encouraging preclinical gene therapy studies in small and large animal models. However, the initial clinical results yielded only modest or no improvement in clinical endpoints. The presence of neutralizing antibodies and cellular immune responses directed against the viral vector and/or the gene-modified cells, the insufficient gene expression levels, and the limited gene transduction efficiencies accounted for the overall limited clinical improvements. Nevertheless, further improvements of the gene delivery technology and a better understanding of the underlying biology fostered renewed interest in gene therapy for heart failure. In particular, improved vectors based on emerging cardiotropic serotypes of the adeno-associated viral vector (AAV) are particularly well suited to coax expression of therapeutic genes in the heart. This led to new clinical trials based on the delivery of the sarcoplasmic reticulum Ca(2+)-ATPase protein (SERCA2a). Though the first clinical results were encouraging, a recent Phase IIb trial did not confirm the beneficial clinical outcomes that were initially reported. New approaches based on S100A1 and adenylate cyclase 6 are also being considered for clinical applications. Emerging paradigms based on the use of miRNA regulation or CRISPR/Cas9-based genome engineering open new therapeutic perspectives for treating cardiovascular diseases by gene therapy. Nevertheless, the continuous improvement of cardiac gene delivery is needed to allow the use of safer and more effective vector doses, ultimately bringing gene therapy for heart failure one step closer to reality. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.

Emotional and non-emotional pathways to impulsive behavior and addiction

PubMed Central

Torres, Ana; Catena, Andrés; Megías, Alberto; Maldonado, Antonio; Cándido, Antonio; Verdejo-García, Antonio; Perales, José C.

2013-01-01

Impulsivity is tightly linked to addiction. However, there are several pathways by means of which impulsive individuals are more prone to become addicts, or to suffer an addiction more intensely and for a longer period. One of those pathways involves an inadequate appraisal or regulation of positive and negative emotions, leading to lack of control over hazardous behaviors, and inappropriate decisions. In the present work, we assessed cocaine-dependent individuals (CDI; n = 20), pathological gamblers (PG; n = 21), and healthy controls (HC; n = 23) in trait impulsivity measures (UPPS-P model's dimensions), and decision-making tasks (Go/No-go; delay-discounting task). During the Go/No-go task, electroencephalographic (EEG) activity was recorded, and Go/No-go stimuli-evoked potentials (ERP) were extracted. Theory-driven ERP analyses focused on the No-go > Go difference in the N2 ERP. Our results show that negative urgency is one of the several psychological features that distinguish addicts from HC. Nevertheless, among the dimensions of trait impulsivity, negative urgency is unique at independently covarying with gambling over-pathologization in the PG sample. Cocaine-dependent individuals performed more poorly than gamblers in the Go/No-go task, and showed abnormal Go/No-go stimuli-evoked potentials. The difference between the No-go stimulus-evoked N2, and the Go one was attenuated by severity and intensity of chronic cocaine use. Emotional dimensions of impulsivity, however, did not influence Go/No-go performance. PMID:23441001

Impulsivity and Gambling Type Among Treatment-Seeking Disordered Gamblers: An Explorative Study.

PubMed

Lutri, Vittorio; Soldini, Emiliano; Ronzitti, Silvia; Smith, Neil; Clerici, Massimo; Blaszczynski, Alex; Bowden-Jones, Henrietta

2018-03-03

Several studies have found that certain traits of impulsivity are associated with gambling disorder, and influence its severity. Furthermore, it has been suggested that some forms of gambling, particularly electronic gambling machines, are particularly widespread among pathological gamblers. In the present, exploratory study, we aim to clarify the role played by impulsivity in influencing the choice of specific gambling activities, by examining the relation between individual dimensions of impulsivity, and the choice of specific gambling activities in a clinical population. 100 consecutively admitted pathological gamblers at the National Problem Gambling Clinic in London (UK) in 2014 were administered the UPPS-P and BIS-11 impulsivity questionnaires, the Problem Gambling Severity Index, and underwent a structured interview concerning their gambling activities in the month and year prior to assessment. The correlation between individual gambling activities and impulsivity dimensions was analyzed both at a bivariate level, and using logistic regression. We found a significant correlation between Negative Urgency, Motor impulsivity and low-stakes machine gambling on multivariate analysis. Negative urgency (i.e. the tendency to act impulsively in response to negative affect), and Motor impulsivity (a tendency to rash action and restlessness) might be mediating factors in the choice of electronic gambling machines, particularly among patients whose gambling is escape-oriented. Structural and situational characteristics of gambling machines, particularly the widespread availability of low-stakes-rather than high-stakes-gaming machines, might concur to the choice of this form of gambling among individuals who present higher negative urgency and restlessness.

Impulsive Personality Traits and Alcohol Use: Does Sleeping Help with Thinking?

PubMed Central

Miller, Mary Beth; DiBello, Angelo M.; Lust, Sarah A.; Meisel, Matthew K.; Carey, Kate B.

2016-01-01

Objective Both impulsivity and sleep disturbance have been associated with heavy alcohol use among young adults; yet studies to date have not examined their interactive effects. The current study aimed to determine if adequate sleep moderates the association between impulsive personality traits and alcohol use among young adults. Method College students (N = 568) who had been mandated to alcohol treatment following violation of campus alcohol policy provided information regarding alcohol use and related consequences, impulsive personality traits (measured using the UPPS Impulsive Behavior Scale), and perception of sleep adequacy as part of a larger intervention trial. Results Higher urgency, lower premeditation, and higher sensation-seeking predicted greater levels of alcohol consumption, while higher urgency predicted more alcohol-related consequences. As hypothesized, there was a significant interaction between premeditation and sleep adequacy in the prediction of drinks per week; in contrast to hypotheses, however, premeditation was associated with drinking only among those reporting adequate (rather than inadequate) sleep. Specifically, the tendency to premeditate was associated with less drinking among those who reported adequate sleep and was not associated with drinking among those reporting inadequate sleep. Conclusion Sensation-seeking and urgency are associated with greater alcohol involvement among young adults, regardless of sleep adequacy. Conversely, the ability to plan ahead and anticipate the consequences of one’s behaviors (premeditation) is only protective against heavy drinking among individuals receiving adequate sleep. With replication, these findings may inform alcohol prevention and intervention efforts. PMID:28094998

Defect analysis of the LED structure deposited on the sapphire substrate

NASA Astrophysics Data System (ADS)

Nie, Qichu; Jiang, Zhimin; Gan, Zhiyin; Liu, Sheng; Yan, Han; Fang, Haisheng

2018-04-01

Transmission electron microscope (TEM) and double-crystal X-ray diffraction (DCXRD) measurements have been performed to investigate dislocations of the whole structure of the LED layers deposited on both the conventional (unpatterned sapphire substrate, UPSS) and patterned sapphire substrates (PSS). TEM results show that there exists a dislocation-accumulated region near the substrate/GaN interface, where the dislocation density is much higher with the UPPS than that with the PSS. It indicates that the pattern on the substrate surface is able to block the formation and propagation of dislocations. Further analysis discloses that slope of the pattern is found to suppress the deposition of GaN, and thus to provide more spaces for the epitaxially lateral overgrowth (ELO) of high temperature GaN, which significantly reduces the number of the initial islands, and minimizes dislocation formation due to the island coalescence. V-defect incorporating the threading dislocation is detected in the InGaN/GaN multi-quantum wells (MQWs), and its propagation mechanism is determined as the decrease of the surface energy due to the incorporation of indium. In addition, temperature dependence of dislocation formation is further investigated. The results show that dislocation with the screw component decreases monotonously as temperature goes up. However, edge dislocation firstly drops, and then increases by temperature due to the enhanced thermal mismatch stress. It implies that an optimized range of the growth temperature can be obtained to improve quality of the LED layers.

The Latent Structure of Impulsivity: Impulsive Choice, Impulsive Action, and Impulsive Personality Traits

PubMed Central

MacKillop, James; Weafer, Jessica; Gray, Joshua; Oshri, Assaf; Palmer, Abraham; de Wit, Harriet

2016-01-01

Rationale Impulsivity has been strongly linked to addictive behaviors, but can be operationalized in a number of ways that vary considerably in overlap, suggesting multidimensionality. Objective This study tested the hypothesis that the latent structure among multiple measures of impulsivity would reflect three broad categories: impulsive choice, reflecting discounting of delayed rewards; impulsive action, reflecting ability to inhibit a prepotent motor response; and impulsive personality traits, reflecting self-reported attributions of self-regulatory capacity. Methods The study used a cross-sectional confirmatory factor analysis of multiple impulsivity assessments. Participants were 1252 young adults (62% female) with low levels of addictive behavior who were assessed in individual laboratory rooms at the University of Chicago and the University of Georgia. The battery comprised a delay discounting task, Monetary Choice Questionnaire, Conners Continuous Performance Test, Go/NoGo Task, Stop Signal Task, Barratt Impulsivity Scale, and the UPPS-P Impulsive Behavior Scale. Results The hypothesized three-factor model provided the best fit to the data, although Sensation Seeking was excluded from the final model. The three latent factors were largely unrelated to each other and were variably associated with substance use. Conclusions These findings support the hypothesis that diverse measures of impulsivity can broadly be organized into three categories that are largely distinct from one another. These findings warrant investigation among individuals with clinical levels of addictive behavior and may be applied to understanding the underlying biological mechanisms of these categories. PMID:27449350

What Money Can't Buy: Different Patterns in Decision Making About Sex and Money Predict Past Sexual Coercion Perpetration.

PubMed

Carrier Emond, Fannie; Gagnon, Jean; Nolet, Kevin; Cyr, Gaëlle; Rouleau, Joanne-Lucine

2018-02-01

Self-reported impulsivity has been found to predict the perpetration of sexual coercion in both sexual offenders and male college students. Impulsivity can be conceptualized as a generalized lack of self-control (i.e., general perspective) or as a multifaceted construct that can vary from one context to the other (i.e., domain-specific perspective). Delay discounting, the tendency to prefer sooner smaller rewards over larger delayed rewards, is a measure of impulsive decision making. Recent sexual adaptations of delay discounting tasks can be used to test domain-specific assumptions. The present study used the UPPS-P impulsivity questionnaire, a standard money discounting task, and a sexual discounting task to predict past use of sexual coercion in a sample of 98 male college students. Results indicated that higher negative urgency scores, less impulsive money discounting, and more impulsive sexual discounting all predicted sexual coercion. Consistent with previous studies, sexuality was discounted more steeply than money by both perpetrators and non-perpetrators of sexual coercion, but this difference was twice as large in perpetrators compared to non-perpetrators. Our study identified three different predictors of sexual coercion in male college students: a broad tendency to act rashly under negative emotions, a specific difficulty to postpone sexual gratification, and a pattern of optimal non-sexual decision making. Results highlight the importance of using multiple measures, including sexuality-specific measures, to get a clear portrait of the links between impulsivity and sexual coercion.

Impulsive personality traits and alcohol use: Does sleeping help with thinking?

PubMed

Miller, Mary Beth; DiBello, Angelo M; Lust, Sarah A; Meisel, Matthew K; Carey, Kate B

2017-02-01

Both impulsivity and sleep disturbance have been associated with heavy alcohol use among young adults; yet studies to date have not examined their interactive effects. The current study aimed to determine if adequate sleep moderates the association between impulsive personality traits and alcohol use among young adults. College students (N = 568) who had been mandated to alcohol treatment following violation of campus alcohol policy provided information regarding alcohol use and related consequences, impulsive personality traits (measured using the UPPS Impulsive Behavior Scale), and perception of sleep adequacy as part of a larger intervention trial. Higher urgency, lower premeditation, and higher sensation-seeking predicted greater levels of alcohol consumption, while higher urgency predicted more alcohol-related consequences. As hypothesized, there was a significant interaction between premeditation and sleep adequacy in the prediction of drinks per week; in contrast to hypotheses, however, premeditation was associated with drinking only among those reporting adequate (rather than inadequate) sleep. Specifically, the tendency to premeditate was associated with less drinking among those who reported adequate sleep and was not associated with drinking among those reporting inadequate sleep. Sensation-seeking and urgency are associated with greater alcohol involvement among young adults, regardless of sleep adequacy. Conversely, the ability to plan ahead and anticipate the consequences of one's behaviors (premeditation) is only protective against heavy drinking among individuals receiving adequate sleep. With replication, these findings may inform alcohol prevention and intervention efforts. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

[Raz's technics in the surgical treatment of stress urinary incontinence in women].

PubMed

Gutiérrez Baños, J L; de Diego Rodríguez, E; Portillo Martín, J A; Martín García, B; Hernández Rodríguez, R; Correas Gómez, M A; del Valle Schaan, J I; Roca Edreira, A; Rado Velázquez, M A

1999-05-01

To analyze our results in the surgery of the stress urinary incontinence in women with the Raz's techniques, to assess the association among continence and factors like surgical technique, grade of incontinence and urethral pressure profile. We do a retrospective study of 88 operations in 81 patients between the first of January 1990 and the thirty-one of December 1998. We describe the patients, previous treatments, grade of incontinence ans urodynamics data. We analyze the pre and post-operative complications. The outcome is evaluated by the Kaplan-Meier method, and the results are compared by the log rank test. 11 patients had a previous surgery and 7 had done physiotherapy; the grade of incontinence was 1 in 7 patients, 2 in 56 and 3 in 18. There were neither significative difference between UPP and abdominal leak point pressure and grade of incontinence nor between those parameters and continence. We did the Raz 1 technique in 67 patients, Raz 2 in 3, Raz 3 in 18. There were no significant difference among them. There are a progressive loose in the continence rate along the two first years; after that the continence rates are stabilized about 75%. The complications rate was scarce, except for the postoperative urinary retention, that reached the 20.45%. Our results are similar to those cited in the bibliography, mainly in the Spanish one. The highest rate of failure is in the two first years.

BMI predicts emotion-driven impulsivity and cognitive inflexibility in adolescents with excess weight.

PubMed

Delgado-Rico, Elena; Río-Valle, Jacqueline S; González-Jiménez, Emilio; Campoy, Cristina; Verdejo-García, Antonio

2012-08-01

Adolescent obesity is increasingly viewed as a brain-related dysfunction, whereby reward-driven urges for pleasurable foods "hijack" response selection systems, such that behavioral control progressively shifts from impulsivity to compulsivity. In this study, we aimed to examine the link between personality factors (sensitivity to reward (SR) and punishment (SP), BMI, and outcome measures of impulsivity vs. flexibility in--otherwise healthy--excessive weight adolescents. Sixty-three adolescents (aged 12-17) classified as obese (n = 26), overweight (n = 16), or normal weight (n = 21) participated in the study. We used psychometric assessments of the SR and SP motivational systems, impulsivity (using the UPPS-P scale), and neurocognitive measures with discriminant validity to dissociate inhibition vs. flexibility deficits (using the process-approach version of the Stroop test). We tested the relative contribution of age, SR/SP, and BMI on estimates of impulsivity and inhibition vs. switching performance using multistep hierarchical regression models. BMI significantly predicted elevations in emotion-driven impulsivity (positive and negative urgency) and inferior flexibility performance in adolescents with excess weight--exceeding the predictive capacity of SR and SP. SR was the main predictor of elevations in sensation seeking and lack of premeditation. These findings demonstrate that increases in BMI are specifically associated with elevations in emotion-driven impulsivity and cognitive inflexibility, supporting a dimensional path in which adolescents with excess weight increase their proneness to overindulge when under strong affective states, and their difficulties to switch or reverse habitual behavioral patterns.

Analysis of developmental gene conservation in the Actinomycetales using DNA/DNA microarray comparisons.

PubMed

Kirby, Ralph; Herron, Paul; Hoskisson, Paul

2011-02-01

Based on available genome sequences, Actinomycetales show significant gene synteny across a wide range of species and genera. In addition, many genera show varying degrees of complex morphological development. Using the presence of gene synteny as a basis, it is clear that an analysis of gene conservation across the Streptomyces and various other Actinomycetales will provide information on both the importance of genes and gene clusters and the evolution of morphogenesis in these bacteria. Genome sequencing, although becoming cheaper, is still relatively expensive for comparing large numbers of strains. Thus, a heterologous DNA/DNA microarray hybridization dataset based on a Streptomyces coelicolor microarray allows a cheaper and greater depth of analysis of gene conservation. This study, using both bioinformatical and microarray approaches, was able to classify genes previously identified as involved in morphogenesis in Streptomyces into various subgroups in terms of conservation across species and genera. This will allow the targeting of genes for further study based on their importance at the species level and at higher evolutionary levels.

A Stationary Wavelet Entropy-Based Clustering Approach Accurately Predicts Gene Expression

PubMed Central

Nguyen, Nha; Vo, An; Choi, Inchan

2015-01-01

Abstract Studying epigenetic landscapes is important to understand the condition for gene regulation. Clustering is a useful approach to study epigenetic landscapes by grouping genes based on their epigenetic conditions. However, classical clustering approaches that often use a representative value of the signals in a fixed-sized window do not fully use the information written in the epigenetic landscapes. Clustering approaches to maximize the information of the epigenetic signals are necessary for better understanding gene regulatory environments. For effective clustering of multidimensional epigenetic signals, we developed a method called Dewer, which uses the entropy of stationary wavelet of epigenetic signals inside enriched regions for gene clustering. Interestingly, the gene expression levels were highly correlated with the entropy levels of epigenetic signals. Dewer separates genes better than a window-based approach in the assessment using gene expression and achieved a correlation coefficient above 0.9 without using any training procedure. Our results show that the changes of the epigenetic signals are useful to study gene regulation. PMID:25383910

Mitochondrial Gene Therapy: Advances in Mitochondrial Gene Cloning, Plasmid Production, and Nanosystems Targeted to Mitochondria.

PubMed

Coutinho, Eduarda; Batista, Cátia; Sousa, Fani; Queiroz, João; Costa, Diana

2017-03-06

Mitochondrial gene therapy seems to be a valuable and promising strategy to treat mitochondrial disorders. The use of a therapeutic vector based on mitochondrial DNA, along with its affinity to the site of mitochondria, can be considered a powerful tool in the reestablishment of normal mitochondrial function. In line with this and for the first time, we successfully cloned the mitochondrial gene ND1 that was stably maintained in multicopy pCAG-GFP plasmid, which is used to transform E. coli. This mitochondrial-gene-based plasmid was encapsulated into nanoparticles. Furthermore, the functionalization of nanoparticles with polymers, such as cellulose or gelatin, enhances their overall properties and performance for gene therapy. The fluorescence arising from rhodamine nanoparticles in mitochondria and a fluorescence microscopy study show pCAG-GFP-ND1-based nanoparticles' cell internalization and mitochondria targeting. The quantification of GFP expression strongly supports this finding. This work highlights the viability of gene therapy based on mitochondrial DNA instigating further in vitro research and clinical translation.

Large-scale image-based profiling of single-cell phenotypes in arrayed CRISPR-Cas9 gene perturbation screens.

PubMed

de Groot, Reinoud; Lüthi, Joel; Lindsay, Helen; Holtackers, René; Pelkmans, Lucas

2018-01-23

High-content imaging using automated microscopy and computer vision allows multivariate profiling of single-cell phenotypes. Here, we present methods for the application of the CISPR-Cas9 system in large-scale, image-based, gene perturbation experiments. We show that CRISPR-Cas9-mediated gene perturbation can be achieved in human tissue culture cells in a timeframe that is compatible with image-based phenotyping. We developed a pipeline to construct a large-scale arrayed library of 2,281 sequence-verified CRISPR-Cas9 targeting plasmids and profiled this library for genes affecting cellular morphology and the subcellular localization of components of the nuclear pore complex (NPC). We conceived a machine-learning method that harnesses genetic heterogeneity to score gene perturbations and identify phenotypically perturbed cells for in-depth characterization of gene perturbation effects. This approach enables genome-scale image-based multivariate gene perturbation profiling using CRISPR-Cas9. © 2018 The Authors. Published under the terms of the CC BY 4.0 license.

[Study on action mechanism and material base of compound Danshen dripping pills in treatment of carotid atherosclerosis based on techniques of gene expression profile and molecular fingerprint].

PubMed

Zhou, Wei; Song, Xiang-gang; Chen, Chao; Wang, Shu-mei; Liang, Sheng-wang

2015-08-01

Action mechanism and material base of compound Danshen dripping pills in treatment of carotid atherosclerosis were discussed based on gene expression profile and molecular fingerprint in this paper. First, gene expression profiles of atherosclerotic carotid artery tissues and histologically normal tissues in human body were collected, and were screened using significance analysis of microarray (SAM) to screen out differential gene expressions; then differential genes were analyzed by Gene Ontology (GO) analysis and KEGG pathway analysis; to avoid some genes with non-outstanding differential expression but biologically importance, Gene Set Enrichment Analysis (GSEA) were performed, and 7 chemical ingredients with higher negative enrichment score were obtained by Cmap method, implying that they could reversely regulate the gene expression profiles of pathological tissues; and last, based on the hypotheses that similar structures have similar activities, 336 ingredients of compound Danshen dripping pills were compared with 7 drug molecules in 2D molecular fingerprints method. The results showed that 147 differential genes including 60 up-regulated genes and 87 down regulated genes were screened out by SAM. And in GO analysis, Biological Process ( BP) is mainly concerned with biological adhesion, response to wounding and inflammatory response; Cellular Component (CC) is mainly concerned with extracellular region, extracellular space and plasma membrane; while Molecular Function (MF) is mainly concerned with antigen binding, metalloendopeptidase activity and peptide binding. KEGG pathway analysis is mainly concerned with JAK-STAT, RIG-I like receptor and PPAR signaling pathway. There were 10 compounds, such as hexadecane, with Tanimoto coefficients greater than 0.85, which implied that they may be the active ingredients (AIs) of compound Danshen dripping pills in treatment of carotid atherosclerosis (CAs). The present method can be applied to the research on material base and molecular action mechanism of TCM.

Comparative study on gene set and pathway topology-based enrichment methods.

PubMed

Bayerlová, Michaela; Jung, Klaus; Kramer, Frank; Klemm, Florian; Bleckmann, Annalen; Beißbarth, Tim

2015-10-22

Enrichment analysis is a popular approach to identify pathways or sets of genes which are significantly enriched in the context of differentially expressed genes. The traditional gene set enrichment approach considers a pathway as a simple gene list disregarding any knowledge of gene or protein interactions. In contrast, the new group of so called pathway topology-based methods integrates the topological structure of a pathway into the analysis. We comparatively investigated gene set and pathway topology-based enrichment approaches, considering three gene set and four topological methods. These methods were compared in two extensive simulation studies and on a benchmark of 36 real datasets, providing the same pathway input data for all methods. In the benchmark data analysis both types of methods showed a comparable ability to detect enriched pathways. The first simulation study was conducted with KEGG pathways, which showed considerable gene overlaps between each other. In this study with original KEGG pathways, none of the topology-based methods outperformed the gene set approach. Therefore, a second simulation study was performed on non-overlapping pathways created by unique gene IDs. Here, methods accounting for pathway topology reached higher accuracy than the gene set methods, however their sensitivity was lower. We conducted one of the first comprehensive comparative works on evaluating gene set against pathway topology-based enrichment methods. The topological methods showed better performance in the simulation scenarios with non-overlapping pathways, however, they were not conclusively better in the other scenarios. This suggests that simple gene set approach might be sufficient to detect an enriched pathway under realistic circumstances. Nevertheless, more extensive studies and further benchmark data are needed to systematically evaluate these methods and to assess what gain and cost pathway topology information introduces into enrichment analysis. Both types of methods for enrichment analysis require further improvements in order to deal with the problem of pathway overlaps.

A Genome-Scale Investigation of How Sequence, Function, and Tree-Based Gene Properties Influence Phylogenetic Inference.

PubMed

Shen, Xing-Xing; Salichos, Leonidas; Rokas, Antonis

2016-09-02

Molecular phylogenetic inference is inherently dependent on choices in both methodology and data. Many insightful studies have shown how choices in methodology, such as the model of sequence evolution or optimality criterion used, can strongly influence inference. In contrast, much less is known about the impact of choices in the properties of the data, typically genes, on phylogenetic inference. We investigated the relationships between 52 gene properties (24 sequence-based, 19 function-based, and 9 tree-based) with each other and with three measures of phylogenetic signal in two assembled data sets of 2,832 yeast and 2,002 mammalian genes. We found that most gene properties, such as evolutionary rate (measured through the percent average of pairwise identity across taxa) and total tree length, were highly correlated with each other. Similarly, several gene properties, such as gene alignment length, Guanine-Cytosine content, and the proportion of tree distance on internal branches divided by relative composition variability (treeness/RCV), were strongly correlated with phylogenetic signal. Analysis of partial correlations between gene properties and phylogenetic signal in which gene evolutionary rate and alignment length were simultaneously controlled, showed similar patterns of correlations, albeit weaker in strength. Examination of the relative importance of each gene property on phylogenetic signal identified gene alignment length, alongside with number of parsimony-informative sites and variable sites, as the most important predictors. Interestingly, the subsets of gene properties that optimally predicted phylogenetic signal differed considerably across our three phylogenetic measures and two data sets; however, gene alignment length and RCV were consistently included as predictors of all three phylogenetic measures in both yeasts and mammals. These results suggest that a handful of sequence-based gene properties are reliable predictors of phylogenetic signal and could be useful in guiding the choice of phylogenetic markers. © The Author 2016. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution.

AUCTSP: an improved biomarker gene pair class predictor.

PubMed

Kagaris, Dimitri; Khamesipour, Alireza; Yiannoutsos, Constantin T

2018-06-26

The Top Scoring Pair (TSP) classifier, based on the concept of relative ranking reversals in the expressions of pairs of genes, has been proposed as a simple, accurate, and easily interpretable decision rule for classification and class prediction of gene expression profiles. The idea that differences in gene expression ranking are associated with presence or absence of disease is compelling and has strong biological plausibility. Nevertheless, the TSP formulation ignores significant available information which can improve classification accuracy and is vulnerable to selecting genes which do not have differential expression in the two conditions ("pivot" genes). We introduce the AUCTSP classifier as an alternative rank-based estimator of the magnitude of the ranking reversals involved in the original TSP. The proposed estimator is based on the Area Under the Receiver Operating Characteristic (ROC) Curve (AUC) and as such, takes into account the separation of the entire distribution of gene expression levels in gene pairs under the conditions considered, as opposed to comparing gene rankings within individual subjects as in the original TSP formulation. Through extensive simulations and case studies involving classification in ovarian, leukemia, colon, breast and prostate cancers and diffuse large b-cell lymphoma, we show the superiority of the proposed approach in terms of improving classification accuracy, avoiding overfitting and being less prone to selecting non-informative (pivot) genes. The proposed AUCTSP is a simple yet reliable and robust rank-based classifier for gene expression classification. While the AUCTSP works by the same principle as TSP, its ability to determine the top scoring gene pair based on the relative rankings of two marker genes across all subjects as opposed to each individual subject results in significant performance gains in classification accuracy. In addition, the proposed method tends to avoid selection of non-informative (pivot) genes as members of the top-scoring pair.

Multi-membership gene regulation in pathway based microarray analysis

PubMed Central

2011-01-01

Background Gene expression analysis has been intensively researched for more than a decade. Recently, there has been elevated interest in the integration of microarray data analysis with other types of biological knowledge in a holistic analytical approach. We propose a methodology that can be facilitated for pathway based microarray data analysis, based on the observation that a substantial proportion of genes present in biochemical pathway databases are members of a number of distinct pathways. Our methodology aims towards establishing the state of individual pathways, by identifying those truly affected by the experimental conditions based on the behaviour of such genes. For that purpose it considers all the pathways in which a gene participates and the general census of gene expression per pathway. Results We utilise hill climbing, simulated annealing and a genetic algorithm to analyse the consistency of the produced results, through the application of fuzzy adjusted rand indexes and hamming distance. All algorithms produce highly consistent genes to pathways allocations, revealing the contribution of genes to pathway functionality, in agreement with current pathway state visualisation techniques, with the simulated annealing search proving slightly superior in terms of efficiency. Conclusions We show that the expression values of genes, which are members of a number of biochemical pathways or modules, are the net effect of the contribution of each gene to these biochemical processes. We show that by manipulating the pathway and module contribution of such genes to follow underlying trends we can interpret microarray results centred on the behaviour of these genes. PMID:21939531

Multi-membership gene regulation in pathway based microarray analysis.

PubMed

Pavlidis, Stelios P; Payne, Annette M; Swift, Stephen M

2011-09-22

Gene expression analysis has been intensively researched for more than a decade. Recently, there has been elevated interest in the integration of microarray data analysis with other types of biological knowledge in a holistic analytical approach. We propose a methodology that can be facilitated for pathway based microarray data analysis, based on the observation that a substantial proportion of genes present in biochemical pathway databases are members of a number of distinct pathways. Our methodology aims towards establishing the state of individual pathways, by identifying those truly affected by the experimental conditions based on the behaviour of such genes. For that purpose it considers all the pathways in which a gene participates and the general census of gene expression per pathway. We utilise hill climbing, simulated annealing and a genetic algorithm to analyse the consistency of the produced results, through the application of fuzzy adjusted rand indexes and hamming distance. All algorithms produce highly consistent genes to pathways allocations, revealing the contribution of genes to pathway functionality, in agreement with current pathway state visualisation techniques, with the simulated annealing search proving slightly superior in terms of efficiency. We show that the expression values of genes, which are members of a number of biochemical pathways or modules, are the net effect of the contribution of each gene to these biochemical processes. We show that by manipulating the pathway and module contribution of such genes to follow underlying trends we can interpret microarray results centred on the behaviour of these genes.

An ensemble of SVM classifiers based on gene pairs.

PubMed

Tong, Muchenxuan; Liu, Kun-Hong; Xu, Chungui; Ju, Wenbin

2013-07-01

In this paper, a genetic algorithm (GA) based ensemble support vector machine (SVM) classifier built on gene pairs (GA-ESP) is proposed. The SVMs (base classifiers of the ensemble system) are trained on different informative gene pairs. These gene pairs are selected by the top scoring pair (TSP) criterion. Each of these pairs projects the original microarray expression onto a 2-D space. Extensive permutation of gene pairs may reveal more useful information and potentially lead to an ensemble classifier with satisfactory accuracy and interpretability. GA is further applied to select an optimized combination of base classifiers. The effectiveness of the GA-ESP classifier is evaluated on both binary-class and multi-class datasets. Copyright © 2013 Elsevier Ltd. All rights reserved.

GO(vis), a gene ontology visualization tool based on multi-dimensional values.

PubMed

Ning, Zi; Jiang, Zhenran

2010-05-01

Most of gene product similarity measurements concentrate on the information content of Gene Ontology (GO) terms or use a path-based similarity between GO terms, which may ignore other important information contained in the structure of the ontology. In our study, we integrate different GO similarity measure approaches to analyze the functional relationship of genes and gene products with a new triangle-based visualization tool called GO(Vis). The purpose of this tool is to demonstrate the effect of three important information factors when measuring the similarity between gene products. One advantage of this tool is that its important ratio can be adjusted to meet different measuring requirements according to the biological knowledge of each factor. The experimental results demonstrate that GO(Vis) can display diagrams of the functional relationship for gene products effectively.

HGDB: A web retrieving cardiovascular-associated gene data.

PubMed

Noorabad-Ghahroodi, Faezeh; Abdi, Samaneh; Zand, Amir Hossein; Najafi, Mohammad

2017-04-01

The use of data obtained from high throughput techniques in genetics studies is an essential subject in biology. The system approaches of networking and enriching may improve the data management. Here, we annotated the molecular features for cardiovascular-associated genes and presented the HGDB search-based database (www.hgdb.ir). The initial seed data was primarily used from Gene Ontology and was automatically enriched with other molecular features. The data was managed in a SQL popular and open source. The search tabs on the HGDB homepage were applied for ID/Name Gene, chromosome, cell organelle and all gene options. The search results were presented on the gene text-based and source link-based descriptions. The HGDB is a friendly website to present gene data in the cardiovascular field. Copyright © 2017 Elsevier B.V. All rights reserved.

An improved method for functional similarity analysis of genes based on Gene Ontology.

PubMed

Tian, Zhen; Wang, Chunyu; Guo, Maozu; Liu, Xiaoyan; Teng, Zhixia

2016-12-23

Measures of gene functional similarity are essential tools for gene clustering, gene function prediction, evaluation of protein-protein interaction, disease gene prioritization and other applications. In recent years, many gene functional similarity methods have been proposed based on the semantic similarity of GO terms. However, these leading approaches may make errorprone judgments especially when they measure the specificity of GO terms as well as the IC of a term set. Therefore, how to estimate the gene functional similarity reliably is still a challenging problem. We propose WIS, an effective method to measure the gene functional similarity. First of all, WIS computes the IC of a term by employing its depth, the number of its ancestors as well as the topology of its descendants in the GO graph. Secondly, WIS calculates the IC of a term set by means of considering the weighted inherited semantics of terms. Finally, WIS estimates the gene functional similarity based on the IC overlap ratio of term sets. WIS is superior to some other representative measures on the experiments of functional classification of genes in a biological pathway, collaborative evaluation of GO-based semantic similarity measures, protein-protein interaction prediction and correlation with gene expression. Further analysis suggests that WIS takes fully into account the specificity of terms and the weighted inherited semantics of terms between GO terms. The proposed WIS method is an effective and reliable way to compare gene function. The web service of WIS is freely available at http://nclab.hit.edu.cn/WIS/ .

Confident difference criterion: a new Bayesian differentially expressed gene selection algorithm with applications.

PubMed

Yu, Fang; Chen, Ming-Hui; Kuo, Lynn; Talbott, Heather; Davis, John S

2015-08-07

Recently, the Bayesian method becomes more popular for analyzing high dimensional gene expression data as it allows us to borrow information across different genes and provides powerful estimators for evaluating gene expression levels. It is crucial to develop a simple but efficient gene selection algorithm for detecting differentially expressed (DE) genes based on the Bayesian estimators. In this paper, by extending the two-criterion idea of Chen et al. (Chen M-H, Ibrahim JG, Chi Y-Y. A new class of mixture models for differential gene expression in DNA microarray data. J Stat Plan Inference. 2008;138:387-404), we propose two new gene selection algorithms for general Bayesian models and name these new methods as the confident difference criterion methods. One is based on the standardized differences between two mean expression values among genes; the other adds the differences between two variances to it. The proposed confident difference criterion methods first evaluate the posterior probability of a gene having different gene expressions between competitive samples and then declare a gene to be DE if the posterior probability is large. The theoretical connection between the proposed first method based on the means and the Bayes factor approach proposed by Yu et al. (Yu F, Chen M-H, Kuo L. Detecting differentially expressed genes using alibrated Bayes factors. Statistica Sinica. 2008;18:783-802) is established under the normal-normal-model with equal variances between two samples. The empirical performance of the proposed methods is examined and compared to those of several existing methods via several simulations. The results from these simulation studies show that the proposed confident difference criterion methods outperform the existing methods when comparing gene expressions across different conditions for both microarray studies and sequence-based high-throughput studies. A real dataset is used to further demonstrate the proposed methodology. In the real data application, the confident difference criterion methods successfully identified more clinically important DE genes than the other methods. The confident difference criterion method proposed in this paper provides a new efficient approach for both microarray studies and sequence-based high-throughput studies to identify differentially expressed genes.

Analyzing gene expression time-courses based on multi-resolution shape mixture model.

PubMed

Li, Ying; He, Ye; Zhang, Yu

2016-11-01

Biological processes actually are a dynamic molecular process over time. Time course gene expression experiments provide opportunities to explore patterns of gene expression change over a time and understand the dynamic behavior of gene expression, which is crucial for study on development and progression of biology and disease. Analysis of the gene expression time-course profiles has not been fully exploited so far. It is still a challenge problem. We propose a novel shape-based mixture model clustering method for gene expression time-course profiles to explore the significant gene groups. Based on multi-resolution fractal features and mixture clustering model, we proposed a multi-resolution shape mixture model algorithm. Multi-resolution fractal features is computed by wavelet decomposition, which explore patterns of change over time of gene expression at different resolution. Our proposed multi-resolution shape mixture model algorithm is a probabilistic framework which offers a more natural and robust way of clustering time-course gene expression. We assessed the performance of our proposed algorithm using yeast time-course gene expression profiles compared with several popular clustering methods for gene expression profiles. The grouped genes identified by different methods are evaluated by enrichment analysis of biological pathways and known protein-protein interactions from experiment evidence. The grouped genes identified by our proposed algorithm have more strong biological significance. A novel multi-resolution shape mixture model algorithm based on multi-resolution fractal features is proposed. Our proposed model provides a novel horizons and an alternative tool for visualization and analysis of time-course gene expression profiles. The R and Matlab program is available upon the request. Copyright © 2016 Elsevier Inc. All rights reserved.

Illustrating, Quantifying, and Correcting for Bias in Post-hoc Analysis of Gene-Based Rare Variant Tests of Association

PubMed Central

Grinde, Kelsey E.; Arbet, Jaron; Green, Alden; O'Connell, Michael; Valcarcel, Alessandra; Westra, Jason; Tintle, Nathan

2017-01-01

To date, gene-based rare variant testing approaches have focused on aggregating information across sets of variants to maximize statistical power in identifying genes showing significant association with diseases. Beyond identifying genes that are associated with diseases, the identification of causal variant(s) in those genes and estimation of their effect is crucial for planning replication studies and characterizing the genetic architecture of the locus. However, we illustrate that straightforward single-marker association statistics can suffer from substantial bias introduced by conditioning on gene-based test significance, due to the phenomenon often referred to as “winner's curse.” We illustrate the ramifications of this bias on variant effect size estimation and variant prioritization/ranking approaches, outline parameters of genetic architecture that affect this bias, and propose a bootstrap resampling method to correct for this bias. We find that our correction method significantly reduces the bias due to winner's curse (average two-fold decrease in bias, p < 2.2 × 10−6) and, consequently, substantially improves mean squared error and variant prioritization/ranking. The method is particularly helpful in adjustment for winner's curse effects when the initial gene-based test has low power and for relatively more common, non-causal variants. Adjustment for winner's curse is recommended for all post-hoc estimation and ranking of variants after a gene-based test. Further work is necessary to continue seeking ways to reduce bias and improve inference in post-hoc analysis of gene-based tests under a wide variety of genetic architectures. PMID:28959274

MGAS: a powerful tool for multivariate gene-based genome-wide association analysis.

PubMed

Van der Sluis, Sophie; Dolan, Conor V; Li, Jiang; Song, Youqiang; Sham, Pak; Posthuma, Danielle; Li, Miao-Xin

2015-04-01

Standard genome-wide association studies, testing the association between one phenotype and a large number of single nucleotide polymorphisms (SNPs), are limited in two ways: (i) traits are often multivariate, and analysis of composite scores entails loss in statistical power and (ii) gene-based analyses may be preferred, e.g. to decrease the multiple testing problem. Here we present a new method, multivariate gene-based association test by extended Simes procedure (MGAS), that allows gene-based testing of multivariate phenotypes in unrelated individuals. Through extensive simulation, we show that under most trait-generating genotype-phenotype models MGAS has superior statistical power to detect associated genes compared with gene-based analyses of univariate phenotypic composite scores (i.e. GATES, multiple regression), and multivariate analysis of variance (MANOVA). Re-analysis of metabolic data revealed 32 False Discovery Rate controlled genome-wide significant genes, and 12 regions harboring multiple genes; of these 44 regions, 30 were not reported in the original analysis. MGAS allows researchers to conduct their multivariate gene-based analyses efficiently, and without the loss of power that is often associated with an incorrectly specified genotype-phenotype models. MGAS is freely available in KGG v3.0 (http://statgenpro.psychiatry.hku.hk/limx/kgg/download.php). Access to the metabolic dataset can be requested at dbGaP (https://dbgap.ncbi.nlm.nih.gov/). The R-simulation code is available from http://ctglab.nl/people/sophie_van_der_sluis. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press.

Republished review: Gene therapy for ocular diseases.

PubMed

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-07-01

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Gene therapy for ocular diseases.

PubMed

Liu, Melissa M; Tuo, Jingsheng; Chan, Chi-Chao

2011-05-01

The eye is an easily accessible, highly compartmentalised and immune-privileged organ that offers unique advantages as a gene therapy target. Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing have been implicated as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis. This review describes current developments and future prospects for ocular gene therapy. Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirus-mediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.

Gene-based interaction analysis shows GABAergic genes interacting with parenting in adolescent depressive symptoms.

PubMed

Van Assche, Evelien; Moons, Tim; Cinar, Ozan; Viechtbauer, Wolfgang; Oldehinkel, Albertine J; Van Leeuwen, Karla; Verschueren, Karine; Colpin, Hilde; Lambrechts, Diether; Van den Noortgate, Wim; Goossens, Luc; Claes, Stephan; van Winkel, Ruud

2017-12-01

Most gene-environment interaction studies (G × E) have focused on single candidate genes. This approach is criticized for its expectations of large effect sizes and occurrence of spurious results. We describe an approach that accounts for the polygenic nature of most psychiatric phenotypes and reduces the risk of false-positive findings. We apply this method focusing on the role of perceived parental support, psychological control, and harsh punishment in depressive symptoms in adolescence. Analyses were conducted on 982 adolescents of Caucasian origin (M age (SD) = 13.78 (.94) years) genotyped for 4,947 SNPs in 263 genes, selected based on a literature survey. The Leuven Adolescent Perceived Parenting Scale (LAPPS) and the Parental Behavior Scale (PBS) were used to assess perceived parental psychological control, harsh punishment, and support. The Center for Epidemiologic Studies Depression Scale (CES-D) was the outcome. We used gene-based testing taking into account linkage disequilibrium to identify genes containing SNPs exhibiting an interaction with environmental factors yielding a p-value per single gene. Significant results at the corrected p-value of p < 1.90 × 10 -4 were examined in an independent replication sample of Dutch adolescents (N = 1354). Two genes showed evidence for interaction with perceived support: GABRR1 (p = 4.62 × 10 -5 ) and GABRR2 (p = 9.05 × 10 -6 ). No genes interacted significantly with psychological control or harsh punishment. Gene-based analysis was unable to confirm the interaction of GABRR1 or GABRR2 with support in the replication sample. However, for GABRR2, but not GABRR1, the correlation of the estimates between the two datasets was significant (r (46) = .32; p = .027) and a gene-based analysis of the combined datasets supported GABRR2 × support interaction (p = 1.63 × 10 -4 ). We present a gene-based method for gene-environment interactions in a polygenic context and show that genes interact differently with particular aspects of parenting. This accentuates the importance of polygenic approaches and the need to accurately assess environmental exposure in G × E. © 2017 Association for Child and Adolescent Mental Health.

Reconstructing genome-wide regulatory network of E. coli using transcriptome data and predicted transcription factor activities

PubMed Central

2011-01-01

Background Gene regulatory networks play essential roles in living organisms to control growth, keep internal metabolism running and respond to external environmental changes. Understanding the connections and the activity levels of regulators is important for the research of gene regulatory networks. While relevance score based algorithms that reconstruct gene regulatory networks from transcriptome data can infer genome-wide gene regulatory networks, they are unfortunately prone to false positive results. Transcription factor activities (TFAs) quantitatively reflect the ability of the transcription factor to regulate target genes. However, classic relevance score based gene regulatory network reconstruction algorithms use models do not include the TFA layer, thus missing a key regulatory element. Results This work integrates TFA prediction algorithms with relevance score based network reconstruction algorithms to reconstruct gene regulatory networks with improved accuracy over classic relevance score based algorithms. This method is called Gene expression and Transcription factor activity based Relevance Network (GTRNetwork). Different combinations of TFA prediction algorithms and relevance score functions have been applied to find the most efficient combination. When the integrated GTRNetwork method was applied to E. coli data, the reconstructed genome-wide gene regulatory network predicted 381 new regulatory links. This reconstructed gene regulatory network including the predicted new regulatory links show promising biological significances. Many of the new links are verified by known TF binding site information, and many other links can be verified from the literature and databases such as EcoCyc. The reconstructed gene regulatory network is applied to a recent transcriptome analysis of E. coli during isobutanol stress. In addition to the 16 significantly changed TFAs detected in the original paper, another 7 significantly changed TFAs have been detected by using our reconstructed network. Conclusions The GTRNetwork algorithm introduces the hidden layer TFA into classic relevance score-based gene regulatory network reconstruction processes. Integrating the TFA biological information with regulatory network reconstruction algorithms significantly improves both detection of new links and reduces that rate of false positives. The application of GTRNetwork on E. coli gene transcriptome data gives a set of potential regulatory links with promising biological significance for isobutanol stress and other conditions. PMID:21668997

Mining disease genes using integrated protein-protein interaction and gene-gene co-regulation information.

PubMed

Li, Jin; Wang, Limei; Guo, Maozu; Zhang, Ruijie; Dai, Qiguo; Liu, Xiaoyan; Wang, Chunyu; Teng, Zhixia; Xuan, Ping; Zhang, Mingming

2015-01-01

In humans, despite the rapid increase in disease-associated gene discovery, a large proportion of disease-associated genes are still unknown. Many network-based approaches have been used to prioritize disease genes. Many networks, such as the protein-protein interaction (PPI), KEGG, and gene co-expression networks, have been used. Expression quantitative trait loci (eQTLs) have been successfully applied for the determination of genes associated with several diseases. In this study, we constructed an eQTL-based gene-gene co-regulation network (GGCRN) and used it to mine for disease genes. We adopted the random walk with restart (RWR) algorithm to mine for genes associated with Alzheimer disease. Compared to the Human Protein Reference Database (HPRD) PPI network alone, the integrated HPRD PPI and GGCRN networks provided faster convergence and revealed new disease-related genes. Therefore, using the RWR algorithm for integrated PPI and GGCRN is an effective method for disease-associated gene mining.

Construction of diagnosis system and gene regulatory networks based on microarray analysis.

PubMed

Hong, Chun-Fu; Chen, Ying-Chen; Chen, Wei-Chun; Tu, Keng-Chang; Tsai, Meng-Hsiun; Chan, Yung-Kuan; Yu, Shyr Shen

2018-05-01

A microarray analysis generally contains expression data of thousands of genes, but most of them are irrelevant to the disease of interest, making analyzing the genes concerning specific diseases complicated. Therefore, filtering out a few essential genes as well as their regulatory networks is critical, and a disease can be easily diagnosed just depending on the expression profiles of a few critical genes. In this study, a target gene screening (TGS) system, which is a microarray-based information system that integrates F-statistics, pattern recognition matching, a two-layer K-means classifier, a Parameter Detection Genetic Algorithm (PDGA), a genetic-based gene selector (GBG selector) and the association rule, was developed to screen out a small subset of genes that can discriminate malignant stages of cancers. During the first stage, F-statistic, pattern recognition matching, and a two-layer K-means classifier were applied in the system to filter out the 20 critical genes most relevant to ovarian cancer from 9600 genes, and the PDGA was used to decide the fittest values of the parameters for these critical genes. Among the 20 critical genes, 15 are associated with cancer progression. In the second stage, we further employed a GBG selector and the association rule to screen out seven target gene sets, each with only four to six genes, and each of which can precisely identify the malignancy stage of ovarian cancer based on their expression profiles. We further deduced the gene regulatory networks of the 20 critical genes by applying the Pearson correlation coefficient to evaluate the correlationship between the expression of each gene at the same stages and at different stages. Correlationships between gene pairs were calculated, and then, three regulatory networks were deduced. Their correlationships were further confirmed by the Ingenuity pathway analysis. The prognostic significances of the genes identified via regulatory networks were examined using online tools, and most represented biomarker candidates. In summary, our proposed system provides a new strategy to identify critical genes or biomarkers, as well as their regulatory networks, from microarray data. Copyright © 2018. Published by Elsevier Inc.

Network-Based Method for Identifying Co-Regeneration Genes in Bone, Dentin, Nerve and Vessel Tissues

PubMed Central

Pan, Hongying; Zhang, Yu-Hang; Feng, Kaiyan; Kong, XiangYin; Cai, Yu-Dong

2017-01-01

Bone and dental diseases are serious public health problems. Most current clinical treatments for these diseases can produce side effects. Regeneration is a promising therapy for bone and dental diseases, yielding natural tissue recovery with few side effects. Because soft tissues inside the bone and dentin are densely populated with nerves and vessels, the study of bone and dentin regeneration should also consider the co-regeneration of nerves and vessels. In this study, a network-based method to identify co-regeneration genes for bone, dentin, nerve and vessel was constructed based on an extensive network of protein–protein interactions. Three procedures were applied in the network-based method. The first procedure, searching, sought the shortest paths connecting regeneration genes of one tissue type with regeneration genes of other tissues, thereby extracting possible co-regeneration genes. The second procedure, testing, employed a permutation test to evaluate whether possible genes were false discoveries; these genes were excluded by the testing procedure. The last procedure, screening, employed two rules, the betweenness ratio rule and interaction score rule, to select the most essential genes. A total of seventeen genes were inferred by the method, which were deemed to contribute to co-regeneration of at least two tissues. All these seventeen genes were extensively discussed to validate the utility of the method. PMID:28974058

Network-Based Method for Identifying Co- Regeneration Genes in Bone, Dentin, Nerve and Vessel Tissues.

PubMed

Chen, Lei; Pan, Hongying; Zhang, Yu-Hang; Feng, Kaiyan; Kong, XiangYin; Huang, Tao; Cai, Yu-Dong

2017-10-02

Bone and dental diseases are serious public health problems. Most current clinical treatments for these diseases can produce side effects. Regeneration is a promising therapy for bone and dental diseases, yielding natural tissue recovery with few side effects. Because soft tissues inside the bone and dentin are densely populated with nerves and vessels, the study of bone and dentin regeneration should also consider the co-regeneration of nerves and vessels. In this study, a network-based method to identify co-regeneration genes for bone, dentin, nerve and vessel was constructed based on an extensive network of protein-protein interactions. Three procedures were applied in the network-based method. The first procedure, searching, sought the shortest paths connecting regeneration genes of one tissue type with regeneration genes of other tissues, thereby extracting possible co-regeneration genes. The second procedure, testing, employed a permutation test to evaluate whether possible genes were false discoveries; these genes were excluded by the testing procedure. The last procedure, screening, employed two rules, the betweenness ratio rule and interaction score rule, to select the most essential genes. A total of seventeen genes were inferred by the method, which were deemed to contribute to co-regeneration of at least two tissues. All these seventeen genes were extensively discussed to validate the utility of the method.

A transversal approach to predict gene product networks from ontology-based similarity

PubMed Central

Chabalier, Julie; Mosser, Jean; Burgun, Anita

2007-01-01

Background Interpretation of transcriptomic data is usually made through a "standard" approach which consists in clustering the genes according to their expression patterns and exploiting Gene Ontology (GO) annotations within each expression cluster. This approach makes it difficult to underline functional relationships between gene products that belong to different expression clusters. To address this issue, we propose a transversal analysis that aims to predict functional networks based on a combination of GO processes and data expression. Results The transversal approach presented in this paper consists in computing the semantic similarity between gene products in a Vector Space Model. Through a weighting scheme over the annotations, we take into account the representativity of the terms that annotate a gene product. Comparing annotation vectors results in a matrix of gene product similarities. Combined with expression data, the matrix is displayed as a set of functional gene networks. The transversal approach was applied to 186 genes related to the enterocyte differentiation stages. This approach resulted in 18 functional networks proved to be biologically relevant. These results were compared with those obtained through a standard approach and with an approach based on information content similarity. Conclusion Complementary to the standard approach, the transversal approach offers new insight into the cellular mechanisms and reveals new research hypotheses by combining gene product networks based on semantic similarity, and data expression. PMID:17605807

A Modified ABCDE Model of Flowering in Orchids Based on Gene Expression Profiling Studies of the Moth Orchid Phalaenopsis aphrodite

PubMed Central

Lee, Ann-Ying; Chen, Chun-Yi; Chang, Yao-Chien Alex; Chao, Ya-Ting; Shih, Ming-Che

2013-01-01

Previously we developed genomic resources for orchids, including transcriptomic analyses using next-generation sequencing techniques and construction of a web-based orchid genomic database. Here, we report a modified molecular model of flower development in the Orchidaceae based on functional analysis of gene expression profiles in Phalaenopsis aphrodite (a moth orchid) that revealed novel roles for the transcription factors involved in floral organ pattern formation. Phalaenopsis orchid floral organ-specific genes were identified by microarray analysis. Several critical transcription factors including AP3, PI, AP1 and AGL6, displayed distinct spatial distribution patterns. Phylogenetic analysis of orchid MADS box genes was conducted to infer the evolutionary relationship among floral organ-specific genes. The results suggest that gene duplication MADS box genes in orchid may have resulted in their gaining novel functions during evolution. Based on these analyses, a modified model of orchid flowering was proposed. Comparison of the expression profiles of flowers of a peloric mutant and wild-type Phalaenopsis orchid further identified genes associated with lip morphology and peloric effects. Large scale investigation of gene expression profiles revealed that homeotic genes from the ABCDE model of flower development classes A and B in the Phalaenopsis orchid have novel functions due to evolutionary diversification, and display differential expression patterns. PMID:24265826

Genes encoding major light-harvesting polypeptides are clustered on the genome of the cyanobacterium Fremyella diplosiphon.

PubMed Central

Conley, P B; Lemaux, P G; Lomax, T L; Grossman, A R

1986-01-01

The polypeptide composition of the phycobilisome, the major light-harvesting complex of prokaryotic cyanobacteria and certain eukaryotic algae, can be modulated by different light qualities in cyanobacteria exhibiting chromatic adaptation. We have identified genomic fragments encoding a cluster of phycobilisome polypeptides (phycobiliproteins) from the chromatically adapting cyanobacterium Fremyella diplosiphon using previously characterized DNA fragments of phycobiliprotein genes from the eukaryotic alga Cyanophora paradoxa and from F. diplosiphon. Characterization of two lambda-EMBL3 clones containing overlapping genomic fragments indicates that three sets of phycobiliprotein genes--the alpha- and beta-allophycocyanin genes plus two sets of alpha- and beta-phycocyanin genes--are clustered within 13 kilobases on the cyanobacterial genome and transcribed off the same strand. The gene order (alpha-allophycocyanin followed by beta-allophycocyanin and beta-phycocyanin followed by alpha-phycocyanin) appears to be a conserved arrangement found previously in a eukaryotic alga and another cyanobacterium. We have reported that one set of phycocyanin genes is transcribed as two abundant red light-induced mRNAs (1600 and 3800 bases). We now present data showing that the allophycocyanin genes and a second set of phycocyanin genes are transcribed into major mRNAs of 1400 and 1600 bases, respectively. These transcripts are present in RNA isolated from cultures grown in red and green light, although lower levels of the 1600-base phycocyanin transcript are present in cells grown in green light. Furthermore, a larger transcript of 1750 bases hybridizes to the allophycocyanin genes and may be a precursor to the 1400-base species. Images PMID:3086870

Systems biology definition of the core proteome of metabolism and expression is consistent with high-throughput data.

PubMed

Yang, Laurence; Tan, Justin; O'Brien, Edward J; Monk, Jonathan M; Kim, Donghyuk; Li, Howard J; Charusanti, Pep; Ebrahim, Ali; Lloyd, Colton J; Yurkovich, James T; Du, Bin; Dräger, Andreas; Thomas, Alex; Sun, Yuekai; Saunders, Michael A; Palsson, Bernhard O

2015-08-25

Finding the minimal set of gene functions needed to sustain life is of both fundamental and practical importance. Minimal gene lists have been proposed by using comparative genomics-based core proteome definitions. A definition of a core proteome that is supported by empirical data, is understood at the systems-level, and provides a basis for computing essential cell functions is lacking. Here, we use a systems biology-based genome-scale model of metabolism and expression to define a functional core proteome consisting of 356 gene products, accounting for 44% of the Escherichia coli proteome by mass based on proteomics data. This systems biology core proteome includes 212 genes not found in previous comparative genomics-based core proteome definitions, accounts for 65% of known essential genes in E. coli, and has 78% gene function overlap with minimal genomes (Buchnera aphidicola and Mycoplasma genitalium). Based on transcriptomics data across environmental and genetic backgrounds, the systems biology core proteome is significantly enriched in nondifferentially expressed genes and depleted in differentially expressed genes. Compared with the noncore, core gene expression levels are also similar across genetic backgrounds (two times higher Spearman rank correlation) and exhibit significantly more complex transcriptional and posttranscriptional regulatory features (40% more transcription start sites per gene, 22% longer 5'UTR). Thus, genome-scale systems biology approaches rigorously identify a functional core proteome needed to support growth. This framework, validated by using high-throughput datasets, facilitates a mechanistic understanding of systems-level core proteome function through in silico models; it de facto defines a paleome.

A Risk Stratification Model for Lung Cancer Based on Gene Coexpression Network and Deep Learning

PubMed Central

2018-01-01

Risk stratification model for lung cancer with gene expression profile is of great interest. Instead of previous models based on individual prognostic genes, we aimed to develop a novel system-level risk stratification model for lung adenocarcinoma based on gene coexpression network. Using multiple microarray, gene coexpression network analysis was performed to identify survival-related networks. A deep learning based risk stratification model was constructed with representative genes of these networks. The model was validated in two test sets. Survival analysis was performed using the output of the model to evaluate whether it could predict patients' survival independent of clinicopathological variables. Five networks were significantly associated with patients' survival. Considering prognostic significance and representativeness, genes of the two survival-related networks were selected for input of the model. The output of the model was significantly associated with patients' survival in two test sets and training set (p < 0.00001, p < 0.0001 and p = 0.02 for training and test sets 1 and 2, resp.). In multivariate analyses, the model was associated with patients' prognosis independent of other clinicopathological features. Our study presents a new perspective on incorporating gene coexpression networks into the gene expression signature and clinical application of deep learning in genomic data science for prognosis prediction. PMID:29581968

Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data.

PubMed

Cha, Kihoon; Hwang, Taeho; Oh, Kimin; Yi, Gwan-Su

2015-01-01

It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation.

Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data

PubMed Central

2015-01-01

Background It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. Results In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. Conclusions This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation. PMID:26043779

Genome Editing of Monkey.

PubMed

Liu, Zhen; Cai, Yijun; Sun, Qiang

2017-01-01

Gene-modified monkey models would be particularly valuable in biomedical and neuroscience research. Virus-based transgenic and programmable nucleases-based site-specific gene editing methods (TALEN, CRISPR-cas9) enable the generation of gene-modified monkeys with gain or loss of function of specific genes. Here, we describe the generation of transgenic and knock-out (KO) monkeys with high efficiency by lentivirus and programmable nucleases.

An Optimal Mean Based Block Robust Feature Extraction Method to Identify Colorectal Cancer Genes with Integrated Data.

PubMed

Liu, Jian; Cheng, Yuhu; Wang, Xuesong; Zhang, Lin; Liu, Hui

2017-08-17

It is urgent to diagnose colorectal cancer in the early stage. Some feature genes which are important to colorectal cancer development have been identified. However, for the early stage of colorectal cancer, less is known about the identity of specific cancer genes that are associated with advanced clinical stage. In this paper, we conducted a feature extraction method named Optimal Mean based Block Robust Feature Extraction method (OMBRFE) to identify feature genes associated with advanced colorectal cancer in clinical stage by using the integrated colorectal cancer data. Firstly, based on the optimal mean and L 2,1 -norm, a novel feature extraction method called Optimal Mean based Robust Feature Extraction method (OMRFE) is proposed to identify feature genes. Then the OMBRFE method which introduces the block ideology into OMRFE method is put forward to process the colorectal cancer integrated data which includes multiple genomic data: copy number alterations, somatic mutations, methylation expression alteration, as well as gene expression changes. Experimental results demonstrate that the OMBRFE is more effective than previous methods in identifying the feature genes. Moreover, genes identified by OMBRFE are verified to be closely associated with advanced colorectal cancer in clinical stage.

Map-Based Cloning of Genes Important for Maize Anther Development

NASA Astrophysics Data System (ADS)

Anaya, Y.; Walbot, V.; Nan, G.

2012-12-01

Map-Based cloning for maize mutant MS13 . Scientists still do not understand what decides the fate of a cell in plants. Many maize genes are important for anther development and when they are disrupted, the anthers do not shed pollen, i.e. male sterile. Since the maize genome has been fully sequenced, we conduct map-based cloning using a bulk segregant analysis strategy. Using PCR (polymerase chain reaction), we look for biomarkers that are linked to our gene of interest, Male Sterile 13 (MS13). Recombinations occur more often if the biomarkers are further away from the gene, therefore we can estimate where the gene is and design more PCR primers to get closer to our gene. Genetic and molecular analysis will help distinguish the role of key genes in setting cell fates before meiosis and for being in charge of the switch from mitosis to meiosis.

Creating genetic resistance to HIV.

PubMed

Burnett, John C; Zaia, John A; Rossi, John J

2012-10-01

HIV/AIDS remains a chronic and incurable disease, in spite of the notable successes of combination antiretroviral therapy. Gene therapy offers the prospect of creating genetic resistance to HIV that supplants the need for antiviral drugs. In sight of this goal, a variety of anti-HIV genes have reached clinical testing, including gene-editing enzymes, protein-based inhibitors, and RNA-based therapeutics. Combinations of therapeutic genes against viral and host targets are designed to improve the overall antiviral potency and reduce the likelihood of viral resistance. In cell-based therapies, therapeutic genes are expressed in gene modified T lymphocytes or in hematopoietic stem cells that generate an HIV-resistant immune system. Such strategies must promote the selective proliferation of the transplanted cells and the prolonged expression of therapeutic genes. This review focuses on the current advances and limitations in genetic therapies against HIV, including the status of several recent and ongoing clinical studies. Copyright © 2012 Elsevier Ltd. All rights reserved.

A method to identify differential expression profiles of time-course gene data with Fourier transformation.

PubMed

Kim, Jaehee; Ogden, Robert Todd; Kim, Haseong

2013-10-18

Time course gene expression experiments are an increasingly popular method for exploring biological processes. Temporal gene expression profiles provide an important characterization of gene function, as biological systems are both developmental and dynamic. With such data it is possible to study gene expression changes over time and thereby to detect differential genes. Much of the early work on analyzing time series expression data relied on methods developed originally for static data and thus there is a need for improved methodology. Since time series expression is a temporal process, its unique features such as autocorrelation between successive points should be incorporated into the analysis. This work aims to identify genes that show different gene expression profiles across time. We propose a statistical procedure to discover gene groups with similar profiles using a nonparametric representation that accounts for the autocorrelation in the data. In particular, we first represent each profile in terms of a Fourier basis, and then we screen out genes that are not differentially expressed based on the Fourier coefficients. Finally, we cluster the remaining gene profiles using a model-based approach in the Fourier domain. We evaluate the screening results in terms of sensitivity, specificity, FDR and FNR, compare with the Gaussian process regression screening in a simulation study and illustrate the results by application to yeast cell-cycle microarray expression data with alpha-factor synchronization.The key elements of the proposed methodology: (i) representation of gene profiles in the Fourier domain; (ii) automatic screening of genes based on the Fourier coefficients and taking into account autocorrelation in the data, while controlling the false discovery rate (FDR); (iii) model-based clustering of the remaining gene profiles. Using this method, we identified a set of cell-cycle-regulated time-course yeast genes. The proposed method is general and can be potentially used to identify genes which have the same patterns or biological processes, and help facing the present and forthcoming challenges of data analysis in functional genomics.

A novel method to identify pathways associated with renal cell carcinoma based on a gene co-expression network

PubMed Central

RUAN, XIYUN; LI, HONGYUN; LIU, BO; CHEN, JIE; ZHANG, SHIBAO; SUN, ZEQIANG; LIU, SHUANGQING; SUN, FAHAI; LIU, QINGYONG

2015-01-01

The aim of the present study was to develop a novel method for identifying pathways associated with renal cell carcinoma (RCC) based on a gene co-expression network. A framework was established where a co-expression network was derived from the database as well as various co-expression approaches. First, the backbone of the network based on differentially expressed (DE) genes between RCC patients and normal controls was constructed by the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The differentially co-expressed links were detected by Pearson’s correlation, the empirical Bayesian (EB) approach and Weighted Gene Co-expression Network Analysis (WGCNA). The co-expressed gene pairs were merged by a rank-based algorithm. We obtained 842; 371; 2,883 and 1,595 co-expressed gene pairs from the co-expression networks of the STRING database, Pearson’s correlation EB method and WGCNA, respectively. Two hundred and eighty-one differentially co-expressed (DC) gene pairs were obtained from the merged network using this novel method. Pathway enrichment analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and the network enrichment analysis (NEA) method were performed to verify feasibility of the merged method. Results of the KEGG and NEA pathway analyses showed that the network was associated with RCC. The suggested method was computationally efficient to identify pathways associated with RCC and has been identified as a useful complement to traditional co-expression analysis. PMID:26058425

A systematic analysis of genomic changes in Tg2576 mice.

PubMed

Tan, Lu; Wang, Xiong; Ni, Zhong-Fei; Zhu, Xiuming; Wu, Wei; Zhu, Ling-Qiang; Liu, Dan

2013-06-01

Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by intelligence decline, behavioral disorders and cognitive disability. The purpose of this study was to investigate gene expression in AD, based on published microarray data on Tg2576 mice. Hierarchical Cluster Analysis and Gene Ontology were employed to group genes together on the basis of their product characteristics and annotation data. Genes with prominent alterations were clustered into apoptosis and axon guidance pathways. Based on our findings and those of previous studies, we propose that the mitochondria-mediated apoptotic pathway plays a crucial role in the neuronal loss and synaptic dysfunction associated with AD. Furthermore, based on the findings of Positional Gene Enrichment analysis and Gene Set Enrichment analysis, we propose that the regulation of transcription of AD genes may be an important pathogenic factor in this neurodegenerative disease. Our results highlight the importance of genes that could subsequently be examined for their potential as prognostic markers for AD.

Microarray-based cancer prediction using soft computing approach.

PubMed

Wang, Xiaosheng; Gotoh, Osamu

2009-05-26

One of the difficulties in using gene expression profiles to predict cancer is how to effectively select a few informative genes to construct accurate prediction models from thousands or ten thousands of genes. We screen highly discriminative genes and gene pairs to create simple prediction models involved in single genes or gene pairs on the basis of soft computing approach and rough set theory. Accurate cancerous prediction is obtained when we apply the simple prediction models for four cancerous gene expression datasets: CNS tumor, colon tumor, lung cancer and DLBCL. Some genes closely correlated with the pathogenesis of specific or general cancers are identified. In contrast with other models, our models are simple, effective and robust. Meanwhile, our models are interpretable for they are based on decision rules. Our results demonstrate that very simple models may perform well on cancerous molecular prediction and important gene markers of cancer can be detected if the gene selection approach is chosen reasonably.

Identification of estrogen-responsive genes using a genome-wide analysis of promoter elements for transcription factor binding sites.

PubMed

Kamalakaran, Sitharthan; Radhakrishnan, Senthil K; Beck, William T

2005-06-03

We developed a pipeline to identify novel genes regulated by the steroid hormone-dependent transcription factor, estrogen receptor, through a systematic analysis of upstream regions of all human and mouse genes. We built a data base of putative promoter regions for 23,077 human and 19,984 mouse transcripts from National Center for Biotechnology Information annotation and 8793 human and 6785 mouse promoters from the Data Base of Transcriptional Start Sites. We used this data base of putative promoters to identify potential targets of estrogen receptor by identifying estrogen response elements (EREs) in their promoters. Our program correctly identified EREs in genes known to be regulated by estrogen in addition to several new genes whose putative promoters contained EREs. We validated six genes (KIAA1243, NRIP1, MADH9, NME3, TPD52L, and ABCG2) to be estrogen-responsive in MCF7 cells using reverse transcription PCR. To allow for extensibility of our program in identifying targets of other transcription factors, we have built a Web interface to access our data base and programs. Our Web-based program for Promoter Analysis of Genome, PAGen@UIC, allows a user to identify putative target genes for vertebrate transcription factors through the analysis of their upstream sequences. The interface allows the user to search the human and mouse promoter data bases for potential target genes containing one or more listed transcription factor binding sites (TFBSs) in their upstream elements, using either regular expression-based consensus or position weight matrices. The data base can also be searched for promoters harboring user-defined TFBSs given as a consensus or a position weight matrix. Furthermore, the user can retrieve putative promoter sequences for any given gene together with identified TFBSs located on its promoter. Orthologous promoters are also analyzed to determine conserved elements.

Recurrence of 49-base decamers, nonomers, and octamers within mouse C mu gene of Ig heavy chain and its primordial building block.

PubMed Central

Yazaki, A; Ohno, S

1983-01-01

Within the published 2,168-base-long mouse C mu gene of Ig heavy chain consisting of four coding and four noncoding segments, 2 base decamers, 8 nonomers, and 39 octamers recurred. Recurring base heptamers (about 100) and hexamers (about 350) were simply too numerous to merit individual identification. In spite of extensive overlaps between these recurring base decamers to hexamers, they occupied nearly the entire length of mouse Ig C mu gene. As with other genes of the beta-sheet-forming beta 2-microglobulin family, the Ig C mu gene (flanking and intervening noncoding sequences included) is not a unique sequence but rather it is degenerate repeats of the 45-base-long primordial building-block sequence uniquely its own. This primordial building block must originally have specified the 15-amino-acid-residue-long primordial arm of beta-sheet-forming loops, the characteristics of the beta 2-microglobulin family of polypeptides. PMID:6403948

Gene-based association study of genes linked to hippocampal sclerosis of aging neuropathology: GRN, TMEM106B, ABCC9, and KCNMB2

PubMed Central

Katsumata, Yuriko; Nelson, Peter T.; Ellingson, Sally R.; Fardo, David W.

2017-01-01

Hippocampal sclerosis of aging (HS-Aging) is a common neurodegenerative condition associated with dementia. To learn more about genetic risk of HS-Aging pathology, we tested gene-based associations of the GRN, TMEM106B, ABCC9, and KCNMB2 genes, which were reported to be associated with HS-Aging pathology in previous studies. Genetic data were obtained from the Alzheimer’s Disease Genetics Consortium (ADGC), linked to autopsy-derived neuropathological outcomes from the National Alzheimer’s Coordinating Center (NACC). Of the 3,251 subjects included in the study, 271 (8.3%) were identified as an HS-Aging case. The significant gene-based association between the ABCC9 gene and HS-Aging appeared to be driven by a region in which a significant haplotype-based association was found. We tested this haplotype as an expression Quantitative Trait Locus (eQTL) using two different public-access brain gene expression databases. The HS-Aging pathology protective ABCC9 haplotype was associated with decreased ABCC9 expression, indicating a possible toxic gain of function. PMID:28131462

Gene Discovery of Characteristic Metabolic Pathways in the Tea Plant (Camellia sinensis) Using ‘Omics’-Based Network Approaches: A Future Perspective

PubMed Central

Zhang, Shihua; Zhang, Liang; Tai, Yuling; Wang, Xuewen; Ho, Chi-Tang; Wan, Xiaochun

2018-01-01

Characteristic secondary metabolites, including flavonoids, theanine and caffeine, in the tea plant (Camellia sinensis) are the primary sources of the rich flavors, fresh taste, and health benefits of tea. The decoding of genes involved in these characteristic components is still significantly lagging, which lays an obstacle for applied genetic improvement and metabolic engineering. With the popularity of high-throughout transcriptomics and metabolomics, ‘omics’-based network approaches, such as gene co-expression network and gene-to-metabolite network, have emerged as powerful tools for gene discovery of plant-specialized (secondary) metabolism. Thus, it is pivotal to summarize and introduce such system-based strategies in facilitating gene identification of characteristic metabolic pathways in the tea plant (or other plants). In this review, we describe recent advances in transcriptomics and metabolomics for transcript and metabolite profiling, and highlight ‘omics’-based network strategies using successful examples in model and non-model plants. Further, we summarize recent progress in ‘omics’ analysis for gene identification of characteristic metabolites in the tea plant. Limitations of the current strategies are discussed by comparison with ‘omics’-based network approaches. Finally, we demonstrate the potential of introducing such network strategies in the tea plant, with a prospects ending for a promising network discovery of characteristic metabolite genes in the tea plant. PMID:29915604

Genome-wide and gene-based association implicates FRMD6 in Alzheimer disease.

PubMed

Hong, Mun-Gwan; Reynolds, Chandra A; Feldman, Adina L; Kallin, Mikael; Lambert, Jean-Charles; Amouyel, Philippe; Ingelsson, Erik; Pedersen, Nancy L; Prince, Jonathan A

2012-03-01

Genome-wide association studies (GWAS) that allow for allelic heterogeneity may facilitate the discovery of novel genes not detectable by models that require replication of a single variant site. One strategy to accomplish this is to focus on genes rather than markers as units of association, and so potentially capture a spectrum of causal alleles that differ across populations. Here, we conducted a GWAS of Alzheimer disease (AD) in 2,586 Swedes and performed gene-based meta-analysis with three additional studies from France, Canada, and the United States, in total encompassing 4,259 cases and 8,284 controls. Implementing a newly designed gene-based algorithm, we identified two loci apart from the region around APOE that achieved study-wide significance in combined samples, the strongest finding being for FRMD6 on chromosome 14q (P = 2.6 × 10(-14)) and a weaker signal for NARS2 that is immediately adjacent to GAB2 on chromosome 11q (P = 7.8 × 10(-9)). Ontology-based pathway analyses revealed significant enrichment of genes involved in glycosylation. Results suggest that gene-based approaches that accommodate allelic heterogeneity in GWAS can provide a complementary avenue for gene discovery and may help to explain a portion of the missing heritability not detectable with single nucleotide polymorphisms (SNPs) derived from marker-specific meta-analysis. © 2011 Wiley Periodicals, Inc.

Gene Expression Signatures Based on Variability can Robustly Predict Tumor Progression and Prognosis

PubMed Central

Dinalankara, Wikum; Bravo, Héctor Corrada

2015-01-01

Gene expression signatures are commonly used to create cancer prognosis and diagnosis methods, yet only a small number of them are successfully deployed in the clinic since many fail to replicate performance on subsequent validation. A primary reason for this lack of reproducibility is the fact that these signatures attempt to model the highly variable and unstable genomic behavior of cancer. Our group recently introduced gene expression anti-profiles as a robust methodology to derive gene expression signatures based on the observation that while gene expression measurements are highly heterogeneous across tumors of a specific cancer type relative to the normal tissue, their degree of deviation from normal tissue expression in specific genes involved in tissue differentiation is a stable tumor mark that is reproducible across experiments and cancer types. Here we show that constructing gene expression signatures based on variability and the anti-profile approach yields classifiers capable of successfully distinguishing benign growths from cancerous growths based on deviation from normal expression. We then show that this same approach generates stable and reproducible signatures that predict probability of relapse and survival based on tumor gene expression. These results suggest that using the anti-profile framework for the discovery of genomic signatures is an avenue leading to the development of reproducible signatures suitable for adoption in clinical settings. PMID:26078586

Dynamic association rules for gene expression data analysis.

PubMed

Chen, Shu-Chuan; Tsai, Tsung-Hsien; Chung, Cheng-Han; Li, Wen-Hsiung

2015-10-14

The purpose of gene expression analysis is to look for the association between regulation of gene expression levels and phenotypic variations. This association based on gene expression profile has been used to determine whether the induction/repression of genes correspond to phenotypic variations including cell regulations, clinical diagnoses and drug development. Statistical analyses on microarray data have been developed to resolve gene selection issue. However, these methods do not inform us of causality between genes and phenotypes. In this paper, we propose the dynamic association rule algorithm (DAR algorithm) which helps ones to efficiently select a subset of significant genes for subsequent analysis. The DAR algorithm is based on association rules from market basket analysis in marketing. We first propose a statistical way, based on constructing a one-sided confidence interval and hypothesis testing, to determine if an association rule is meaningful. Based on the proposed statistical method, we then developed the DAR algorithm for gene expression data analysis. The method was applied to analyze four microarray datasets and one Next Generation Sequencing (NGS) dataset: the Mice Apo A1 dataset, the whole genome expression dataset of mouse embryonic stem cells, expression profiling of the bone marrow of Leukemia patients, Microarray Quality Control (MAQC) data set and the RNA-seq dataset of a mouse genomic imprinting study. A comparison of the proposed method with the t-test on the expression profiling of the bone marrow of Leukemia patients was conducted. We developed a statistical way, based on the concept of confidence interval, to determine the minimum support and minimum confidence for mining association relationships among items. With the minimum support and minimum confidence, one can find significant rules in one single step. The DAR algorithm was then developed for gene expression data analysis. Four gene expression datasets showed that the proposed DAR algorithm not only was able to identify a set of differentially expressed genes that largely agreed with that of other methods, but also provided an efficient and accurate way to find influential genes of a disease. In the paper, the well-established association rule mining technique from marketing has been successfully modified to determine the minimum support and minimum confidence based on the concept of confidence interval and hypothesis testing. It can be applied to gene expression data to mine significant association rules between gene regulation and phenotype. The proposed DAR algorithm provides an efficient way to find influential genes that underlie the phenotypic variance.

The cyc1-11 mutation in yeast reverts by recombination with a nonallelic gene: composite genes determining the iso-cytochromes c.

PubMed Central

Ernst, J F; Stewart, J W; Sherman, F

1981-01-01

DNA sequence analysis of a cloned fragment directly established that the cyc1-11 mutation of iso-1-cytochrome c in the yeast Saccharomyces cerevisiae is a two-base-pair substitution that changes the CCA proline codon at amino acid position 76 to a UAA nonsense codon. Analysis of 11 revertant proteins and one cloned revertant gene showed that reversion of the cyc1-11 mutation can occur in three ways: a single base-pair substitution, which produces a serine replacement at position 76; recombination with the nonallelic CYC7 gene of iso-2-cytochrome c, which causes replacement of a segment in the cyc1-11 gene by the corresponding segment of the CYC7 gene; and either a two-base-pair substitution or recombination with the CYC7 gene, which causes the formation of the normal iso-1-cytochrome c sequence. These results demonstrate the occurrence of low frequencies of recombination between nonallelic genes having extensive but not complete homology. The formation of composite genes that share sequences from nonallelic genes may be an evolutionary mechanism for producing protein diversities and for maintaining identical sequences at different loci. Images PMID:6273865

A novel gene delivery composite system based on biodegradable folate-poly (ester amine) polymer and thermosensitive hydrogel for sustained gene release

PubMed Central

Yang, Yi; Zhao, Hang; Jia, YanPeng; Guo, QingFa; Qu, Ying; Su, Jing; Lu, XiaoLing; Zhao, YongXiang; Qian, ZhiYong

2016-01-01

Local anti-oncogene delivery providing high local concentration of gene, increasing antitumor effect and decreasing systemic side effects is currently attracting interest in cancer therapy. In this paper, a novel local sustained anti-oncogene delivery system, PECE thermoresponsive hydrogel containing folate-poly (ester amine) (FA-PEA) polymer/DNA (tumor suppressor) complexes, is demonstrated. First, a tumor-targeted biodegradable folate-poly (ester amine) (FA-PEA) polymer based on low-molecular-weight polyethyleneimine (PEI) was synthesized and characterized, and the application for targeted gene delivery was investigated. The polymer had slight cytotoxicity and high transfection efficiency in vitro compared with PEI 25k, which indicated that FA-PEA was a potential vector for targeted gene delivery. Meanwhile, we successfully prepared a thermoresponsive PECE hydrogel composite containing FA-PEA/DNA complexes which could contain the genes and slowly release the genes into cells. We concluded the folate-poly (ester amine) (FA-PEA) polymer would be useful for targeted gene delivery, and the novel gene delivery composite based on biodegradable folate-poly (ester amine) polymer and thermosensitive PECE hydrogel showed potential for sustained gene release. PMID:26883682

Ontology-based literature mining of E. coli vaccine-associated gene interaction networks.

PubMed

Hur, Junguk; Özgür, Arzucan; He, Yongqun

2017-03-14

Pathogenic Escherichia coli infections cause various diseases in humans and many animal species. However, with extensive E. coli vaccine research, we are still unable to fully protect ourselves against E. coli infections. To more rational development of effective and safe E. coli vaccine, it is important to better understand E. coli vaccine-associated gene interaction networks. In this study, we first extended the Vaccine Ontology (VO) to semantically represent various E. coli vaccines and genes used in the vaccine development. We also normalized E. coli gene names compiled from the annotations of various E. coli strains using a pan-genome-based annotation strategy. The Interaction Network Ontology (INO) includes a hierarchy of various interaction-related keywords useful for literature mining. Using VO, INO, and normalized E. coli gene names, we applied an ontology-based SciMiner literature mining strategy to mine all PubMed abstracts and retrieve E. coli vaccine-associated E. coli gene interactions. Four centrality metrics (i.e., degree, eigenvector, closeness, and betweenness) were calculated for identifying highly ranked genes and interaction types. Using vaccine-related PubMed abstracts, our study identified 11,350 sentences that contain 88 unique INO interactions types and 1,781 unique E. coli genes. Each sentence contained at least one interaction type and two unique E. coli genes. An E. coli gene interaction network of genes and INO interaction types was created. From this big network, a sub-network consisting of 5 E. coli vaccine genes, including carA, carB, fimH, fepA, and vat, and 62 other E. coli genes, and 25 INO interaction types was identified. While many interaction types represent direct interactions between two indicated genes, our study has also shown that many of these retrieved interaction types are indirect in that the two genes participated in the specified interaction process in a required but indirect process. Our centrality analysis of these gene interaction networks identified top ranked E. coli genes and 6 INO interaction types (e.g., regulation and gene expression). Vaccine-related E. coli gene-gene interaction network was constructed using ontology-based literature mining strategy, which identified important E. coli vaccine genes and their interactions with other genes through specific interaction types.

Identification and VIGS-based characterization of Bx1 ortholog in rye (Secale cereale L.)

PubMed Central

Groszyk, Jolanta; Kowalczyk, Mariusz; Yanushevska, Yuliya; Stochmal, Anna; Rakoczy-Trojanowska, Monika

2017-01-01

The first step of the benzoxazinoid (BX) synthesis pathway is catalyzed by an enzyme with indole-3-glycerol phosphate lyase activity encoded by 3 genes, Bx1, TSA and Igl. A gene highly homologous to maize and wheat Bx1 has been identified in rye. The goal of the study was to analyze the gene and to experimentally verify its role in the rye BX biosynthesis pathway as a rye ortholog of the Bx1 gene. Expression of the gene showed peak values 3 days after imbibition (dai) and at 21 dai it was undetectable. Changes of the BX content in leaves were highly correlated with the expression pattern until 21 dai. In plants older than 21 dai despite the undetectable expression of the analyzed gene there was still low accumulation of BXs. Function of the gene was verified by correlating its native expression and virus-induced silencing with BX accumulation. Barley stripe mosaic virus (BSMV)-based vectors were used to induce transcriptional (TGS) and posttranscriptional (PTGS) silencing of the analyzed gene. Both strategies (PTGS and TGS) significantly reduced the transcript level of the analyzed gene, and this was highly correlated with lowered BX content. Inoculation with virus-based vectors specifically induced expression of the analyzed gene, indicating up-regulation by biotic stressors. This is the first report of using the BSMV-based system for functional analysis of rye gene. The findings prove that the analyzed gene is a rye ortholog of the Bx1 gene. Its expression is developmentally regulated and is strongly induced by biotic stress. Stable accumulation of BXs in plants older than 21 dai associated with undetectable expression of ScBx1 indicates that the function of the ScBx1 in the BX biosynthesis is redundant with another gene. We anticipate that the unknown gene is a putative ortholog of the Igl, which still remains to be identified in rye. PMID:28234909

Identification and VIGS-based characterization of Bx1 ortholog in rye (Secale cereale L.).

PubMed

Groszyk, Jolanta; Kowalczyk, Mariusz; Yanushevska, Yuliya; Stochmal, Anna; Rakoczy-Trojanowska, Monika; Orczyk, Waclaw

2017-01-01

The first step of the benzoxazinoid (BX) synthesis pathway is catalyzed by an enzyme with indole-3-glycerol phosphate lyase activity encoded by 3 genes, Bx1, TSA and Igl. A gene highly homologous to maize and wheat Bx1 has been identified in rye. The goal of the study was to analyze the gene and to experimentally verify its role in the rye BX biosynthesis pathway as a rye ortholog of the Bx1 gene. Expression of the gene showed peak values 3 days after imbibition (dai) and at 21 dai it was undetectable. Changes of the BX content in leaves were highly correlated with the expression pattern until 21 dai. In plants older than 21 dai despite the undetectable expression of the analyzed gene there was still low accumulation of BXs. Function of the gene was verified by correlating its native expression and virus-induced silencing with BX accumulation. Barley stripe mosaic virus (BSMV)-based vectors were used to induce transcriptional (TGS) and posttranscriptional (PTGS) silencing of the analyzed gene. Both strategies (PTGS and TGS) significantly reduced the transcript level of the analyzed gene, and this was highly correlated with lowered BX content. Inoculation with virus-based vectors specifically induced expression of the analyzed gene, indicating up-regulation by biotic stressors. This is the first report of using the BSMV-based system for functional analysis of rye gene. The findings prove that the analyzed gene is a rye ortholog of the Bx1 gene. Its expression is developmentally regulated and is strongly induced by biotic stress. Stable accumulation of BXs in plants older than 21 dai associated with undetectable expression of ScBx1 indicates that the function of the ScBx1 in the BX biosynthesis is redundant with another gene. We anticipate that the unknown gene is a putative ortholog of the Igl, which still remains to be identified in rye.

Multiple copies of a bile acid-inducible gene in Eubacterium sp. strain VPI 12708.

PubMed Central

Gopal-Srivastava, R; Mallonee, D H; White, W B; Hylemon, P B

1990-01-01

Eubacterium sp. strain VPI 12708 is an anaerobic intestinal bacterium which possesses inducible bile acid 7-dehydroxylation activity. Several new polypeptides are produced in this strain following induction with cholic acid. Genes coding for two copies of a bile acid-inducible 27,000-dalton polypeptide (baiA1 and baiA2) have been previously cloned and sequenced. We now report on a gene coding for a third copy of this 27,000-dalton polypeptide (baiA3). The baiA3 gene has been cloned in lambda DASH on an 11.2-kilobase DNA fragment from a partial Sau3A digest of the Eubacterium DNA. DNA sequence analysis of the baiA3 gene revealed 100% homology with the baiA1 gene within the coding region of the 27,000-dalton polypeptides. The baiA2 gene shares 81% sequence identity with the other two genes at the nucleotide level. The flanking nucleotide sequences associated with the baiA1 and baiA3 genes are identical for 930 bases in the 5' direction from the initiation codon and for at least 325 bases in the 3' direction from the stop codon, including the putative promoter regions for the genes. An additional open reading frame (occupying from 621 to 648 bases, depending on the correct start codon) was found in the identical 5' regions associated with the baiA1 and baiA3 clones. The 5' sequence 930 bases upstream from the baiA1 and baiA3 genes was totally divergent. The baiA2 gene, which is part of a large bile acid-inducible operon, showed no homology with the other two genes either in the 5' or 3' direction from the polypeptide coding region, except for a 15-base-pair presumed ribosome-binding site in the 5' region. These studies strongly suggest that a gene duplication (baiA1 and baiA3) has occurred and is stably maintained in this bacterium. Images PMID:2376563

Multiconstrained gene clustering based on generalized projections

PubMed Central

2010-01-01

Background Gene clustering for annotating gene functions is one of the fundamental issues in bioinformatics. The best clustering solution is often regularized by multiple constraints such as gene expressions, Gene Ontology (GO) annotations and gene network structures. How to integrate multiple pieces of constraints for an optimal clustering solution still remains an unsolved problem. Results We propose a novel multiconstrained gene clustering (MGC) method within the generalized projection onto convex sets (POCS) framework used widely in image reconstruction. Each constraint is formulated as a corresponding set. The generalized projector iteratively projects the clustering solution onto these sets in order to find a consistent solution included in the intersection set that satisfies all constraints. Compared with previous MGC methods, POCS can integrate multiple constraints from different nature without distorting the original constraints. To evaluate the clustering solution, we also propose a new performance measure referred to as Gene Log Likelihood (GLL) that considers genes having more than one function and hence in more than one cluster. Comparative experimental results show that our POCS-based gene clustering method outperforms current state-of-the-art MGC methods. Conclusions The POCS-based MGC method can successfully combine multiple constraints from different nature for gene clustering. Also, the proposed GLL is an effective performance measure for the soft clustering solutions. PMID:20356386

Integrative structural annotation of de novo RNA-Seq provides an accurate reference gene set of the enormous genome of the onion (Allium cepa L.)

PubMed Central

Kim, Seungill; Kim, Myung-Shin; Kim, Yong-Min; Yeom, Seon-In; Cheong, Kyeongchae; Kim, Ki-Tae; Jeon, Jongbum; Kim, Sunggil; Kim, Do-Sun; Sohn, Seong-Han; Lee, Yong-Hwan; Choi, Doil

2015-01-01

The onion (Allium cepa L.) is one of the most widely cultivated and consumed vegetable crops in the world. Although a considerable amount of onion transcriptome data has been deposited into public databases, the sequences of the protein-coding genes are not accurate enough to be used, owing to non-coding sequences intermixed with the coding sequences. We generated a high-quality, annotated onion transcriptome from de novo sequence assembly and intensive structural annotation using the integrated structural gene annotation pipeline (ISGAP), which identified 54,165 protein-coding genes among 165,179 assembled transcripts totalling 203.0 Mb by eliminating the intron sequences. ISGAP performed reliable annotation, recognizing accurate gene structures based on reference proteins, and ab initio gene models of the assembled transcripts. Integrative functional annotation and gene-based SNP analysis revealed a whole biological repertoire of genes and transcriptomic variation in the onion. The method developed in this study provides a powerful tool for the construction of reference gene sets for organisms based solely on de novo transcriptome data. Furthermore, the reference genes and their variation described here for the onion represent essential tools for molecular breeding and gene cloning in Allium spp. PMID:25362073

Analysis of genetic association using hierarchical clustering and cluster validation indices.

PubMed

Pagnuco, Inti A; Pastore, Juan I; Abras, Guillermo; Brun, Marcel; Ballarin, Virginia L

2017-10-01

It is usually assumed that co-expressed genes suggest co-regulation in the underlying regulatory network. Determining sets of co-expressed genes is an important task, based on some criteria of similarity. This task is usually performed by clustering algorithms, where the genes are clustered into meaningful groups based on their expression values in a set of experiment. In this work, we propose a method to find sets of co-expressed genes, based on cluster validation indices as a measure of similarity for individual gene groups, and a combination of variants of hierarchical clustering to generate the candidate groups. We evaluated its ability to retrieve significant sets on simulated correlated and real genomics data, where the performance is measured based on its detection ability of co-regulated sets against a full search. Additionally, we analyzed the quality of the best ranked groups using an online bioinformatics tool that provides network information for the selected genes. Copyright © 2017 Elsevier Inc. All rights reserved.

Gene Selection and Cancer Classification: A Rough Sets Based Approach

NASA Astrophysics Data System (ADS)

Sun, Lijun; Miao, Duoqian; Zhang, Hongyun

Indentification of informative gene subsets responsible for discerning between available samples of gene expression data is an important task in bioinformatics. Reducts, from rough sets theory, corresponding to a minimal set of essential genes for discerning samples, is an efficient tool for gene selection. Due to the compuational complexty of the existing reduct algoritms, feature ranking is usually used to narrow down gene space as the first step and top ranked genes are selected . In this paper,we define a novel certierion based on the expression level difference btween classes and contribution to classification of the gene for scoring genes and present a algorithm for generating all possible reduct from informative genes.The algorithm takes the whole attribute sets into account and find short reduct with a significant reduction in computational complexity. An exploration of this approach on benchmark gene expression data sets demonstrates that this approach is successful for selecting high discriminative genes and the classification accuracy is impressive.

Efficient Exploration of the Space of Reconciled Gene Trees

PubMed Central

Szöllősi, Gergely J.; Rosikiewicz, Wojciech; Boussau, Bastien; Tannier, Eric; Daubin, Vincent

2013-01-01

Gene trees record the combination of gene-level events, such as duplication, transfer and loss (DTL), and species-level events, such as speciation and extinction. Gene tree–species tree reconciliation methods model these processes by drawing gene trees into the species tree using a series of gene and species-level events. The reconstruction of gene trees based on sequence alone almost always involves choosing between statistically equivalent or weakly distinguishable relationships that could be much better resolved based on a putative species tree. To exploit this potential for accurate reconstruction of gene trees, the space of reconciled gene trees must be explored according to a joint model of sequence evolution and gene tree–species tree reconciliation. Here we present amalgamated likelihood estimation (ALE), a probabilistic approach to exhaustively explore all reconciled gene trees that can be amalgamated as a combination of clades observed in a sample of gene trees. We implement the ALE approach in the context of a reconciliation model (Szöllősi et al. 2013), which allows for the DTL of genes. We use ALE to efficiently approximate the sum of the joint likelihood over amalgamations and to find the reconciled gene tree that maximizes the joint likelihood among all such trees. We demonstrate using simulations that gene trees reconstructed using the joint likelihood are substantially more accurate than those reconstructed using sequence alone. Using realistic gene tree topologies, branch lengths, and alignment sizes, we demonstrate that ALE produces more accurate gene trees even if the model of sequence evolution is greatly simplified. Finally, examining 1099 gene families from 36 cyanobacterial genomes we find that joint likelihood-based inference results in a striking reduction in apparent phylogenetic discord, with respectively. 24%, 59%, and 46% reductions in the mean numbers of duplications, transfers, and losses per gene family. The open source implementation of ALE is available from https://github.com/ssolo/ALE.git. [amalgamation; gene tree reconciliation; gene tree reconstruction; lateral gene transfer; phylogeny.] PMID:23925510

A Weighted Multipath Measurement Based on Gene Ontology for Estimating Gene Products Similarity

PubMed Central

Liu, Lizhen; Dai, Xuemin; Song, Wei; Lu, Jingli

2014-01-01

Abstract Many different methods have been proposed for calculating the semantic similarity of term pairs based on gene ontology (GO). Most existing methods are based on information content (IC), and the methods based on IC are used more commonly than those based on the structure of GO. However, most IC-based methods not only fail to handle identical annotations but also show a strong bias toward well-annotated proteins. We propose a new method called weighted multipath measurement (WMM) for estimating the semantic similarity of gene products based on the structure of the GO. We not only considered the contribution of every path between two GO terms but also took the depth of the lowest common ancestors into account. We assigned different weights for different kinds of edges in GO graph. The similarity values calculated by WMM can be reused because they are only relative to the characteristics of GO terms. Experimental results showed that the similarity values obtained by WMM have a higher accuracy. We compared the performance of WMM with that of other methods using GO data and gene annotation datasets for yeast and humans downloaded from the GO database. We found that WMM is more suited for prediction of gene function than most existing IC-based methods and that it can distinguish proteins with identical annotations (two proteins are annotated with the same terms) from each other. PMID:25229994

Functional clustering of time series gene expression data by Granger causality

PubMed Central

2012-01-01

Background A common approach for time series gene expression data analysis includes the clustering of genes with similar expression patterns throughout time. Clustered gene expression profiles point to the joint contribution of groups of genes to a particular cellular process. However, since genes belong to intricate networks, other features, besides comparable expression patterns, should provide additional information for the identification of functionally similar genes. Results In this study we perform gene clustering through the identification of Granger causality between and within sets of time series gene expression data. Granger causality is based on the idea that the cause of an event cannot come after its consequence. Conclusions This kind of analysis can be used as a complementary approach for functional clustering, wherein genes would be clustered not solely based on their expression similarity but on their topological proximity built according to the intensity of Granger causality among them. PMID:23107425

Finding gene regulatory network candidates using the gene expression knowledge base.

PubMed

Venkatesan, Aravind; Tripathi, Sushil; Sanz de Galdeano, Alejandro; Blondé, Ward; Lægreid, Astrid; Mironov, Vladimir; Kuiper, Martin

2014-12-10

Network-based approaches for the analysis of large-scale genomics data have become well established. Biological networks provide a knowledge scaffold against which the patterns and dynamics of 'omics' data can be interpreted. The background information required for the construction of such networks is often dispersed across a multitude of knowledge bases in a variety of formats. The seamless integration of this information is one of the main challenges in bioinformatics. The Semantic Web offers powerful technologies for the assembly of integrated knowledge bases that are computationally comprehensible, thereby providing a potentially powerful resource for constructing biological networks and network-based analysis. We have developed the Gene eXpression Knowledge Base (GeXKB), a semantic web technology based resource that contains integrated knowledge about gene expression regulation. To affirm the utility of GeXKB we demonstrate how this resource can be exploited for the identification of candidate regulatory network proteins. We present four use cases that were designed from a biological perspective in order to find candidate members relevant for the gastrin hormone signaling network model. We show how a combination of specific query definitions and additional selection criteria derived from gene expression data and prior knowledge concerning candidate proteins can be used to retrieve a set of proteins that constitute valid candidates for regulatory network extensions. Semantic web technologies provide the means for processing and integrating various heterogeneous information sources. The GeXKB offers biologists such an integrated knowledge resource, allowing them to address complex biological questions pertaining to gene expression. This work illustrates how GeXKB can be used in combination with gene expression results and literature information to identify new potential candidates that may be considered for extending a gene regulatory network.

Systematic prediction of gene function in Arabidopsis thaliana using a probabilistic functional gene network

PubMed Central

Hwang, Sohyun; Rhee, Seung Y; Marcotte, Edward M; Lee, Insuk

2012-01-01

AraNet is a functional gene network for the reference plant Arabidopsis and has been constructed in order to identify new genes associated with plant traits. It is highly predictive for diverse biological pathways and can be used to prioritize genes for functional screens. Moreover, AraNet provides a web-based tool with which plant biologists can efficiently discover novel functions of Arabidopsis genes (http://www.functionalnet.org/aranet/). This protocol explains how to conduct network-based prediction of gene functions using AraNet and how to interpret the prediction results. Functional discovery in plant biology is facilitated by combining candidate prioritization by AraNet with focused experimental tests. PMID:21886106

Complete mitochondrial genome of Zeugodacus tau (Insecta: Tephritidae) and differentiation of Z. tau species complex by mitochondrial cytochrome c oxidase subunit I gene

PubMed Central

Yong, Hoi-Sen; Lim, Phaik-Eem; Eamsobhana, Praphathip

2017-01-01

The tephritid fruit fly Zeugodacus tau (Walker) is a polyphagous fruit pest of economic importance in Asia. Studies based on genetic markers indicate that it forms a species complex. We report here (1) the complete mitogenome of Z. tau from Malaysia and comparison with that of China as well as the mitogenome of other congeners, and (2) the relationship of Z. tau taxa from different geographical regions based on sequences of cytochrome c oxidase subunit I gene. The complete mitogenome of Z. tau had a total length of 15631 bp for the Malaysian specimen (ZT3) and 15835 bp for the China specimen (ZT1), with similar gene order comprising 37 genes (13 protein-coding genes—PCGs, 2 rRNA genes, and 22 tRNA genes) and a non-coding A + T-rich control region (D-loop). Based on 13 PCGs and 15 mt-genes, Z. tau NC_027290 (China) and Z. tau ZT1 (China) formed a sister group in the lineage containing also Z. tau ZT3 (Malaysia). Phylogenetic analysis based on partial sequences of cox1 gene indicates that the taxa from China, Japan, Laos, Malaysia, Bangladesh, India, Sri Lanka, and Z. tau sp. A from Thailand belong to Z. tau sensu stricto. A complete cox1 gene (or 13 PCGs or 15 mt-genes) instead of partial sequence is more appropriate for determining phylogenetic relationship. PMID:29216281

Gene-based rare allele analysis identified a risk gene of Alzheimer's disease.

PubMed

Kim, Jong Hun; Song, Pamela; Lim, Hyunsun; Lee, Jae-Hyung; Lee, Jun Hong; Park, Sun Ah

2014-01-01

Alzheimer's disease (AD) has a strong propensity to run in families. However, the known risk genes excluding APOE are not clinically useful. In various complex diseases, gene studies have targeted rare alleles for unsolved heritability. Our study aims to elucidate previously unknown risk genes for AD by targeting rare alleles. We used data from five publicly available genetic studies from the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the database of Genotypes and Phenotypes (dbGaP). A total of 4,171 cases and 9,358 controls were included. The genotype information of rare alleles was imputed using 1,000 genomes. We performed gene-based analysis of rare alleles (minor allele frequency≤3%). The genome-wide significance level was defined as meta P<1.8×10(-6) (0.05/number of genes in human genome = 0.05/28,517). ZNF628, which is located at chromosome 19q13.42, showed a genome-wide significant association with AD. The association of ZNF628 with AD was not dependent on APOE ε4. APOE and TREM2 were also significantly associated with AD, although not at genome-wide significance levels. Other genes identified by targeting common alleles could not be replicated in our gene-based rare allele analysis. We identified that rare variants in ZNF628 are associated with AD. The protein encoded by ZNF628 is known as a transcription factor. Furthermore, the associations of APOE and TREM2 with AD were highly significant, even in gene-based rare allele analysis, which implies that further deep sequencing of these genes is required in AD heritability studies.

Inference of combinatorial Boolean rules of synergistic gene sets from cancer microarray datasets.

PubMed

Park, Inho; Lee, Kwang H; Lee, Doheon

2010-06-15

Gene set analysis has become an important tool for the functional interpretation of high-throughput gene expression datasets. Moreover, pattern analyses based on inferred gene set activities of individual samples have shown the ability to identify more robust disease signatures than individual gene-based pattern analyses. Although a number of approaches have been proposed for gene set-based pattern analysis, the combinatorial influence of deregulated gene sets on disease phenotype classification has not been studied sufficiently. We propose a new approach for inferring combinatorial Boolean rules of gene sets for a better understanding of cancer transcriptome and cancer classification. To reduce the search space of the possible Boolean rules, we identify small groups of gene sets that synergistically contribute to the classification of samples into their corresponding phenotypic groups (such as normal and cancer). We then measure the significance of the candidate Boolean rules derived from each group of gene sets; the level of significance is based on the class entropy of the samples selected in accordance with the rules. By applying the present approach to publicly available prostate cancer datasets, we identified 72 significant Boolean rules. Finally, we discuss several identified Boolean rules, such as the rule of glutathione metabolism (down) and prostaglandin synthesis regulation (down), which are consistent with known prostate cancer biology. Scripts written in Python and R are available at http://biosoft.kaist.ac.kr/~ihpark/. The refined gene sets and the full list of the identified Boolean rules are provided in the Supplementary Material. Supplementary data are available at Bioinformatics online.

[Phylogenetic and diversity analysis of Acidithiobacillus spp. based on 16S rRNA and RubisCO genes homologues].

PubMed

Liu, Minrui; Lin, Pengwu; Qi, Xing'e; Ni, Yongqing

2016-04-14

The purpose of the study was to reveal geographic region-related Acidithiobacillus spp. distribution and allopatric speciation. Phylogenetic and diversity analysis was done to expand our knowledge on microbial phylogeography, diversity-maintaining mechanisms and molecular biogeography. We amplified 16S rRNA gene and RubisCO genes to construct corresponding phylogenetic trees based on the sequence homology and analyzed genetic diversity of Acidithiobacillus spp.. Thirty-five strains were isolated from three different regions in China (Yunnan, Hubei, Xinjiang). The whole isolates were classified into five groups. Four strains were identified as A. ferrivorans, six as A. ferridurans, YNTR4-15 Leptspirillum ferrooxidans and HBDY3-31 as Leptospirillum ferrodiazotrophum. The remaining strains were identified as A. ferrooxidans. Analysis of cbbL and cbbM genes sequences of representative 26 strains indicated that cbbL gene of 19 were two copies (cbbL1 and cbbL2) and 7 possessed only cbbL1. cbbM gene was single copy. In nucleotide-based trees, cbbL1 gene sequences of strains were separated into three sequence types, and the cbbL2 was similar to cbbL1 with three types. Codon bias of RubisCO genes was not obvious in Acidithiobacillus spp.. Strains isolated from three different regions in China indicated a great genetic diversity in Acidithiobacillus spp. and their 16S rRNA/RubisCO genes sequence was of significant difference. Phylogenetic tree based on 16S rRNA genes and RubisCO genes was different in Acidithiobacillus spp..

confFuse: High-Confidence Fusion Gene Detection across Tumor Entities.

PubMed

Huang, Zhiqin; Jones, David T W; Wu, Yonghe; Lichter, Peter; Zapatka, Marc

2017-01-01

Background: Fusion genes play an important role in the tumorigenesis of many cancers. Next-generation sequencing (NGS) technologies have been successfully applied in fusion gene detection for the last several years, and a number of NGS-based tools have been developed for identifying fusion genes during this period. Most fusion gene detection tools based on RNA-seq data report a large number of candidates (mostly false positives), making it hard to prioritize candidates for experimental validation and further analysis. Selection of reliable fusion genes for downstream analysis becomes very important in cancer research. We therefore developed confFuse, a scoring algorithm to reliably select high-confidence fusion genes which are likely to be biologically relevant. Results: confFuse takes multiple parameters into account in order to assign each fusion candidate a confidence score, of which score ≥8 indicates high-confidence fusion gene predictions. These parameters were manually curated based on our experience and on certain structural motifs of fusion genes. Compared with alternative tools, based on 96 published RNA-seq samples from different tumor entities, our method can significantly reduce the number of fusion candidates (301 high-confidence from 8,083 total predicted fusion genes) and keep high detection accuracy (recovery rate 85.7%). Validation of 18 novel, high-confidence fusions detected in three breast tumor samples resulted in a 100% validation rate. Conclusions: confFuse is a novel downstream filtering method that allows selection of highly reliable fusion gene candidates for further downstream analysis and experimental validations. confFuse is available at https://github.com/Zhiqin-HUANG/confFuse.

Random forests-based differential analysis of gene sets for gene expression data.

PubMed

Hsueh, Huey-Miin; Zhou, Da-Wei; Tsai, Chen-An

2013-04-10

In DNA microarray studies, gene-set analysis (GSA) has become the focus of gene expression data analysis. GSA utilizes the gene expression profiles of functionally related gene sets in Gene Ontology (GO) categories or priori-defined biological classes to assess the significance of gene sets associated with clinical outcomes or phenotypes. Many statistical approaches have been proposed to determine whether such functionally related gene sets express differentially (enrichment and/or deletion) in variations of phenotypes. However, little attention has been given to the discriminatory power of gene sets and classification of patients. In this study, we propose a method of gene set analysis, in which gene sets are used to develop classifications of patients based on the Random Forest (RF) algorithm. The corresponding empirical p-value of an observed out-of-bag (OOB) error rate of the classifier is introduced to identify differentially expressed gene sets using an adequate resampling method. In addition, we discuss the impacts and correlations of genes within each gene set based on the measures of variable importance in the RF algorithm. Significant classifications are reported and visualized together with the underlying gene sets and their contribution to the phenotypes of interest. Numerical studies using both synthesized data and a series of publicly available gene expression data sets are conducted to evaluate the performance of the proposed methods. Compared with other hypothesis testing approaches, our proposed methods are reliable and successful in identifying enriched gene sets and in discovering the contributions of genes within a gene set. The classification results of identified gene sets can provide an valuable alternative to gene set testing to reveal the unknown, biologically relevant classes of samples or patients. In summary, our proposed method allows one to simultaneously assess the discriminatory ability of gene sets and the importance of genes for interpretation of data in complex biological systems. The classifications of biologically defined gene sets can reveal the underlying interactions of gene sets associated with the phenotypes, and provide an insightful complement to conventional gene set analyses. Copyright © 2012 Elsevier B.V. All rights reserved.

Benzaldehyde Schiff bases regulation to the metabolism, hemolysis, and virulence genes expression in vitro and their structure-microbicidal activity relationship.

PubMed

Xia, Lei; Xia, Yu-Fen; Huang, Li-Rong; Xiao, Xiao; Lou, Hua-Yong; Liu, Tang-Jingjun; Pan, Wei-Dong; Luo, Heng

2015-06-05

There is an urgent need to develop new antibacterial agents because of multidrug resistance by bacteria and fungi. Schiff bases (aldehyde or ketone-like compounds) exhibit intense antibacterial characteristics, and are therefore, promising candidates as antibacterial agents. To investigate the mechanism of action of newly designed benzaldehyde Schiff bases, a series of high-yielding benzaldehyde Schiff bases were synthesized, and their structures were determined by NMR and MS spectra data. The structure-microbicidal activity relationship of derivatives was investigated, and the antibacterial mechanisms were investigated by gene assays for the expression of functional genes in vitro using Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. The active compounds were selective for certain active groups. The polar substitution of the R2 group of the amino acids in the Schiff bases, affected the antibacterial activity against E. coli and S. aureus; specific active group at the R3 or R4 groups of the acylhydrazone Schiff bases could improve their inhibitory activity against these three tested organisms. The antibacterial mechanism of the active benzaldehyde Schiff bases appeared to regulate the expression of metabolism-associated genes in E. coli, hemolysis-associated genes in B. subtilis, and key virulence genes in S. aureus. Some benzaldehyde Schiff bases were bactericidal to all the three strains and appeared to regulate gene expression associated with metabolism, hemolysis, and virulence, in vitro. The newly designed benzaldehyde Schiff bases possessed unique antibacterial activity and might be potentially useful for prophylactic or therapeutic intervention of bacterial infections. Copyright © 2015. Published by Elsevier Masson SAS.

Constructing an integrated gene similarity network for the identification of disease genes.

PubMed

Tian, Zhen; Guo, Maozu; Wang, Chunyu; Xing, LinLin; Wang, Lei; Zhang, Yin

2017-09-20

Discovering novel genes that are involved human diseases is a challenging task in biomedical research. In recent years, several computational approaches have been proposed to prioritize candidate disease genes. Most of these methods are mainly based on protein-protein interaction (PPI) networks. However, since these PPI networks contain false positives and only cover less half of known human genes, their reliability and coverage are very low. Therefore, it is highly necessary to fuse multiple genomic data to construct a credible gene similarity network and then infer disease genes on the whole genomic scale. We proposed a novel method, named RWRB, to infer causal genes of interested diseases. First, we construct five individual gene (protein) similarity networks based on multiple genomic data of human genes. Then, an integrated gene similarity network (IGSN) is reconstructed based on similarity network fusion (SNF) method. Finally, we employee the random walk with restart algorithm on the phenotype-gene bilayer network, which combines phenotype similarity network, IGSN as well as phenotype-gene association network, to prioritize candidate disease genes. We investigate the effectiveness of RWRB through leave-one-out cross-validation methods in inferring phenotype-gene relationships. Results show that RWRB is more accurate than state-of-the-art methods on most evaluation metrics. Further analysis shows that the success of RWRB is benefited from IGSN which has a wider coverage and higher reliability comparing with current PPI networks. Moreover, we conduct a comprehensive case study for Alzheimer's disease and predict some novel disease genes that supported by literature. RWRB is an effective and reliable algorithm in prioritizing candidate disease genes on the genomic scale. Software and supplementary information are available at http://nclab.hit.edu.cn/~tianzhen/RWRB/ .

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Jing; Ma, Zihao; Carr, Steven A.

Coexpression of mRNAs under multiple conditions is commonly used to infer cofunctionality of their gene products despite well-known limitations of this “guilt-by-association” (GBA) approach. Recent advancements in mass spectrometry-based proteomic technologies have enabled global expression profiling at the protein level; however, whether proteome profiling data can outperform transcriptome profiling data for coexpression based gene function prediction has not been systematically investigated. Here, we address this question by constructing and analyzing mRNA and protein coexpression networks for three cancer types with matched mRNA and protein profiling data from The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC).more » Our analyses revealed a marked difference in wiring between the mRNA and protein coexpression networks. Whereas protein coexpression was driven primarily by functional similarity between coexpressed genes, mRNA coexpression was driven by both cofunction and chromosomal colocalization of the genes. Functionally coherent mRNA modules were more likely to have their edges preserved in corresponding protein networks than functionally incoherent mRNA modules. Proteomic data strengthened the link between gene expression and function for at least 75% of Gene Ontology (GO) biological processes and 90% of KEGG pathways. A web application Gene2Net (http://cptac.gene2net.org) developed based on the three protein coexpression networks revealed novel gene-function relationships, such as linking ERBB2 (HER2) to lipid biosynthetic process in breast cancer, identifying PLG as a new gene involved in complement activation, and identifying AEBP1 as a new epithelial-mesenchymal transition (EMT) marker. Our results demonstrate that proteome profiling outperforms transcriptome profiling for coexpression based gene function prediction. Proteomics should be integrated if not preferred in gene function and human disease studies. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.060301, 121–134, 2017.« less

Query-based biclustering of gene expression data using Probabilistic Relational Models.

PubMed

Zhao, Hui; Cloots, Lore; Van den Bulcke, Tim; Wu, Yan; De Smet, Riet; Storms, Valerie; Meysman, Pieter; Engelen, Kristof; Marchal, Kathleen

2011-02-15

With the availability of large scale expression compendia it is now possible to view own findings in the light of what is already available and retrieve genes with an expression profile similar to a set of genes of interest (i.e., a query or seed set) for a subset of conditions. To that end, a query-based strategy is needed that maximally exploits the coexpression behaviour of the seed genes to guide the biclustering, but that at the same time is robust against the presence of noisy genes in the seed set as seed genes are often assumed, but not guaranteed to be coexpressed in the queried compendium. Therefore, we developed ProBic, a query-based biclustering strategy based on Probabilistic Relational Models (PRMs) that exploits the use of prior distributions to extract the information contained within the seed set. We applied ProBic on a large scale Escherichia coli compendium to extend partially described regulons with potentially novel members. We compared ProBic's performance with previously published query-based biclustering algorithms, namely ISA and QDB, from the perspective of bicluster expression quality, robustness of the outcome against noisy seed sets and biological relevance.This comparison learns that ProBic is able to retrieve biologically relevant, high quality biclusters that retain their seed genes and that it is particularly strong in handling noisy seeds. ProBic is a query-based biclustering algorithm developed in a flexible framework, designed to detect biologically relevant, high quality biclusters that retain relevant seed genes even in the presence of noise or when dealing with low quality seed sets.

A cluster merging method for time series microarray with production values.

PubMed

Chira, Camelia; Sedano, Javier; Camara, Monica; Prieto, Carlos; Villar, Jose R; Corchado, Emilio

2014-09-01

A challenging task in time-course microarray data analysis is to cluster genes meaningfully combining the information provided by multiple replicates covering the same key time points. This paper proposes a novel cluster merging method to accomplish this goal obtaining groups with highly correlated genes. The main idea behind the proposed method is to generate a clustering starting from groups created based on individual temporal series (representing different biological replicates measured in the same time points) and merging them by taking into account the frequency by which two genes are assembled together in each clustering. The gene groups at the level of individual time series are generated using several shape-based clustering methods. This study is focused on a real-world time series microarray task with the aim to find co-expressed genes related to the production and growth of a certain bacteria. The shape-based clustering methods used at the level of individual time series rely on identifying similar gene expression patterns over time which, in some models, are further matched to the pattern of production/growth. The proposed cluster merging method is able to produce meaningful gene groups which can be naturally ranked by the level of agreement on the clustering among individual time series. The list of clusters and genes is further sorted based on the information correlation coefficient and new problem-specific relevant measures. Computational experiments and results of the cluster merging method are analyzed from a biological perspective and further compared with the clustering generated based on the mean value of time series and the same shape-based algorithm.

MorphDB: Prioritizing Genes for Specialized Metabolism Pathways and Gene Ontology Categories in Plants.

PubMed

Zwaenepoel, Arthur; Diels, Tim; Amar, David; Van Parys, Thomas; Shamir, Ron; Van de Peer, Yves; Tzfadia, Oren

2018-01-01

Recent times have seen an enormous growth of "omics" data, of which high-throughput gene expression data are arguably the most important from a functional perspective. Despite huge improvements in computational techniques for the functional classification of gene sequences, common similarity-based methods often fall short of providing full and reliable functional information. Recently, the combination of comparative genomics with approaches in functional genomics has received considerable interest for gene function analysis, leveraging both gene expression based guilt-by-association methods and annotation efforts in closely related model organisms. Besides the identification of missing genes in pathways, these methods also typically enable the discovery of biological regulators (i.e., transcription factors or signaling genes). A previously built guilt-by-association method is MORPH, which was proven to be an efficient algorithm that performs particularly well in identifying and prioritizing missing genes in plant metabolic pathways. Here, we present MorphDB, a resource where MORPH-based candidate genes for large-scale functional annotations (Gene Ontology, MapMan bins) are integrated across multiple plant species. Besides a gene centric query utility, we present a comparative network approach that enables researchers to efficiently browse MORPH predictions across functional gene sets and species, facilitating efficient gene discovery and candidate gene prioritization. MorphDB is available at http://bioinformatics.psb.ugent.be/webtools/morphdb/morphDB/index/. We also provide a toolkit, named "MORPH bulk" (https://github.com/arzwa/morph-bulk), for running MORPH in bulk mode on novel data sets, enabling researchers to apply MORPH to their own species of interest.

SomInaClust: detection of cancer genes based on somatic mutation patterns of inactivation and clustering.

PubMed

Van den Eynden, Jimmy; Fierro, Ana Carolina; Verbeke, Lieven P C; Marchal, Kathleen

2015-04-23

With the advances in high throughput technologies, increasing amounts of cancer somatic mutation data are being generated and made available. Only a small number of (driver) mutations occur in driver genes and are responsible for carcinogenesis, while the majority of (passenger) mutations do not influence tumour biology. In this study, SomInaClust is introduced, a method that accurately identifies driver genes based on their mutation pattern across tumour samples and then classifies them into oncogenes or tumour suppressor genes respectively. SomInaClust starts from the observation that oncogenes mainly contain mutations that, due to positive selection, cluster at similar positions in a gene across patient samples, whereas tumour suppressor genes contain a high number of protein-truncating mutations throughout the entire gene length. The method was shown to prioritize driver genes in 9 different solid cancers. Furthermore it was found to be complementary to existing similar-purpose methods with the additional advantages that it has a higher sensitivity, also for rare mutations (occurring in less than 1% of all samples), and it accurately classifies candidate driver genes in putative oncogenes and tumour suppressor genes. Pathway enrichment analysis showed that the identified genes belong to known cancer signalling pathways, and that the distinction between oncogenes and tumour suppressor genes is biologically relevant. SomInaClust was shown to detect candidate driver genes based on somatic mutation patterns of inactivation and clustering and to distinguish oncogenes from tumour suppressor genes. The method could be used for the identification of new cancer genes or to filter mutation data for further data-integration purposes.

Cloning, sequencing and characterization of lipase genes from a polyhydroxyalkanoate- (PHA-) synthesizing Pseudomonas resinovorans

USDA-ARS?s Scientific Manuscript database

Lipase (lip) and lipase-specific foldase (lif) genes of a biodegradable polyhydroxyalkanoate- (PHA-) synthesizing Pseudomonas resinovorans NRRL B-2649 were cloned using primers based on consensus sequences, followed by PCR-based genome walking. Sequence analyses showed a putative Lip gene-product (...

Avirulence (AVR) Gene-Based Diagnosis Complements Existing Pathogen Surveillance Tools for Effective Deployment of Resistance (R) Genes Against Rice Blast Disease.

PubMed

Selisana, S M; Yanoria, M J; Quime, B; Chaipanya, C; Lu, G; Opulencia, R; Wang, G-L; Mitchell, T; Correll, J; Talbot, N J; Leung, H; Zhou, B

2017-06-01

Avirulence (AVR) genes in Magnaporthe oryzae, the fungal pathogen that causes the devastating rice blast disease, have been documented to be major targets subject to mutations to avoid recognition by resistance (R) genes. In this study, an AVR-gene-based diagnosis tool for determining the virulence spectrum of a rice blast pathogen population was developed and validated. A set of 77 single-spore field isolates was subjected to pathotype analysis using differential lines, each containing a single R gene, and classified into 20 virulent pathotypes, except for 4 isolates that lost pathogenicity. In all, 10 differential lines showed low frequency (<24%) of resistance whereas 8 lines showed a high frequency (>95%), inferring the effectiveness of R genes present in the respective differential lines. In addition, the haplotypes of seven AVR genes were determined by polymerase chain reaction amplification and sequencing, if applicable. The calculated frequency of different AVR genes displayed significant variations in the population. AVRPiz-t and AVR-Pii were detected in 100 and 84.9% of the isolates, respectively. Five AVR genes such as AVR-Pik-D (20.5%) and AVR-Pik-E (1.4%), AVRPiz-t (2.7%), AVR-Pita (0%), AVR-Pia (0%), and AVR1-CO39 (0%) displayed low or even zero frequency. The frequency of AVR genes correlated almost perfectly with the resistance frequency of the cognate R genes in differential lines, except for International Rice Research Institute-bred blast-resistant lines IRBLzt-T, IRBLta-K1, and IRBLkp-K60. Both genetic analysis and molecular marker validation revealed an additional R gene, most likely Pi19 or its allele, in these three differential lines. This can explain the spuriously higher resistance frequency of each target R gene based on conventional pathotyping. This study demonstrates that AVR-gene-based diagnosis provides a precise, R-gene-specific, and differential line-free assessment method that can be used for determining the virulence spectrum of a rice blast pathogen population and for predicting the effectiveness of target R genes in rice varieties.

Inferring gene dependency network specific to phenotypic alteration based on gene expression data and clinical information of breast cancer.

PubMed

Zhou, Xionghui; Liu, Juan

2014-01-01

Although many methods have been proposed to reconstruct gene regulatory network, most of them, when applied in the sample-based data, can not reveal the gene regulatory relations underlying the phenotypic change (e.g. normal versus cancer). In this paper, we adopt phenotype as a variable when constructing the gene regulatory network, while former researches either neglected it or only used it to select the differentially expressed genes as the inputs to construct the gene regulatory network. To be specific, we integrate phenotype information with gene expression data to identify the gene dependency pairs by using the method of conditional mutual information. A gene dependency pair (A,B) means that the influence of gene A on the phenotype depends on gene B. All identified gene dependency pairs constitute a directed network underlying the phenotype, namely gene dependency network. By this way, we have constructed gene dependency network of breast cancer from gene expression data along with two different phenotype states (metastasis and non-metastasis). Moreover, we have found the network scale free, indicating that its hub genes with high out-degrees may play critical roles in the network. After functional investigation, these hub genes are found to be biologically significant and specially related to breast cancer, which suggests that our gene dependency network is meaningful. The validity has also been justified by literature investigation. From the network, we have selected 43 discriminative hubs as signature to build the classification model for distinguishing the distant metastasis risks of breast cancer patients, and the result outperforms those classification models with published signatures. In conclusion, we have proposed a promising way to construct the gene regulatory network by using sample-based data, which has been shown to be effective and accurate in uncovering the hidden mechanism of the biological process and identifying the gene signature for phenotypic change.

GeneCOST: a novel scoring-based prioritization framework for identifying disease causing genes.

PubMed

Ozer, Bugra; Sağıroğlu, Mahmut; Demirci, Hüseyin

2015-11-15

Due to the big data produced by next-generation sequencing studies, there is an evident need for methods to extract the valuable information gathered from these experiments. In this work, we propose GeneCOST, a novel scoring-based method to evaluate every gene for their disease association. Without any prior filtering and any prior knowledge, we assign a disease likelihood score to each gene in correspondence with their variations. Then, we rank all genes based on frequency, conservation, pedigree and detailed variation information to find out the causative reason of the disease state. We demonstrate the usage of GeneCOST with public and real life Mendelian disease cases including recessive, dominant, compound heterozygous and sporadic models. As a result, we were able to identify causative reason behind the disease state in top rankings of our list, proving that this novel prioritization framework provides a powerful environment for the analysis in genetic disease studies alternative to filtering-based approaches. GeneCOST software is freely available at www.igbam.bilgem.tubitak.gov.tr/en/softwares/genecost-en/index.html. buozer@gmail.com Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Metabolic Pathway Assignment of Plant Genes based on Phylogenetic Profiling–A Feasibility Study

PubMed Central

Weißenborn, Sandra; Walther, Dirk

2017-01-01

Despite many developed experimental and computational approaches, functional gene annotation remains challenging. With the rapidly growing number of sequenced genomes, the concept of phylogenetic profiling, which predicts functional links between genes that share a common co-occurrence pattern across different genomes, has gained renewed attention as it promises to annotate gene functions based on presence/absence calls alone. We applied phylogenetic profiling to the problem of metabolic pathway assignments of plant genes with a particular focus on secondary metabolism pathways. We determined phylogenetic profiles for 40,960 metabolic pathway enzyme genes with assigned EC numbers from 24 plant species based on sequence and pathway annotation data from KEGG and Ensembl Plants. For gene sequence family assignments, needed to determine the presence or absence of particular gene functions in the given plant species, we included data of all 39 species available at the Ensembl Plants database and established gene families based on pairwise sequence identities and annotation information. Aside from performing profiling comparisons, we used machine learning approaches to predict pathway associations from phylogenetic profiles alone. Selected metabolic pathways were indeed found to be composed of gene families of greater than expected phylogenetic profile similarity. This was particularly evident for primary metabolism pathways, whereas for secondary pathways, both the available annotation in different species as well as the abstraction of functional association via distinct pathways proved limiting. While phylogenetic profile similarity was generally not found to correlate with gene co-expression, direct physical interactions of proteins were reflected by a significantly increased profile similarity suggesting an application of phylogenetic profiling methods as a filtering step in the identification of protein-protein interactions. This feasibility study highlights the potential and challenges associated with phylogenetic profiling methods for the detection of functional relationships between genes as well as the need to enlarge the set of plant genes with proven secondary metabolism involvement as well as the limitations of distinct pathways as abstractions of relationships between genes. PMID:29163570

Candidate gene prioritization by network analysis of differential expression using machine learning approaches

PubMed Central

2010-01-01

Background Discovering novel disease genes is still challenging for diseases for which no prior knowledge - such as known disease genes or disease-related pathways - is available. Performing genetic studies frequently results in large lists of candidate genes of which only few can be followed up for further investigation. We have recently developed a computational method for constitutional genetic disorders that identifies the most promising candidate genes by replacing prior knowledge by experimental data of differential gene expression between affected and healthy individuals. To improve the performance of our prioritization strategy, we have extended our previous work by applying different machine learning approaches that identify promising candidate genes by determining whether a gene is surrounded by highly differentially expressed genes in a functional association or protein-protein interaction network. Results We have proposed three strategies scoring disease candidate genes relying on network-based machine learning approaches, such as kernel ridge regression, heat kernel, and Arnoldi kernel approximation. For comparison purposes, a local measure based on the expression of the direct neighbors is also computed. We have benchmarked these strategies on 40 publicly available knockout experiments in mice, and performance was assessed against results obtained using a standard procedure in genetics that ranks candidate genes based solely on their differential expression levels (Simple Expression Ranking). Our results showed that our four strategies could outperform this standard procedure and that the best results were obtained using the Heat Kernel Diffusion Ranking leading to an average ranking position of 8 out of 100 genes, an AUC value of 92.3% and an error reduction of 52.8% relative to the standard procedure approach which ranked the knockout gene on average at position 17 with an AUC value of 83.7%. Conclusion In this study we could identify promising candidate genes using network based machine learning approaches even if no knowledge is available about the disease or phenotype. PMID:20840752

GENE-Counter: A Computational Pipeline for the Analysis of RNA-Seq Data for Gene Expression Differences

PubMed Central

Di, Yanming; Schafer, Daniel W.; Wilhelm, Larry J.; Fox, Samuel E.; Sullivan, Christopher M.; Curzon, Aron D.; Carrington, James C.; Mockler, Todd C.; Chang, Jeff H.

2011-01-01

GENE-counter is a complete Perl-based computational pipeline for analyzing RNA-Sequencing (RNA-Seq) data for differential gene expression. In addition to its use in studying transcriptomes of eukaryotic model organisms, GENE-counter is applicable for prokaryotes and non-model organisms without an available genome reference sequence. For alignments, GENE-counter is configured for CASHX, Bowtie, and BWA, but an end user can use any Sequence Alignment/Map (SAM)-compliant program of preference. To analyze data for differential gene expression, GENE-counter can be run with any one of three statistics packages that are based on variations of the negative binomial distribution. The default method is a new and simple statistical test we developed based on an over-parameterized version of the negative binomial distribution. GENE-counter also includes three different methods for assessing differentially expressed features for enriched gene ontology (GO) terms. Results are transparent and data are systematically stored in a MySQL relational database to facilitate additional analyses as well as quality assessment. We used next generation sequencing to generate a small-scale RNA-Seq dataset derived from the heavily studied defense response of Arabidopsis thaliana and used GENE-counter to process the data. Collectively, the support from analysis of microarrays as well as the observed and substantial overlap in results from each of the three statistics packages demonstrates that GENE-counter is well suited for handling the unique characteristics of small sample sizes and high variability in gene counts. PMID:21998647

Minimising Immunohistochemical False Negative ER Classification Using a Complementary 23 Gene Expression Signature of ER Status

PubMed Central

Li, Qiyuan; Eklund, Aron C.; Juul, Nicolai; Haibe-Kains, Benjamin; Workman, Christopher T.; Richardson, Andrea L.; Szallasi, Zoltan; Swanton, Charles

2010-01-01

Background Expression of the oestrogen receptor (ER) in breast cancer predicts benefit from endocrine therapy. Minimising the frequency of false negative ER status classification is essential to identify all patients with ER positive breast cancers who should be offered endocrine therapies in order to improve clinical outcome. In routine oncological practice ER status is determined by semi-quantitative methods such as immunohistochemistry (IHC) or other immunoassays in which the ER expression level is compared to an empirical threshold[1], [2]. The clinical relevance of gene expression-based ER subtypes as compared to IHC-based determination has not been systematically evaluated. Here we attempt to reduce the frequency of false negative ER status classification using two gene expression approaches and compare these methods to IHC based ER status in terms of predictive and prognostic concordance with clinical outcome. Methodology/Principal Findings Firstly, ER status was discriminated by fitting the bimodal expression of ESR1 to a mixed Gaussian model. The discriminative power of ESR1 suggested bimodal expression as an efficient way to stratify breast cancer; therefore we identified a set of genes whose expression was both strongly bimodal, mimicking ESR expression status, and highly expressed in breast epithelial cell lines, to derive a 23-gene ER expression signature-based classifier. We assessed our classifiers in seven published breast cancer cohorts by comparing the gene expression-based ER status to IHC-based ER status as a predictor of clinical outcome in both untreated and tamoxifen treated cohorts. In untreated breast cancer cohorts, the 23 gene signature-based ER status provided significantly improved prognostic power compared to IHC-based ER status (P = 0.006). In tamoxifen-treated cohorts, the 23 gene ER expression signature predicted clinical outcome (HR = 2.20, P = 0.00035). These complementary ER signature-based strategies estimated that between 15.1% and 21.8% patients of IHC-based negative ER status would be classified with ER positive breast cancer. Conclusion/Significance Expression-based ER status classification may complement IHC to minimise false negative ER status classification and optimise patient stratification for endocrine therapies. PMID:21152022

GBOOST: a GPU-based tool for detecting gene-gene interactions in genome-wide case control studies.

PubMed

Yung, Ling Sing; Yang, Can; Wan, Xiang; Yu, Weichuan

2011-05-01

Collecting millions of genetic variations is feasible with the advanced genotyping technology. With a huge amount of genetic variations data in hand, developing efficient algorithms to carry out the gene-gene interaction analysis in a timely manner has become one of the key problems in genome-wide association studies (GWAS). Boolean operation-based screening and testing (BOOST), a recent work in GWAS, completes gene-gene interaction analysis in 2.5 days on a desktop computer. Compared with central processing units (CPUs), graphic processing units (GPUs) are highly parallel hardware and provide massive computing resources. We are, therefore, motivated to use GPUs to further speed up the analysis of gene-gene interactions. We implement the BOOST method based on a GPU framework and name it GBOOST. GBOOST achieves a 40-fold speedup compared with BOOST. It completes the analysis of Wellcome Trust Case Control Consortium Type 2 Diabetes (WTCCC T2D) genome data within 1.34 h on a desktop computer equipped with Nvidia GeForce GTX 285 display card. GBOOST code is available at http://bioinformatics.ust.hk/BOOST.html#GBOOST.

[Gene Therapy for Inherited RETINAL AND OPTIC NERVE Disorders: Current Knowledge].

PubMed

Ďuďáková, Ľ; Kousal, B; Kolářová, H; Hlavatá, L; Lišková, P

The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i.e. testing the efficacy and safety.Because of the relatively easy accessibility of the retina and its ease of visualization which allows monitoring of efficacy, gene-based therapies for inherited retinal disorders represent a very promising treatment option. With the development of novel therapeutic approaches, the importance of establishing not only clinical but also molecular genetic diagnosis is obvious.Key words: gene therapy, monogenic retinal diseases, optic nerve atrophy, mitochondrial disease.

Partial Least Squares Based Gene Expression Analysis in EBV- Positive and EBV-Negative Posttransplant Lymphoproliferative Disorders.

PubMed

Wu, Sa; Zhang, Xin; Li, Zhi-Ming; Shi, Yan-Xia; Huang, Jia-Jia; Xia, Yi; Yang, Hang; Jiang, Wen-Qi

2013-01-01

Post-transplant lymphoproliferative disorder (PTLD) is a common complication of therapeutic immunosuppression after organ transplantation. Gene expression profile facilitates the identification of biological difference between Epstein-Barr virus (EBV) positive and negative PTLDs. Previous studies mainly implemented variance/regression analysis without considering unaccounted array specific factors. The aim of this study is to investigate the gene expression difference between EBV positive and negative PTLDs through partial least squares (PLS) based analysis. With a microarray data set from the Gene Expression Omnibus database, we performed PLS based analysis. We acquired 1188 differentially expressed genes. Pathway and Gene Ontology enrichment analysis identified significantly over-representation of dysregulated genes in immune response and cancer related biological processes. Network analysis identified three hub genes with degrees higher than 15, including CREBBP, ATXN1, and PML. Proteins encoded by CREBBP and PML have been reported to be interact with EBV before. Our findings shed light on expression distinction of EBV positive and negative PTLDs with the hope to offer theoretical support for future therapeutic study.

Fast gene ontology based clustering for microarray experiments.

PubMed

Ovaska, Kristian; Laakso, Marko; Hautaniemi, Sampsa

2008-11-21

Analysis of a microarray experiment often results in a list of hundreds of disease-associated genes. In order to suggest common biological processes and functions for these genes, Gene Ontology annotations with statistical testing are widely used. However, these analyses can produce a very large number of significantly altered biological processes. Thus, it is often challenging to interpret GO results and identify novel testable biological hypotheses. We present fast software for advanced gene annotation using semantic similarity for Gene Ontology terms combined with clustering and heat map visualisation. The methodology allows rapid identification of genes sharing the same Gene Ontology cluster. Our R based semantic similarity open-source package has a speed advantage of over 2000-fold compared to existing implementations. From the resulting hierarchical clustering dendrogram genes sharing a GO term can be identified, and their differences in the gene expression patterns can be seen from the heat map. These methods facilitate advanced annotation of genes resulting from data analysis.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Belinsky, Steven A; Palmisano, William A

A molecular marker-based method for monitoring and detecting cancer in humans. Aberrant methylation of gene promoters is a marker for cancer risk in humans. A two-stage, or "nested" polymerase chain reaction method is disclosed for detecting methylated DNA sequences at sufficiently high levels of sensitivity to permit cancer screening in biological fluid samples, such as sputum, obtained non-invasively. The method is for detecting the aberrant methylation of the p16 gene, O 6-methylguanine-DNA methyltransferase gene, Death-associated protein kinase gene, RAS-associated family 1 gene, or other gene promoters. The method offers a potentially powerful approach to population-based screening for the detection ofmore » lung and other cancers.« less

Recursive feature selection with significant variables of support vectors.

PubMed

Tsai, Chen-An; Huang, Chien-Hsun; Chang, Ching-Wei; Chen, Chun-Houh

2012-01-01

The development of DNA microarray makes researchers screen thousands of genes simultaneously and it also helps determine high- and low-expression level genes in normal and disease tissues. Selecting relevant genes for cancer classification is an important issue. Most of the gene selection methods use univariate ranking criteria and arbitrarily choose a threshold to choose genes. However, the parameter setting may not be compatible to the selected classification algorithms. In this paper, we propose a new gene selection method (SVM-t) based on the use of t-statistics embedded in support vector machine. We compared the performance to two similar SVM-based methods: SVM recursive feature elimination (SVMRFE) and recursive support vector machine (RSVM). The three methods were compared based on extensive simulation experiments and analyses of two published microarray datasets. In the simulation experiments, we found that the proposed method is more robust in selecting informative genes than SVMRFE and RSVM and capable to attain good classification performance when the variations of informative and noninformative genes are different. In the analysis of two microarray datasets, the proposed method yields better performance in identifying fewer genes with good prediction accuracy, compared to SVMRFE and RSVM.

Diurnal Transcriptome and Gene Network Represented through Sparse Modeling in Brachypodium distachyon.

PubMed

Koda, Satoru; Onda, Yoshihiko; Matsui, Hidetoshi; Takahagi, Kotaro; Yamaguchi-Uehara, Yukiko; Shimizu, Minami; Inoue, Komaki; Yoshida, Takuhiro; Sakurai, Tetsuya; Honda, Hiroshi; Eguchi, Shinto; Nishii, Ryuei; Mochida, Keiichi

2017-01-01

We report the comprehensive identification of periodic genes and their network inference, based on a gene co-expression analysis and an Auto-Regressive eXogenous (ARX) model with a group smoothly clipped absolute deviation (SCAD) method using a time-series transcriptome dataset in a model grass, Brachypodium distachyon . To reveal the diurnal changes in the transcriptome in B. distachyon , we performed RNA-seq analysis of its leaves sampled through a diurnal cycle of over 48 h at 4 h intervals using three biological replications, and identified 3,621 periodic genes through our wavelet analysis. The expression data are feasible to infer network sparsity based on ARX models. We found that genes involved in biological processes such as transcriptional regulation, protein degradation, and post-transcriptional modification and photosynthesis are significantly enriched in the periodic genes, suggesting that these processes might be regulated by circadian rhythm in B. distachyon . On the basis of the time-series expression patterns of the periodic genes, we constructed a chronological gene co-expression network and identified putative transcription factors encoding genes that might be involved in the time-specific regulatory transcriptional network. Moreover, we inferred a transcriptional network composed of the periodic genes in B. distachyon , aiming to identify genes associated with other genes through variable selection by grouping time points for each gene. Based on the ARX model with the group SCAD regularization using our time-series expression datasets of the periodic genes, we constructed gene networks and found that the networks represent typical scale-free structure. Our findings demonstrate that the diurnal changes in the transcriptome in B. distachyon leaves have a sparse network structure, demonstrating the spatiotemporal gene regulatory network over the cyclic phase transitions in B. distachyon diurnal growth.

Comparative analysis of grapevine whole-genome gene predictions, functional annotation, categorization and integration of the predicted gene sequences

PubMed Central

2012-01-01

Background The first draft assembly and gene prediction of the grapevine genome (8X base coverage) was made available to the scientific community in 2007, and functional annotation was developed on this gene prediction. Since then additional Sanger sequences were added to the 8X sequences pool and a new version of the genomic sequence with superior base coverage (12X) was produced. Results In order to more efficiently annotate the function of the genes predicted in the new assembly, it is important to build on as much of the previous work as possible, by transferring 8X annotation of the genome to the 12X version. The 8X and 12X assemblies and gene predictions of the grapevine genome were compared to answer the question, “Can we uniquely map 8X predicted genes to 12X predicted genes?” The results show that while the assemblies and gene structure predictions are too different to make a complete mapping between them, most genes (18,725) showed a one-to-one relationship between 8X predicted genes and the last version of 12X predicted genes. In addition, reshuffled genomic sequence structures appeared. These highlight regions of the genome where the gene predictions need to be taken with caution. Based on the new grapevine gene functional annotation and in-depth functional categorization, twenty eight new molecular networks have been created for VitisNet while the existing networks were updated. Conclusions The outcomes of this study provide a functional annotation of the 12X genes, an update of VitisNet, the system of the grapevine molecular networks, and a new functional categorization of genes. Data are available at the VitisNet website (http://www.sdstate.edu/ps/research/vitis/pathways.cfm). PMID:22554261

GeneAnalytics: An Integrative Gene Set Analysis Tool for Next Generation Sequencing, RNAseq and Microarray Data.

PubMed

Ben-Ari Fuchs, Shani; Lieder, Iris; Stelzer, Gil; Mazor, Yaron; Buzhor, Ella; Kaplan, Sergey; Bogoch, Yoel; Plaschkes, Inbar; Shitrit, Alina; Rappaport, Noa; Kohn, Asher; Edgar, Ron; Shenhav, Liraz; Safran, Marilyn; Lancet, Doron; Guan-Golan, Yaron; Warshawsky, David; Shtrichman, Ronit

2016-03-01

Postgenomics data are produced in large volumes by life sciences and clinical applications of novel omics diagnostics and therapeutics for precision medicine. To move from "data-to-knowledge-to-innovation," a crucial missing step in the current era is, however, our limited understanding of biological and clinical contexts associated with data. Prominent among the emerging remedies to this challenge are the gene set enrichment tools. This study reports on GeneAnalytics™ ( geneanalytics.genecards.org ), a comprehensive and easy-to-apply gene set analysis tool for rapid contextualization of expression patterns and functional signatures embedded in the postgenomics Big Data domains, such as Next Generation Sequencing (NGS), RNAseq, and microarray experiments. GeneAnalytics' differentiating features include in-depth evidence-based scoring algorithms, an intuitive user interface and proprietary unified data. GeneAnalytics employs the LifeMap Science's GeneCards suite, including the GeneCards®--the human gene database; the MalaCards-the human diseases database; and the PathCards--the biological pathways database. Expression-based analysis in GeneAnalytics relies on the LifeMap Discovery®--the embryonic development and stem cells database, which includes manually curated expression data for normal and diseased tissues, enabling advanced matching algorithm for gene-tissue association. This assists in evaluating differentiation protocols and discovering biomarkers for tissues and cells. Results are directly linked to gene, disease, or cell "cards" in the GeneCards suite. Future developments aim to enhance the GeneAnalytics algorithm as well as visualizations, employing varied graphical display items. Such attributes make GeneAnalytics a broadly applicable postgenomics data analyses and interpretation tool for translation of data to knowledge-based innovation in various Big Data fields such as precision medicine, ecogenomics, nutrigenomics, pharmacogenomics, vaccinomics, and others yet to emerge on the postgenomics horizon.

Scuba: scalable kernel-based gene prioritization.

PubMed

Zampieri, Guido; Tran, Dinh Van; Donini, Michele; Navarin, Nicolò; Aiolli, Fabio; Sperduti, Alessandro; Valle, Giorgio

2018-01-25

The uncovering of genes linked to human diseases is a pressing challenge in molecular biology and precision medicine. This task is often hindered by the large number of candidate genes and by the heterogeneity of the available information. Computational methods for the prioritization of candidate genes can help to cope with these problems. In particular, kernel-based methods are a powerful resource for the integration of heterogeneous biological knowledge, however, their practical implementation is often precluded by their limited scalability. We propose Scuba, a scalable kernel-based method for gene prioritization. It implements a novel multiple kernel learning approach, based on a semi-supervised perspective and on the optimization of the margin distribution. Scuba is optimized to cope with strongly unbalanced settings where known disease genes are few and large scale predictions are required. Importantly, it is able to efficiently deal both with a large amount of candidate genes and with an arbitrary number of data sources. As a direct consequence of scalability, Scuba integrates also a new efficient strategy to select optimal kernel parameters for each data source. We performed cross-validation experiments and simulated a realistic usage setting, showing that Scuba outperforms a wide range of state-of-the-art methods. Scuba achieves state-of-the-art performance and has enhanced scalability compared to existing kernel-based approaches for genomic data. This method can be useful to prioritize candidate genes, particularly when their number is large or when input data is highly heterogeneous. The code is freely available at https://github.com/gzampieri/Scuba .

Gene and enhancer trap tagging of vascular-expressed genes in poplar trees

Treesearch

Andrew Groover; Joseph R. Fontana; Gayle Dupper; Caiping Ma; Robert Martienssen; Steven Strauss; Richard Meilan

2004-01-01

We report a gene discovery system for poplar trees based on gene and enhancer traps. Gene and enhancer trap vectors carrying the β-glucuronidase (GUS) reporter gene were inserted into the poplar genome via Agrobacterium tumefaciens transformation, where they reveal the expression pattern of genes at or near the insertion sites. Because GUS...

Gene Polymorphism Studies in a Teaching Laboratory

NASA Astrophysics Data System (ADS)

Shultz, Jeffry

2009-02-01

I present a laboratory procedure for illustrating transcription, post-transcriptional modification, gene conservation, and comparative genetics for use in undergraduate biology education. Students are individually assigned genes in a targeted biochemical pathway, for which they design and test polymerase chain reaction (PCR) primers. In this example, students used genes annotated for the steroid biosynthesis pathway in soybean. The authoritative Kyoto encyclopedia of genes and genomes (KEGG) interactive database and other online resources were used to design primers based first on soybean expressed sequence tags (ESTs), then on ESTs from an alternate organism if soybean sequence was unavailable. Students designed a total of 50 gene-based primer pairs (37 soybean, 13 alternative) and tested these for polymorphism state and similarity between two soybean and two pea lines. Student assessment was based on acquisition of laboratory skills and successful project completion. This simple procedure illustrates conservation of genes and is not limited to soybean or pea. Cost per student estimates are included, along with a detailed protocol and flow diagram of the procedure.

Enriching regulatory networks by bootstrap learning using optimised GO-based gene similarity and gene links mined from PubMed abstracts

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taylor, Ronald C.; Sanfilippo, Antonio P.; McDermott, Jason E.

2011-02-18

Transcriptional regulatory networks are being determined using “reverse engineering” methods that infer connections based on correlations in gene state. Corroboration of such networks through independent means such as evidence from the biomedical literature is desirable. Here, we explore a novel approach, a bootstrapping version of our previous Cross-Ontological Analytic method (XOA) that can be used for semi-automated annotation and verification of inferred regulatory connections, as well as for discovery of additional functional relationships between the genes. First, we use our annotation and network expansion method on a biological network learned entirely from the literature. We show how new relevant linksmore » between genes can be iteratively derived using a gene similarity measure based on the Gene Ontology that is optimized on the input network at each iteration. Second, we apply our method to annotation, verification, and expansion of a set of regulatory connections found by the Context Likelihood of Relatedness algorithm.« less

A statistical method for measuring activation of gene regulatory networks.

PubMed

Esteves, Gustavo H; Reis, Luiz F L

2018-06-13

Gene expression data analysis is of great importance for modern molecular biology, given our ability to measure the expression profiles of thousands of genes and enabling studies rooted in systems biology. In this work, we propose a simple statistical model for the activation measuring of gene regulatory networks, instead of the traditional gene co-expression networks. We present the mathematical construction of a statistical procedure for testing hypothesis regarding gene regulatory network activation. The real probability distribution for the test statistic is evaluated by a permutation based study. To illustrate the functionality of the proposed methodology, we also present a simple example based on a small hypothetical network and the activation measuring of two KEGG networks, both based on gene expression data collected from gastric and esophageal samples. The two KEGG networks were also analyzed for a public database, available through NCBI-GEO, presented as Supplementary Material. This method was implemented in an R package that is available at the BioConductor project website under the name maigesPack.

Partial least squares based identification of Duchenne muscular dystrophy specific genes.

PubMed

An, Hui-bo; Zheng, Hua-cheng; Zhang, Li; Ma, Lin; Liu, Zheng-yan

2013-11-01

Large-scale parallel gene expression analysis has provided a greater ease for investigating the underlying mechanisms of Duchenne muscular dystrophy (DMD). Previous studies typically implemented variance/regression analysis, which would be fundamentally flawed when unaccounted sources of variability in the arrays existed. Here we aim to identify genes that contribute to the pathology of DMD using partial least squares (PLS) based analysis. We carried out PLS-based analysis with two datasets downloaded from the Gene Expression Omnibus (GEO) database to identify genes contributing to the pathology of DMD. Except for the genes related to inflammation, muscle regeneration and extracellular matrix (ECM) modeling, we found some genes with high fold change, which have not been identified by previous studies, such as SRPX, GPNMB, SAT1, and LYZ. In addition, downregulation of the fatty acid metabolism pathway was found, which may be related to the progressive muscle wasting process. Our results provide a better understanding for the downstream mechanisms of DMD.

Genetics pathway-based imaging approaches in Chinese Han population with Alzheimer's disease risk.

PubMed

Bai, Feng; Liao, Wei; Yue, Chunxian; Pu, Mengjia; Shi, Yongmei; Yu, Hui; Yuan, Yonggui; Geng, Leiyu; Zhang, Zhijun

2016-01-01

The tau hypothesis has been raised with regard to the pathophysiology of Alzheimer's disease (AD). Mild cognitive impairment (MCI) is associated with a high risk for developing AD. However, no study has directly examined the brain topological alterations based on combined effects of tau protein pathway genes in MCI population. Forty-three patients with MCI and 30 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) in Chinese Han, and a tau protein pathway-based imaging approaches (7 candidate genes: 17 SNPs) were used to investigate changes in the topological organisation of brain activation associated with MCI. Impaired regional activation is related to tau protein pathway genes (5/7 candidate genes) in patients with MCI and likely in topologically convergent and divergent functional alterations patterns associated with genes, and combined effects of tau protein pathway genes disrupt the topological architecture of cortico-cerebellar loops. The associations between the loops and behaviours further suggest that tau protein pathway genes do play a significant role in non-episodic memory impairment. Tau pathway-based imaging approaches might strengthen the credibility in imaging genetic associations and generate pathway frameworks that might provide powerful new insights into the neural mechanisms that underlie MCI.

Determining Cutoff Point of Ensemble Trees Based on Sample Size in Predicting Clinical Dose with DNA Microarray Data.

PubMed

Yılmaz Isıkhan, Selen; Karabulut, Erdem; Alpar, Celal Reha

2016-01-01

Background/Aim . Evaluating the success of dose prediction based on genetic or clinical data has substantially advanced recently. The aim of this study is to predict various clinical dose values from DNA gene expression datasets using data mining techniques. Materials and Methods . Eleven real gene expression datasets containing dose values were included. First, important genes for dose prediction were selected using iterative sure independence screening. Then, the performances of regression trees (RTs), support vector regression (SVR), RT bagging, SVR bagging, and RT boosting were examined. Results . The results demonstrated that a regression-based feature selection method substantially reduced the number of irrelevant genes from raw datasets. Overall, the best prediction performance in nine of 11 datasets was achieved using SVR; the second most accurate performance was provided using a gradient-boosting machine (GBM). Conclusion . Analysis of various dose values based on microarray gene expression data identified common genes found in our study and the referenced studies. According to our findings, SVR and GBM can be good predictors of dose-gene datasets. Another result of the study was to identify the sample size of n = 25 as a cutoff point for RT bagging to outperform a single RT.

The Pathogen-Host Interactions database (PHI-base): additions and future developments

PubMed Central

Urban, Martin; Pant, Rashmi; Raghunath, Arathi; Irvine, Alistair G.; Pedro, Helder; Hammond-Kosack, Kim E.

2015-01-01

Rapidly evolving pathogens cause a diverse array of diseases and epidemics that threaten crop yield, food security as well as human, animal and ecosystem health. To combat infection greater comparative knowledge is required on the pathogenic process in multiple species. The Pathogen-Host Interactions database (PHI-base) catalogues experimentally verified pathogenicity, virulence and effector genes from bacterial, fungal and protist pathogens. Mutant phenotypes are associated with gene information. The included pathogens infect a wide range of hosts including humans, animals, plants, insects, fish and other fungi. The current version, PHI-base 3.6, available at http://www.phi-base.org, stores information on 2875 genes, 4102 interactions, 110 host species, 160 pathogenic species (103 plant, 3 fungal and 54 animal infecting species) and 181 diseases drawn from 1243 references. Phenotypic and gene function information has been obtained by manual curation of the peer-reviewed literature. A controlled vocabulary consisting of nine high-level phenotype terms permits comparisons and data analysis across the taxonomic space. PHI-base phenotypes were mapped via their associated gene information to reference genomes available in Ensembl Genomes. Virulence genes and hotspots can be visualized directly in genome browsers. Future plans for PHI-base include development of tools facilitating community-led curation and inclusion of the corresponding host target(s). PMID:25414340

A potential disruptive technology in vaccine development: gene-based vaccines and their application to infectious diseases.

PubMed

Kaslow, David C

2004-10-01

Vaccine development requires an amalgamation of disparate disciplines and has unique economic and regulatory drivers. Non-viral gene-based delivery systems, such as formulated plasmid DNA, are new and potentially disruptive technologies capable of providing 'cheaper, simpler, and more convenient-to-use' vaccines. Typically and somewhat ironically, disruptive technologies have poorer product performance, at least in the near-term, compared with the existing conventional technologies. Because successful product development requires that the product's performance must meet or exceed the efficacy threshold for a desired application, the appropriate selection of the initial product applications for a disruptive technology is critical for its successful evolution. In this regard, the near-term successes of gene-based vaccines will likely be for protection against bacterial toxins and acute viral and bacterial infections. Recent breakthroughs, however, herald increasing rather than languishing performance improvements in the efficacy of gene-based vaccines. Whether gene-based vaccines ultimately succeed in eliciting protective immunity in humans to persistent intracellular pathogens, such as HIV, malaria and tuberculosis, for which the conventional vaccine technologies have failed, remains to be determined. A success against any one of the persistent intracellular pathogens would be sufficient proof that gene-based vaccines represent a disruptive technology against which future vaccine technologies will be measured.

Structure of the circumsporozoite protein gene in 18 strains of Plasmodium falciparum.

PubMed

Weber, J L; Hockmeyer, W T

1985-06-01

Using the cloned circumsporozoite (CS) protein gene of a Brazilian strain of Plasmodium falciparum as probe, we have analyzed the structure of the CS protein gene from 17 other Asian, African, Central and South American parasite strains by nucleic acid hybridization. Each strain appears to have one CS protein gene which hybridizes readily to the Brazilian strain probe. The 5' and 3' thirds of the genes are invariant in size in all 18 strains whereas the central third containing the 12 base pair tandem repeats varies in size over a range of about 100 base pairs. Several differences were found in the locations of Sau3A sites in the genes. The Sau3A sites are significant because each of the minority Asn-Val-Asp-Pro repeats in the cloned gene has a Sau3A site. DNA melting of hybrids revealed a high degree of homology between the sequences of the cloned gene and genes from an Asian strain and an African strain. A 14 base oligodeoxynucleotide with a sequence from the central repeat region hybridized to all strains tested. We conclude that the CS protein gene is highly conserved among strains of P. falciparum and that malaria vaccine development with the CS protein is unlikely to be complicated by strain variation.

Analysis of differential gene expression by bead-based fiber-optic array in growth-hormone-secreting pituitary adenomas.

PubMed

Jiang, Zhiquan; Gui, Songbo; Zhang, Yazhuo

2010-09-01

Growth-hormone-secreting pituitary adenomas (GHomas) account for approximately 20% of all pituitary neoplasms. However, the pathogenesis of GHomas remains to be elucidated. To explore the possible pathogenesis of GHomas, we used bead-based fiber-optic arrays to examine the gene expression in five GHomas and compared them to three healthy pituitaries. Four differentially expressed genes were chosen randomly for validation by quantitative real-time reverse transcription-polymerase chain reaction. We then performed pathway analysis on the identified differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Array analysis showed significant increases in the expression of 353 genes and 206 expressed sequence tags (ESTs) and decreases in 565 genes and 29 ESTs. Bioinformatic analysis showed that the genes HIGD1B, HOXB2, ANGPT2, HPGD and BTG2 may play an important role in the tumorigenesis and progression of GHomas. Pathway analysis showed that the wingless-type signaling pathway and extracellular-matrix receptor interactions may play a key role in the tumorigenesis and progression of GHomas. Our data suggested that there are numerous aberrantly expressed genes and pathways involved in the pathogenesis of GHomas. Bead-based fiber-optic arrays combined with pathway analysis of differentially expressed genes appear to be a valid method for investigating the pathogenesis of tumors.

Analysis of differential gene expression by bead-based fiber-optic array in growth-hormone-secreting pituitary adenomas

PubMed Central

JIANG, ZHIQUAN; GUI, SONGBO; ZHANG, YAZHUO

2010-01-01

Growth-hormone-secreting pituitary adenomas (GHomas) account for approximately 20% of all pituitary neoplasms. However, the pathogenesis of GHomas remains to be elucidated. To explore the possible pathogenesis of GHomas, we used bead-based fiber-optic arrays to examine the gene expression in five GHomas and compared them to three healthy pituitaries. Four differentially expressed genes were chosen randomly for validation by quantitative real-time reverse transcription-polymerase chain reaction. We then performed pathway analysis on the identified differentially expressed genes using the Kyoto Encyclopedia of Genes and Genomes. Array analysis showed significant increases in the expression of 353 genes and 206 expressed sequence tags (ESTs) and decreases in 565 genes and 29 ESTs. Bioinformatic analysis showed that the genes HIGD1B, HOXB2, ANGPT2, HPGD and BTG2 may play an important role in the tumorigenesis and progression of GHomas. Pathway analysis showed that the wingless-type signaling pathway and extracellular-matrix receptor interactions may play a key role in the tumorigenesis and progression of GHomas. Our data suggested that there are numerous aberrantly expressed genes and pathways involved in the pathogenesis of GHomas. Bead-based fiber-optic arrays combined with pathway analysis of differentially expressed genes appear to be a valid method for investigating the pathogenesis of tumors. PMID:22993617

A network-based method for the identification of putative genes related to infertility.

PubMed

Wang, ShaoPeng; Huang, GuoHua; Hu, Qinghua; Zou, Quan

2016-11-01

Infertility has become one of the major health problems worldwide, with its incidence having risen markedly in recent decades. There is an urgent need to investigate the pathological mechanisms behind infertility and to design effective treatments. However, this is made difficult by the fact that various biological factors have been identified to be related to infertility, including genetic factors. A network-based method was established to identify new genes potentially related to infertility. A network constructed using human protein-protein interactions based on previously validated infertility-related genes enabled the identification of some novel candidate genes. These genes were then filtered by a permutation test and their functional and structural associations with infertility-related genes. Our method identified 23 novel genes, which have strong functional and structural associations with previously validated infertility-related genes. Substantial evidence indicates that the identified genes are strongly related to dysfunction of the four main biological processes of fertility: reproductive development and physiology, gametogenesis, meiosis and recombination, and hormone regulation. The newly discovered genes may provide new directions for investigating infertility. This article is part of a Special Issue entitled "System Genetics" Guest Editor: Dr. Yudong Cai and Dr. Tao Huang. Copyright © 2016 Elsevier B.V. All rights reserved.

Discovering gene annotations in biomedical text databases

PubMed Central

Cakmak, Ali; Ozsoyoglu, Gultekin

2008-01-01

Background Genes and gene products are frequently annotated with Gene Ontology concepts based on the evidence provided in genomics articles. Manually locating and curating information about a genomic entity from the biomedical literature requires vast amounts of human effort. Hence, there is clearly a need forautomated computational tools to annotate the genes and gene products with Gene Ontology concepts by computationally capturing the related knowledge embedded in textual data. Results In this article, we present an automated genomic entity annotation system, GEANN, which extracts information about the characteristics of genes and gene products in article abstracts from PubMed, and translates the discoveredknowledge into Gene Ontology (GO) concepts, a widely-used standardized vocabulary of genomic traits. GEANN utilizes textual "extraction patterns", and a semantic matching framework to locate phrases matching to a pattern and produce Gene Ontology annotations for genes and gene products. In our experiments, GEANN has reached to the precision level of 78% at therecall level of 61%. On a select set of Gene Ontology concepts, GEANN either outperforms or is comparable to two other automated annotation studies. Use of WordNet for semantic pattern matching improves the precision and recall by 24% and 15%, respectively, and the improvement due to semantic pattern matching becomes more apparent as the Gene Ontology terms become more general. Conclusion GEANN is useful for two distinct purposes: (i) automating the annotation of genomic entities with Gene Ontology concepts, and (ii) providing existing annotations with additional "evidence articles" from the literature. The use of textual extraction patterns that are constructed based on the existing annotations achieve high precision. The semantic pattern matching framework provides a more flexible pattern matching scheme with respect to "exactmatching" with the advantage of locating approximate pattern occurrences with similar semantics. Relatively low recall performance of our pattern-based approach may be enhanced either by employing a probabilistic annotation framework based on the annotation neighbourhoods in textual data, or, alternatively, the statistical enrichment threshold may be adjusted to lower values for applications that put more value on achieving higher recall values. PMID:18325104

A method to identify differential expression profiles of time-course gene data with Fourier transformation

PubMed Central

2013-01-01

Background Time course gene expression experiments are an increasingly popular method for exploring biological processes. Temporal gene expression profiles provide an important characterization of gene function, as biological systems are both developmental and dynamic. With such data it is possible to study gene expression changes over time and thereby to detect differential genes. Much of the early work on analyzing time series expression data relied on methods developed originally for static data and thus there is a need for improved methodology. Since time series expression is a temporal process, its unique features such as autocorrelation between successive points should be incorporated into the analysis. Results This work aims to identify genes that show different gene expression profiles across time. We propose a statistical procedure to discover gene groups with similar profiles using a nonparametric representation that accounts for the autocorrelation in the data. In particular, we first represent each profile in terms of a Fourier basis, and then we screen out genes that are not differentially expressed based on the Fourier coefficients. Finally, we cluster the remaining gene profiles using a model-based approach in the Fourier domain. We evaluate the screening results in terms of sensitivity, specificity, FDR and FNR, compare with the Gaussian process regression screening in a simulation study and illustrate the results by application to yeast cell-cycle microarray expression data with alpha-factor synchronization. The key elements of the proposed methodology: (i) representation of gene profiles in the Fourier domain; (ii) automatic screening of genes based on the Fourier coefficients and taking into account autocorrelation in the data, while controlling the false discovery rate (FDR); (iii) model-based clustering of the remaining gene profiles. Conclusions Using this method, we identified a set of cell-cycle-regulated time-course yeast genes. The proposed method is general and can be potentially used to identify genes which have the same patterns or biological processes, and help facing the present and forthcoming challenges of data analysis in functional genomics. PMID:24134721

Discovering gene annotations in biomedical text databases.

PubMed

Cakmak, Ali; Ozsoyoglu, Gultekin

2008-03-06

Genes and gene products are frequently annotated with Gene Ontology concepts based on the evidence provided in genomics articles. Manually locating and curating information about a genomic entity from the biomedical literature requires vast amounts of human effort. Hence, there is clearly a need forautomated computational tools to annotate the genes and gene products with Gene Ontology concepts by computationally capturing the related knowledge embedded in textual data. In this article, we present an automated genomic entity annotation system, GEANN, which extracts information about the characteristics of genes and gene products in article abstracts from PubMed, and translates the discoveredknowledge into Gene Ontology (GO) concepts, a widely-used standardized vocabulary of genomic traits. GEANN utilizes textual "extraction patterns", and a semantic matching framework to locate phrases matching to a pattern and produce Gene Ontology annotations for genes and gene products. In our experiments, GEANN has reached to the precision level of 78% at therecall level of 61%. On a select set of Gene Ontology concepts, GEANN either outperforms or is comparable to two other automated annotation studies. Use of WordNet for semantic pattern matching improves the precision and recall by 24% and 15%, respectively, and the improvement due to semantic pattern matching becomes more apparent as the Gene Ontology terms become more general. GEANN is useful for two distinct purposes: (i) automating the annotation of genomic entities with Gene Ontology concepts, and (ii) providing existing annotations with additional "evidence articles" from the literature. The use of textual extraction patterns that are constructed based on the existing annotations achieve high precision. The semantic pattern matching framework provides a more flexible pattern matching scheme with respect to "exactmatching" with the advantage of locating approximate pattern occurrences with similar semantics. Relatively low recall performance of our pattern-based approach may be enhanced either by employing a probabilistic annotation framework based on the annotation neighbourhoods in textual data, or, alternatively, the statistical enrichment threshold may be adjusted to lower values for applications that put more value on achieving higher recall values.

Reduction of wobble-position GC bases in Corynebacteria genes and enhancement of PCR and heterologous expression.

PubMed

Sanli, G; Blaber, S I; Blaber, M

2001-01-01

Corynebacteria codon usage exhibits an overall GC content of 67%, and a wobble-position GC content of 88%. Escherichia coli, on the other hand has an overall GC content of 51%, and a wobble-position GC content of 55%. The high GC content of Corynebacteria genes results in an unfavorable codon preference for heterologous expression, and can present difficulties for polymerase-based manipulations due to secondary-structure effects. Since these characteristics are due primarily to base composition at the wobble-position, synthetic genes can, in principle, be designed to eliminate these problems and retain the wild-type amino acid sequence. Such genes would obviate the need for special additives or bases during in vitro polymerase-based manipulation and mutant host strains containing uncommon tRNA's for heterologous expression. We have evaluated synthetic genes with reduced wobble-position G/C content using two variants of the enzyme 2,5-diketo-D-gluconic acid reductase (2,5-DKGR A and B) from Corynebacterium. The wild-type genes are refractory to polymerase-based manipulations and exhibit poor heterologous expression in enteric bacteria. The results indicate that a subset of codons for five amino acids (alanine, arginine, glutamate, glycine and valine) contribute the greatest contribution to reduction in G/C content at the wobble-position. Furthermore, changes in codons for two amino acids (leucine and proline) enhance bias for expression in enteric bacteria without affecting the overall G/C content. The synthetic genes are readily amplified using polymerase-based methodologies, and exhibit high levels of heterologous expression in E. coli.

A novel feature extraction approach for microarray data based on multi-algorithm fusion

PubMed Central

Jiang, Zhu; Xu, Rong

2015-01-01

Feature extraction is one of the most important and effective method to reduce dimension in data mining, with emerging of high dimensional data such as microarray gene expression data. Feature extraction for gene selection, mainly serves two purposes. One is to identify certain disease-related genes. The other is to find a compact set of discriminative genes to build a pattern classifier with reduced complexity and improved generalization capabilities. Depending on the purpose of gene selection, two types of feature extraction algorithms including ranking-based feature extraction and set-based feature extraction are employed in microarray gene expression data analysis. In ranking-based feature extraction, features are evaluated on an individual basis, without considering inter-relationship between features in general, while set-based feature extraction evaluates features based on their role in a feature set by taking into account dependency between features. Just as learning methods, feature extraction has a problem in its generalization ability, which is robustness. However, the issue of robustness is often overlooked in feature extraction. In order to improve the accuracy and robustness of feature extraction for microarray data, a novel approach based on multi-algorithm fusion is proposed. By fusing different types of feature extraction algorithms to select the feature from the samples set, the proposed approach is able to improve feature extraction performance. The new approach is tested against gene expression dataset including Colon cancer data, CNS data, DLBCL data, and Leukemia data. The testing results show that the performance of this algorithm is better than existing solutions. PMID:25780277

A novel feature extraction approach for microarray data based on multi-algorithm fusion.

PubMed

Jiang, Zhu; Xu, Rong

2015-01-01

Feature extraction is one of the most important and effective method to reduce dimension in data mining, with emerging of high dimensional data such as microarray gene expression data. Feature extraction for gene selection, mainly serves two purposes. One is to identify certain disease-related genes. The other is to find a compact set of discriminative genes to build a pattern classifier with reduced complexity and improved generalization capabilities. Depending on the purpose of gene selection, two types of feature extraction algorithms including ranking-based feature extraction and set-based feature extraction are employed in microarray gene expression data analysis. In ranking-based feature extraction, features are evaluated on an individual basis, without considering inter-relationship between features in general, while set-based feature extraction evaluates features based on their role in a feature set by taking into account dependency between features. Just as learning methods, feature extraction has a problem in its generalization ability, which is robustness. However, the issue of robustness is often overlooked in feature extraction. In order to improve the accuracy and robustness of feature extraction for microarray data, a novel approach based on multi-algorithm fusion is proposed. By fusing different types of feature extraction algorithms to select the feature from the samples set, the proposed approach is able to improve feature extraction performance. The new approach is tested against gene expression dataset including Colon cancer data, CNS data, DLBCL data, and Leukemia data. The testing results show that the performance of this algorithm is better than existing solutions.

Identification of an Efficient Gene Expression Panel for Glioblastoma Classification

PubMed Central

Zelaya, Ivette; Laks, Dan R.; Zhao, Yining; Kawaguchi, Riki; Gao, Fuying; Kornblum, Harley I.; Coppola, Giovanni

2016-01-01

We present here a novel genetic algorithm-based random forest (GARF) modeling technique that enables a reduction in the complexity of large gene disease signatures to highly accurate, greatly simplified gene panels. When applied to 803 glioblastoma multiforme samples, this method allowed the 840-gene Verhaak et al. gene panel (the standard in the field) to be reduced to a 48-gene classifier, while retaining 90.91% classification accuracy, and outperforming the best available alternative methods. Additionally, using this approach we produced a 32-gene panel which allows for better consistency between RNA-seq and microarray-based classifications, improving cross-platform classification retention from 69.67% to 86.07%. A webpage producing these classifications is available at http://simplegbm.semel.ucla.edu. PMID:27855170

Applicability of a gene expression based prediction method to SD and Wistar rats: an example of CARCINOscreen®.

PubMed

Matsumoto, Hiroshi; Saito, Fumiyo; Takeyoshi, Masahiro

2015-12-01

Recently, the development of several gene expression-based prediction methods has been attempted in the fields of toxicology. CARCINOscreen® is a gene expression-based screening method to predict carcinogenicity of chemicals which target the liver with high accuracy. In this study, we investigated the applicability of the gene expression-based screening method to SD and Wistar rats by using CARCINOscreen®, originally developed with F344 rats, with two carcinogens, 2,4-diaminotoluen and thioacetamide, and two non-carcinogens, 2,6-diaminotoluen and sodium benzoate. After the 28-day repeated dose test was conducted with each chemical in SD and Wistar rats, microarray analysis was performed using total RNA extracted from each liver. Obtained gene expression data were applied to CARCINOscreen®. Predictive scores obtained by the CARCINOscreen® for known carcinogens were > 2 in all strains of rats, while non-carcinogens gave prediction scores below 0.5. These results suggested that the gene expression based screening method, CARCINOscreen®, can be applied to SD and Wistar rats, widely used strains in toxicological studies, by setting of an appropriate boundary line of prediction score to classify the chemicals into carcinogens and non-carcinogens.

Classification of early-stage non-small cell lung cancer by weighing gene expression profiles with connectivity information.

PubMed

Zhang, Ao; Tian, Suyan

2018-05-01

Pathway-based feature selection algorithms, which utilize biological information contained in pathways to guide which features/genes should be selected, have evolved quickly and become widespread in the field of bioinformatics. Based on how the pathway information is incorporated, we classify pathway-based feature selection algorithms into three major categories-penalty, stepwise forward, and weighting. Compared to the first two categories, the weighting methods have been underutilized even though they are usually the simplest ones. In this article, we constructed three different genes' connectivity information-based weights for each gene and then conducted feature selection upon the resulting weighted gene expression profiles. Using both simulations and a real-world application, we have demonstrated that when the data-driven connectivity information constructed from the data of specific disease under study is considered, the resulting weighted gene expression profiles slightly outperform the original expression profiles. In summary, a big challenge faced by the weighting method is how to estimate pathway knowledge-based weights more accurately and precisely. Only until the issue is conquered successfully will wide utilization of the weighting methods be impossible. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Combinatorial codon scrambling enables scalable gene synthesis and amplification of repetitive proteins

NASA Astrophysics Data System (ADS)

Tang, Nicholas C.; Chilkoti, Ashutosh

2016-04-01

Most genes are synthesized using seamless assembly methods that rely on the polymerase chain reaction (PCR). However, PCR of genes encoding repetitive proteins either fails or generates nonspecific products. Motivated by the need to efficiently generate new protein polymers through high-throughput gene synthesis, here we report a codon-scrambling algorithm that enables the PCR-based gene synthesis of repetitive proteins by exploiting the codon redundancy of amino acids and finding the least-repetitive synonymous gene sequence. We also show that the codon-scrambling problem is analogous to the well-known travelling salesman problem, and obtain an exact solution to it by using De Bruijn graphs and a modern mixed integer linear programme solver. As experimental proof of the utility of this approach, we use it to optimize the synthetic genes for 19 repetitive proteins, and show that the gene fragments are amenable to PCR-based gene assembly and recombinant expression.

Codon usage and amino acid usage influence genes expression level.

PubMed

Paul, Prosenjit; Malakar, Arup Kumar; Chakraborty, Supriyo

2018-02-01

Highly expressed genes in any species differ in the usage frequency of synonymous codons. The relative recurrence of an event of the favored codon pair (amino acid pairs) varies between gene and genomes due to varying gene expression and different base composition. Here we propose a new measure for predicting the gene expression level, i.e., codon plus amino bias index (CABI). Our approach is based on the relative bias of the favored codon pair inclination among the genes, illustrated by analyzing the CABI score of the Medicago truncatula genes. CABI showed strong correlation with all other widely used measures (CAI, RCBS, SCUO) for gene expression analysis. Surprisingly, CABI outperforms all other measures by showing better correlation with the wet-lab data. This emphasizes the importance of the neighboring codons of the favored codon in a synonymous group while estimating the expression level of a gene.

Improved methods of AAV-mediated gene targeting for human cell lines using ribosome-skipping 2A peptide

PubMed Central

Karnan, Sivasundaram; Ota, Akinobu; Konishi, Yuko; Wahiduzzaman, Md; Hosokawa, Yoshitaka; Konishi, Hiroyuki

2016-01-01

The adeno-associated virus (AAV)-based targeting vector has been one of the tools commonly used for genome modification in human cell lines. It allows for relatively efficient gene targeting associated with 1–4-log higher ratios of homologous-to-random integration of targeting vectors (H/R ratios) than plasmid-based targeting vectors, without actively introducing DNA double-strand breaks. In this study, we sought to improve the efficiency of AAV-mediated gene targeting by introducing a 2A-based promoter-trap system into targeting constructs. We generated three distinct AAV-based targeting vectors carrying 2A for promoter trapping, each targeting a GFP-based reporter module incorporated into the genome, PIGA exon 6 or PIGA intron 5. The absolute gene targeting efficiencies and H/R ratios attained using these vectors were assessed in multiple human cell lines and compared with those attained using targeting vectors carrying internal ribosome entry site (IRES) for promoter trapping. We found that the use of 2A for promoter trapping increased absolute gene targeting efficiencies by 3.4–28-fold and H/R ratios by 2–5-fold compared to values obtained with IRES. In CRISPR-Cas9-assisted gene targeting using plasmid-based targeting vectors, the use of 2A did not enhance the H/R ratios but did upregulate the absolute gene targeting efficiencies compared to the use of IRES. PMID:26657635

Case-based retrieval framework for gene expression data.

PubMed

Anaissi, Ali; Goyal, Madhu; Catchpoole, Daniel R; Braytee, Ali; Kennedy, Paul J

2015-01-01

The process of retrieving similar cases in a case-based reasoning system is considered a big challenge for gene expression data sets. The huge number of gene expression values generated by microarray technology leads to complex data sets and similarity measures for high-dimensional data are problematic. Hence, gene expression similarity measurements require numerous machine-learning and data-mining techniques, such as feature selection and dimensionality reduction, to be incorporated into the retrieval process. This article proposes a case-based retrieval framework that uses a k-nearest-neighbor classifier with a weighted-feature-based similarity to retrieve previously treated patients based on their gene expression profiles. The herein-proposed methodology is validated on several data sets: a childhood leukemia data set collected from The Children's Hospital at Westmead, as well as the Colon cancer, the National Cancer Institute (NCI), and the Prostate cancer data sets. Results obtained by the proposed framework in retrieving patients of the data sets who are similar to new patients are as follows: 96% accuracy on the childhood leukemia data set, 95% on the NCI data set, 93% on the Colon cancer data set, and 98% on the Prostate cancer data set. The designed case-based retrieval framework is an appropriate choice for retrieving previous patients who are similar to a new patient, on the basis of their gene expression data, for better diagnosis and treatment of childhood leukemia. Moreover, this framework can be applied to other gene expression data sets using some or all of its steps.

The Ad5 [E1-, E2b-]-based vector: a new and versatile gene delivery platform

NASA Astrophysics Data System (ADS)

Jones, Frank R.; Gabitzsch, Elizabeth S.; Balint, Joseph P.

2015-05-01

Based upon advances in gene sequencing and construction, it is now possible to identify specific genes or sequences thereof for gene delivery applications. Recombinant adenovirus serotype-5 (Ad5) viral vectors have been utilized in the settings of gene therapy, vaccination, and immunotherapy but have encountered clinical challenges because they are recognized as foreign entities to the host. This recognition leads to an immunologic clearance of the vector that contains the inserted gene of interest and prevents effective immunization(s). We have reported on a new Ad5-based viral vector technology that can be utilized as an immunization modality to induce immune responses even in the presence of Ad5 vector immunity. We have reported successful immunization and immunotherapy results to infectious diseases and cancers. This improved recombinant viral platform (Ad5 [E1-, E2b-]) can now be utilized in the development of multiple vaccines and immunotherapies.

Integrative structural annotation of de novo RNA-Seq provides an accurate reference gene set of the enormous genome of the onion (Allium cepa L.).

PubMed

Kim, Seungill; Kim, Myung-Shin; Kim, Yong-Min; Yeom, Seon-In; Cheong, Kyeongchae; Kim, Ki-Tae; Jeon, Jongbum; Kim, Sunggil; Kim, Do-Sun; Sohn, Seong-Han; Lee, Yong-Hwan; Choi, Doil

2015-02-01

The onion (Allium cepa L.) is one of the most widely cultivated and consumed vegetable crops in the world. Although a considerable amount of onion transcriptome data has been deposited into public databases, the sequences of the protein-coding genes are not accurate enough to be used, owing to non-coding sequences intermixed with the coding sequences. We generated a high-quality, annotated onion transcriptome from de novo sequence assembly and intensive structural annotation using the integrated structural gene annotation pipeline (ISGAP), which identified 54,165 protein-coding genes among 165,179 assembled transcripts totalling 203.0 Mb by eliminating the intron sequences. ISGAP performed reliable annotation, recognizing accurate gene structures based on reference proteins, and ab initio gene models of the assembled transcripts. Integrative functional annotation and gene-based SNP analysis revealed a whole biological repertoire of genes and transcriptomic variation in the onion. The method developed in this study provides a powerful tool for the construction of reference gene sets for organisms based solely on de novo transcriptome data. Furthermore, the reference genes and their variation described here for the onion represent essential tools for molecular breeding and gene cloning in Allium spp. © The Author 2014. Published by Oxford University Press on behalf of Kazusa DNA Research Institute.

Characterizing gene sets using discriminative random walks with restart on heterogeneous biological networks.

PubMed

Blatti, Charles; Sinha, Saurabh

2016-07-15

Analysis of co-expressed gene sets typically involves testing for enrichment of different annotations or 'properties' such as biological processes, pathways, transcription factor binding sites, etc., one property at a time. This common approach ignores any known relationships among the properties or the genes themselves. It is believed that known biological relationships among genes and their many properties may be exploited to more accurately reveal commonalities of a gene set. Previous work has sought to achieve this by building biological networks that combine multiple types of gene-gene or gene-property relationships, and performing network analysis to identify other genes and properties most relevant to a given gene set. Most existing network-based approaches for recognizing genes or annotations relevant to a given gene set collapse information about different properties to simplify (homogenize) the networks. We present a network-based method for ranking genes or properties related to a given gene set. Such related genes or properties are identified from among the nodes of a large, heterogeneous network of biological information. Our method involves a random walk with restarts, performed on an initial network with multiple node and edge types that preserve more of the original, specific property information than current methods that operate on homogeneous networks. In this first stage of our algorithm, we find the properties that are the most relevant to the given gene set and extract a subnetwork of the original network, comprising only these relevant properties. We then re-rank genes by their similarity to the given gene set, based on a second random walk with restarts, performed on the above subnetwork. We demonstrate the effectiveness of this algorithm for ranking genes related to Drosophila embryonic development and aggressive responses in the brains of social animals. DRaWR was implemented as an R package available at veda.cs.illinois.edu/DRaWR. blatti@illinois.edu Supplementary data are available at Bioinformatics online. © The Author 2016. Published by Oxford University Press.

DeepGene: an advanced cancer type classifier based on deep learning and somatic point mutations.

PubMed

Yuan, Yuchen; Shi, Yi; Li, Changyang; Kim, Jinman; Cai, Weidong; Han, Zeguang; Feng, David Dagan

2016-12-23

With the developments of DNA sequencing technology, large amounts of sequencing data have become available in recent years and provide unprecedented opportunities for advanced association studies between somatic point mutations and cancer types/subtypes, which may contribute to more accurate somatic point mutation based cancer classification (SMCC). However in existing SMCC methods, issues like high data sparsity, small volume of sample size, and the application of simple linear classifiers, are major obstacles in improving the classification performance. To address the obstacles in existing SMCC studies, we propose DeepGene, an advanced deep neural network (DNN) based classifier, that consists of three steps: firstly, the clustered gene filtering (CGF) concentrates the gene data by mutation occurrence frequency, filtering out the majority of irrelevant genes; secondly, the indexed sparsity reduction (ISR) converts the gene data into indexes of its non-zero elements, thereby significantly suppressing the impact of data sparsity; finally, the data after CGF and ISR is fed into a DNN classifier, which extracts high-level features for accurate classification. Experimental results on our curated TCGA-DeepGene dataset, which is a reformulated subset of the TCGA dataset containing 12 selected types of cancer, show that CGF, ISR and DNN all contribute in improving the overall classification performance. We further compare DeepGene with three widely adopted classifiers and demonstrate that DeepGene has at least 24% performance improvement in terms of testing accuracy. Based on deep learning and somatic point mutation data, we devise DeepGene, an advanced cancer type classifier, which addresses the obstacles in existing SMCC studies. Experiments indicate that DeepGene outperforms three widely adopted existing classifiers, which is mainly attributed to its deep learning module that is able to extract the high level features between combinatorial somatic point mutations and cancer types.

Combining evidence, biomedical literature and statistical dependence: new insights for functional annotation of gene sets

PubMed Central

Aubry, Marc; Monnier, Annabelle; Chicault, Celine; de Tayrac, Marie; Galibert, Marie-Dominique; Burgun, Anita; Mosser, Jean

2006-01-01

Background Large-scale genomic studies based on transcriptome technologies provide clusters of genes that need to be functionally annotated. The Gene Ontology (GO) implements a controlled vocabulary organised into three hierarchies: cellular components, molecular functions and biological processes. This terminology allows a coherent and consistent description of the knowledge about gene functions. The GO terms related to genes come primarily from semi-automatic annotations made by trained biologists (annotation based on evidence) or text-mining of the published scientific literature (literature profiling). Results We report an original functional annotation method based on a combination of evidence and literature that overcomes the weaknesses and the limitations of each approach. It relies on the Gene Ontology Annotation database (GOA Human) and the PubGene biomedical literature index. We support these annotations with statistically associated GO terms and retrieve associative relations across the three GO hierarchies to emphasise the major pathways involved by a gene cluster. Both annotation methods and associative relations were quantitatively evaluated with a reference set of 7397 genes and a multi-cluster study of 14 clusters. We also validated the biological appropriateness of our hybrid method with the annotation of a single gene (cdc2) and that of a down-regulated cluster of 37 genes identified by a transcriptome study of an in vitro enterocyte differentiation model (CaCo-2 cells). Conclusion The combination of both approaches is more informative than either separate approach: literature mining can enrich an annotation based only on evidence. Text-mining of the literature can also find valuable associated MEDLINE references that confirm the relevance of the annotation. Eventually, GO terms networks can be built with associative relations in order to highlight cooperative and competitive pathways and their connected molecular functions. PMID:16674810

Convergent Evolution at the Gametophytic Self-Incompatibility System in Malus and Prunus

PubMed Central

Cunha, Ana E.; Fonseca, Nuno A.; Iezzoni, Amy; van Nocker, Steve; Vieira, Cristina P.

2015-01-01

S-RNase-based gametophytic self-incompatibility (GSI) has evolved once before the split of the Asteridae and Rosidae. This conclusion is based on the phylogenetic history of the S-RNase that determines pistil specificity. In Rosaceae, molecular characterizations of Prunus species, and species from the tribe Pyreae (i.e., Malus, Pyrus, Sorbus) revealed different numbers of genes determining S-pollen specificity. In Prunus only one pistil and pollen gene determine GSI, while in Pyreae there is one pistil but multiple pollen genes, implying different specificity recognition mechanisms. It is thus conceivable that within Rosaceae the genes involved in GSI in the two lineages are not orthologous but possibly paralogous. To address this hypothesis we characterised the S-RNase lineage and S-pollen lineage genes present in the genomes of five Rosaceae species from three genera: M. × domestica (apple, self-incompatible (SI); tribe Pyreae), P. persica (peach, self-compatible (SC); Amygdaleae), P. mume (mei, SI; Amygdaleae), Fragaria vesca (strawberry, SC; Potentilleae), and F. nipponica (mori-ichigo, SI; Potentilleae). Phylogenetic analyses revealed that the Malus and Prunus S-RNase and S-pollen genes belong to distinct gene lineages, and that only Prunus S-RNase and SFB-lineage genes are present in Fragaria. Thus, S-RNase based GSI system of Malus evolved independently from the ancestral system of Rosaceae. Using expression patterns based on RNA-seq data, the ancestral S-RNase lineage gene is inferred to be expressed in pistils only, while the ancestral S-pollen lineage gene is inferred to be expressed in tissues other than pollen. PMID:25993016

High-throughput detection and screening of plants modified by gene editing using quantitative real-time polymerase chain reaction.

PubMed

Peng, Cheng; Wang, Hua; Xu, Xiaoli; Wang, Xiaofu; Chen, Xiaoyun; Wei, Wei; Lai, Yongmin; Liu, Guoquan; Godwin, Ian Douglas; Li, Jieqin; Zhang, Ling; Xu, Junfeng

2018-05-15

Gene editing techniques are becoming powerful tools for modifying target genes in organisms. Although several methods have been developed to detect gene-edited organisms, these techniques are time and labour intensive. Meanwhile, few studies have investigated high-throughput detection and screening strategies for plants modified by gene editing. In this study, we developed a simple, sensitive and high-throughput quantitative real-time (qPCR)-based method. The qPCR-based method exploits two differently labelled probes that are placed within one amplicon at the gene editing target site to simultaneously detect the wild-type and a gene-edited mutant. We showed that the qPCR-based method can accurately distinguish CRISPR/Cas9-induced mutants from the wild-type in several different plant species, such as Oryza sativa, Arabidopsis thaliana, Sorghum bicolor, and Zea mays. Moreover, the method can subsequently determine the mutation type by direct sequencing of the qPCR products of mutations due to gene editing. The qPCR-based method is also sufficiently sensitive to distinguish between heterozygous and homozygous mutations in T 0 transgenic plants. In a 384-well plate format, the method enabled the simultaneous analysis of up to 128 samples in three replicates without handling the post-polymerase chain reaction (PCR) products. Thus, we propose that our method is an ideal choice for screening plants modified by gene editing from many candidates in T 0 transgenic plants, which will be widely used in the area of plant gene editing. © 2018 The Authors The Plant Journal © 2018 John Wiley & Sons Ltd.

Convergent evolution at the gametophytic self-incompatibility system in Malus and Prunus.

PubMed

Aguiar, Bruno; Vieira, Jorge; Cunha, Ana E; Fonseca, Nuno A; Iezzoni, Amy; van Nocker, Steve; Vieira, Cristina P

2015-01-01

S-RNase-based gametophytic self-incompatibility (GSI) has evolved once before the split of the Asteridae and Rosidae. This conclusion is based on the phylogenetic history of the S-RNase that determines pistil specificity. In Rosaceae, molecular characterizations of Prunus species, and species from the tribe Pyreae (i.e., Malus, Pyrus, Sorbus) revealed different numbers of genes determining S-pollen specificity. In Prunus only one pistil and pollen gene determine GSI, while in Pyreae there is one pistil but multiple pollen genes, implying different specificity recognition mechanisms. It is thus conceivable that within Rosaceae the genes involved in GSI in the two lineages are not orthologous but possibly paralogous. To address this hypothesis we characterised the S-RNase lineage and S-pollen lineage genes present in the genomes of five Rosaceae species from three genera: M. × domestica (apple, self-incompatible (SI); tribe Pyreae), P. persica (peach, self-compatible (SC); Amygdaleae), P. mume (mei, SI; Amygdaleae), Fragaria vesca (strawberry, SC; Potentilleae), and F. nipponica (mori-ichigo, SI; Potentilleae). Phylogenetic analyses revealed that the Malus and Prunus S-RNase and S-pollen genes belong to distinct gene lineages, and that only Prunus S-RNase and SFB-lineage genes are present in Fragaria. Thus, S-RNase based GSI system of Malus evolved independently from the ancestral system of Rosaceae. Using expression patterns based on RNA-seq data, the ancestral S-RNase lineage gene is inferred to be expressed in pistils only, while the ancestral S-pollen lineage gene is inferred to be expressed in tissues other than pollen.

ATHENA: A knowledge-based hybrid backpropagation-grammatical evolution neural network algorithm for discovering epistasis among quantitative trait Loci

PubMed Central

2010-01-01

Background Growing interest and burgeoning technology for discovering genetic mechanisms that influence disease processes have ushered in a flood of genetic association studies over the last decade, yet little heritability in highly studied complex traits has been explained by genetic variation. Non-additive gene-gene interactions, which are not often explored, are thought to be one source of this "missing" heritability. Methods Stochastic methods employing evolutionary algorithms have demonstrated promise in being able to detect and model gene-gene and gene-environment interactions that influence human traits. Here we demonstrate modifications to a neural network algorithm in ATHENA (the Analysis Tool for Heritable and Environmental Network Associations) resulting in clear performance improvements for discovering gene-gene interactions that influence human traits. We employed an alternative tree-based crossover, backpropagation for locally fitting neural network weights, and incorporation of domain knowledge obtainable from publicly accessible biological databases for initializing the search for gene-gene interactions. We tested these modifications in silico using simulated datasets. Results We show that the alternative tree-based crossover modification resulted in a modest increase in the sensitivity of the ATHENA algorithm for discovering gene-gene interactions. The performance increase was highly statistically significant when backpropagation was used to locally fit NN weights. We also demonstrate that using domain knowledge to initialize the search for gene-gene interactions results in a large performance increase, especially when the search space is larger than the search coverage. Conclusions We show that a hybrid optimization procedure, alternative crossover strategies, and incorporation of domain knowledge from publicly available biological databases can result in marked increases in sensitivity and performance of the ATHENA algorithm for detecting and modelling gene-gene interactions that influence a complex human trait. PMID:20875103

VarWalker: Personalized Mutation Network Analysis of Putative Cancer Genes from Next-Generation Sequencing Data

PubMed Central

Jia, Peilin; Zhao, Zhongming

2014-01-01

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data. PMID:24516372

VarWalker: personalized mutation network analysis of putative cancer genes from next-generation sequencing data.

PubMed

Jia, Peilin; Zhao, Zhongming

2014-02-01

A major challenge in interpreting the large volume of mutation data identified by next-generation sequencing (NGS) is to distinguish driver mutations from neutral passenger mutations to facilitate the identification of targetable genes and new drugs. Current approaches are primarily based on mutation frequencies of single-genes, which lack the power to detect infrequently mutated driver genes and ignore functional interconnection and regulation among cancer genes. We propose a novel mutation network method, VarWalker, to prioritize driver genes in large scale cancer mutation data. VarWalker fits generalized additive models for each sample based on sample-specific mutation profiles and builds on the joint frequency of both mutation genes and their close interactors. These interactors are selected and optimized using the Random Walk with Restart algorithm in a protein-protein interaction network. We applied the method in >300 tumor genomes in two large-scale NGS benchmark datasets: 183 lung adenocarcinoma samples and 121 melanoma samples. In each cancer, we derived a consensus mutation subnetwork containing significantly enriched consensus cancer genes and cancer-related functional pathways. These cancer-specific mutation networks were then validated using independent datasets for each cancer. Importantly, VarWalker prioritizes well-known, infrequently mutated genes, which are shown to interact with highly recurrently mutated genes yet have been ignored by conventional single-gene-based approaches. Utilizing VarWalker, we demonstrated that network-assisted approaches can be effectively adapted to facilitate the detection of cancer driver genes in NGS data.

Network-based differential gene expression analysis suggests cell cycle related genes regulated by E2F1 underlie the molecular difference between smoker and non-smoker lung adenocarcinoma

PubMed Central

2013-01-01

Background Differential gene expression (DGE) analysis is commonly used to reveal the deregulated molecular mechanisms of complex diseases. However, traditional DGE analysis (e.g., the t test or the rank sum test) tests each gene independently without considering interactions between them. Top-ranked differentially regulated genes prioritized by the analysis may not directly relate to the coherent molecular changes underlying complex diseases. Joint analyses of co-expression and DGE have been applied to reveal the deregulated molecular modules underlying complex diseases. Most of these methods consist of separate steps: first to identify gene-gene relationships under the studied phenotype then to integrate them with gene expression changes for prioritizing signature genes, or vice versa. It is warrant a method that can simultaneously consider gene-gene co-expression strength and corresponding expression level changes so that both types of information can be leveraged optimally. Results In this paper, we develop a gene module based method for differential gene expression analysis, named network-based differential gene expression (nDGE) analysis, a one-step integrative process for prioritizing deregulated genes and grouping them into gene modules. We demonstrate that nDGE outperforms existing methods in prioritizing deregulated genes and discovering deregulated gene modules using simulated data sets. When tested on a series of smoker and non-smoker lung adenocarcinoma data sets, we show that top differentially regulated genes identified by the rank sum test in different sets are not consistent while top ranked genes defined by nDGE in different data sets significantly overlap. nDGE results suggest that a differentially regulated gene module, which is enriched for cell cycle related genes and E2F1 targeted genes, plays a role in the molecular differences between smoker and non-smoker lung adenocarcinoma. Conclusions In this paper, we develop nDGE to prioritize deregulated genes and group them into gene modules by simultaneously considering gene expression level changes and gene-gene co-regulations. When applied to both simulated and empirical data, nDGE outperforms the traditional DGE method. More specifically, when applied to smoker and non-smoker lung cancer sets, nDGE results illustrate the molecular differences between smoker and non-smoker lung cancer. PMID:24341432

Dawn of ocular gene therapy: implications for molecular diagnosis in retinal disease

PubMed Central

Jacques, ZANEVELD; Feng, WANG; Xia, WANG; Rui, CHEN

2013-01-01

Personalized medicine aims to utilize genomic information about patients to tailor treatment. Gene replacement therapy for rare genetic disorders is perhaps the most extreme form of personalized medicine, in that the patients’ genome wholly determines their treatment regimen. Gene therapy for retinal disorders is poised to become a clinical reality. The eye is an optimal site for gene therapy due to the relative ease of precise vector delivery, immune system isolation, and availability for monitoring of any potential damage or side effects. Due to these advantages, clinical trials for gene therapy of retinal diseases are currently underway. A necessary precursor to such gene therapies is accurate molecular diagnosis of the mutation(s) underlying disease. In this review, we discuss the application of Next Generation Sequencing (NGS) to obtain such a diagnosis and identify disease causing genes, using retinal disorders as a case study. After reviewing ocular gene therapy, we discuss the application of NGS to the identification of novel Mendelian disease genes. We then compare current, array based mutation detection methods against next NGS-based methods in three retinal diseases: Leber’s Congenital Amaurosis, Retinitis Pigmentosa, and Stargardt’s disease. We conclude that next-generation sequencing based diagnosis offers several advantages over array based methods, including a higher rate of successful diagnosis and the ability to more deeply and efficiently assay a broad spectrum of mutations. However, the relative difficulty of interpreting sequence results and the development of standardized, reliable bioinformatic tools remain outstanding concerns. In this review, recent advances NGS based molecular diagnoses are discussed, as well as their implications for the development of personalized medicine. PMID:23393028

78 FR 26794 - Prospective Grant of Start-Up Exclusive Evaluation Option License Agreement: Gene Therapy and...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-08

...-Up Exclusive Evaluation Option License Agreement: Gene Therapy and Cell-Based Therapy for Cardiac... the field of use may be limited to ``Gene therapy and cell-based therapy for cardiac arrhythmias in...\\2+\\-activated adenylyl cyclase, as well as cardiac cells or cardiac-like cells derived from...

A sight on protein-based nanoparticles as drug/gene delivery systems.

PubMed

Salatin, Sara; Jelvehgari, Mitra; Maleki-Dizaj, Solmaz; Adibkia, Khosro

2015-01-01

Polymeric nanomaterials have extensively been applied for the preparation of targeted and controlled release drug/gene delivery systems. However, problems involved in the formulation of synthetic polymers such as using of the toxic solvents and surfactants have limited their desirable applications. In this regard, natural biomolecules including proteins and polysaccharide are suitable alternatives due to their safety. According to literature, protein-based nanoparticles possess many advantages for drug and gene delivery such as biocompatibility, biodegradability and ability to functionalize with targeting ligands. This review provides a general sight on the application of biodegradable protein-based nanoparticles in drug/gene delivery based on their origins. Their unique physicochemical properties that help them to be formulated as pharmaceutical carriers are also discussed.

Development and application of an interaction network ontology for literature mining of vaccine-associated gene-gene interactions.

PubMed

Hur, Junguk; Özgür, Arzucan; Xiang, Zuoshuang; He, Yongqun

2015-01-01

Literature mining of gene-gene interactions has been enhanced by ontology-based name classifications. However, in biomedical literature mining, interaction keywords have not been carefully studied and used beyond a collection of keywords. In this study, we report the development of a new Interaction Network Ontology (INO) that classifies >800 interaction keywords and incorporates interaction terms from the PSI Molecular Interactions (PSI-MI) and Gene Ontology (GO). Using INO-based literature mining results, a modified Fisher's exact test was established to analyze significantly over- and under-represented enriched gene-gene interaction types within a specific area. Such a strategy was applied to study the vaccine-mediated gene-gene interactions using all PubMed abstracts. The Vaccine Ontology (VO) and INO were used to support the retrieval of vaccine terms and interaction keywords from the literature. INO is aligned with the Basic Formal Ontology (BFO) and imports terms from 10 other existing ontologies. Current INO includes 540 terms. In terms of interaction-related terms, INO imports and aligns PSI-MI and GO interaction terms and includes over 100 newly generated ontology terms with 'INO_' prefix. A new annotation property, 'has literature mining keywords', was generated to allow the listing of different keywords mapping to the interaction types in INO. Using all PubMed documents published as of 12/31/2013, approximately 266,000 vaccine-associated documents were identified, and a total of 6,116 gene-pairs were associated with at least one INO term. Out of 78 INO interaction terms associated with at least five gene-pairs of the vaccine-associated sub-network, 14 terms were significantly over-represented (i.e., more frequently used) and 17 under-represented based on our modified Fisher's exact test. These over-represented and under-represented terms share some common top-level terms but are distinct at the bottom levels of the INO hierarchy. The analysis of these interaction types and their associated gene-gene pairs uncovered many scientific insights. INO provides a novel approach for defining hierarchical interaction types and related keywords for literature mining. The ontology-based literature mining, in combination with an INO-based statistical interaction enrichment test, provides a new platform for efficient mining and analysis of topic-specific gene interaction networks.

Gene context analysis in the Integrated Microbial Genomes (IMG) data management system.

PubMed

Mavromatis, Konstantinos; Chu, Ken; Ivanova, Natalia; Hooper, Sean D; Markowitz, Victor M; Kyrpides, Nikos C

2009-11-24

Computational methods for determining the function of genes in newly sequenced genomes have been traditionally based on sequence similarity to genes whose function has been identified experimentally. Function prediction methods can be extended using gene context analysis approaches such as examining the conservation of chromosomal gene clusters, gene fusion events and co-occurrence profiles across genomes. Context analysis is based on the observation that functionally related genes are often having similar gene context and relies on the identification of such events across phylogenetically diverse collection of genomes. We have used the data management system of the Integrated Microbial Genomes (IMG) as the framework to implement and explore the power of gene context analysis methods because it provides one of the largest available genome integrations. Visualization and search tools to facilitate gene context analysis have been developed and applied across all publicly available archaeal and bacterial genomes in IMG. These computations are now maintained as part of IMG's regular genome content update cycle. IMG is available at: http://img.jgi.doe.gov.

Pathway-based analysis of GWAs data identifies association of sex determination genes with susceptibility to testicular germ cell tumors.

PubMed

Koster, Roelof; Mitra, Nandita; D'Andrea, Kurt; Vardhanabhuti, Saran; Chung, Charles C; Wang, Zhaoming; Loren Erickson, R; Vaughn, David J; Litchfield, Kevin; Rahman, Nazneen; Greene, Mark H; McGlynn, Katherine A; Turnbull, Clare; Chanock, Stephen J; Nathanson, Katherine L; Kanetsky, Peter A

2014-11-15

Genome-wide association (GWA) studies of testicular germ cell tumor (TGCT) have identified 18 susceptibility loci, some containing genes encoding proteins important in male germ cell development. Deletions of one of these genes, DMRT1, lead to male-to-female sex reversal and are associated with development of gonadoblastoma. To further explore genetic association with TGCT, we undertook a pathway-based analysis of SNP marker associations in the Penn GWAs (349 TGCT cases and 919 controls). We analyzed a custom-built sex determination gene set consisting of 32 genes using three different methods of pathway-based analysis. The sex determination gene set ranked highly compared with canonical gene sets, and it was associated with TGCT (FDRG = 2.28 × 10(-5), FDRM = 0.014 and FDRI = 0.008 for Gene Set Analysis-SNP (GSA-SNP), Meta-Analysis Gene Set Enrichment of Variant Associations (MAGENTA) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (i-GSEA4GWAS) analysis, respectively). The association remained after removal of DMRT1 from the gene set (FDRG = 0.0002, FDRM = 0.055 and FDRI = 0.009). Using data from the NCI GWA scan (582 TGCT cases and 1056 controls) and UK scan (986 TGCT cases and 4946 controls), we replicated these findings (NCI: FDRG = 0.006, FDRM = 0.014, FDRI = 0.033, and UK: FDRG = 1.04 × 10(-6), FDRM = 0.016, FDRI = 0.025). After removal of DMRT1 from the gene set, the sex determination gene set remains associated with TGCT in the NCI (FDRG = 0.039, FDRM = 0.050 and FDRI = 0.055) and UK scans (FDRG = 3.00 × 10(-5), FDRM = 0.056 and FDRI = 0.044). With the exception of DMRT1, genes in the sex determination gene set have not previously been identified as TGCT susceptibility loci in these GWA scans, demonstrating the complementary nature of a pathway-based approach for genome-wide analysis of TGCT. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Robust and Comprehensive Analysis of 20 Osteoporosis Candidate Genes by Very High-Density Single-Nucleotide Polymorphism Screen Among 405 White Nuclear Families Identified Significant Association and Gene–Gene Interaction

PubMed Central

Xiong, Dong-Hai; Shen, Hui; Zhao, Lan-Juan; Xiao, Peng; Yang, Tie-Lin; Guo, Yan; Wang, Wei; Guo, Yan-Fang; Liu, Yong-Jun; Recker, Robert R; Deng, Hong-Wen

2007-01-01

Many “novel” osteoporosis candidate genes have been proposed in recent years. To advance our knowledge of their roles in osteoporosis, we screened 20 such genes using a set of high-density SNPs in a large family-based study. Our efforts led to the prioritization of those osteoporosis genes and the detection of gene–gene interactions. Introduction We performed large-scale family-based association analyses of 20 novel osteoporosis candidate genes using 277 single nucleotide polymorphisms (SNPs) for the quantitative trait BMD variation and the qualitative trait osteoporosis (OP) at three clinically important skeletal sites: spine, hip, and ultradistal radius (UD). Materials and Methods One thousand eight hundred seventy-three subjects from 405 white nuclear families were genotyped and analyzed with an average density of one SNP per 4 kb across the 20 genes. We conducted association analyses by SNP- and haplotype-based family-based association test (FBAT) and performed gene–gene interaction analyses using multianalytic approaches such as multifactor-dimensionality reduction (MDR) and conditional logistic regression. Results and Conclusions We detected four genes (DBP, LRP5, CYP17, and RANK) that showed highly suggestive associations (10,000-permutation derived empirical global p ≤ 0.01) with spine BMD/OP; four genes (CYP19, RANK, RANKL, and CYP17) highly suggestive for hip BMD/OP; and four genes (CYP19, BMP2, RANK, and TNFR2) highly suggestive for UD BMD/OP. The associations between BMP2 with UD BMD and those between RANK with OP at the spine, hip, and UD also met the experiment-wide stringent criterion (empirical global p ≤ 0.0007). Sex-stratified analyses further showed that some of the significant associations in the total sample were driven by either male or female subjects. In addition, we identified and validated a two-locus gene–gene interaction model involving GCR and ESR2, for which prior biological evidence exists. Our results suggested the prioritization of osteoporosis candidate genes from among the many proposed in recent years and revealed the significant gene–gene interaction effects influencing osteoporosis risk. PMID:17002564

LCGbase: A Comprehensive Database for Lineage-Based Co-regulated Genes.

PubMed

Wang, Dapeng; Zhang, Yubin; Fan, Zhonghua; Liu, Guiming; Yu, Jun

2012-01-01

Animal genes of different lineages, such as vertebrates and arthropods, are well-organized and blended into dynamic chromosomal structures that represent a primary regulatory mechanism for body development and cellular differentiation. The majority of genes in a genome are actually clustered, which are evolutionarily stable to different extents and biologically meaningful when evaluated among genomes within and across lineages. Until now, many questions concerning gene organization, such as what is the minimal number of genes in a cluster and what is the driving force leading to gene co-regulation, remain to be addressed. Here, we provide a user-friendly database-LCGbase (a comprehensive database for lineage-based co-regulated genes)-hosting information on evolutionary dynamics of gene clustering and ordering within animal kingdoms in two different lineages: vertebrates and arthropods. The database is constructed on a web-based Linux-Apache-MySQL-PHP framework and effective interactive user-inquiry service. Compared to other gene annotation databases with similar purposes, our database has three comprehensible advantages. First, our database is inclusive, including all high-quality genome assemblies of vertebrates and representative arthropod species. Second, it is human-centric since we map all gene clusters from other genomes in an order of lineage-ranks (such as primates, mammals, warm-blooded, and reptiles) onto human genome and start the database from well-defined gene pairs (a minimal cluster where the two adjacent genes are oriented as co-directional, convergent, and divergent pairs) to large gene clusters. Furthermore, users can search for any adjacent genes and their detailed annotations. Third, the database provides flexible parameter definitions, such as the distance of transcription start sites between two adjacent genes, which is extendable to genes that flanking the cluster across species. We also provide useful tools for sequence alignment, gene ontology (GO) annotation, promoter identification, gene expression (co-expression), and evolutionary analysis. This database not only provides a way to define lineage-specific and species-specific gene clusters but also facilitates future studies on gene co-regulation, epigenetic control of gene expression (DNA methylation and histone marks), and chromosomal structures in a context of gene clusters and species evolution. LCGbase is freely available at http://lcgbase.big.ac.cn/LCGbase.

Analysis of blood-based gene expression in idiopathic Parkinson disease.

PubMed

Shamir, Ron; Klein, Christine; Amar, David; Vollstedt, Eva-Juliane; Bonin, Michael; Usenovic, Marija; Wong, Yvette C; Maver, Ales; Poths, Sven; Safer, Hershel; Corvol, Jean-Christophe; Lesage, Suzanne; Lavi, Ofer; Deuschl, Günther; Kuhlenbaeumer, Gregor; Pawlack, Heike; Ulitsky, Igor; Kasten, Meike; Riess, Olaf; Brice, Alexis; Peterlin, Borut; Krainc, Dimitri

2017-10-17

To examine whether gene expression analysis of a large-scale Parkinson disease (PD) patient cohort produces a robust blood-based PD gene signature compared to previous studies that have used relatively small cohorts (≤220 samples). Whole-blood gene expression profiles were collected from a total of 523 individuals. After preprocessing, the data contained 486 gene profiles (n = 205 PD, n = 233 controls, n = 48 other neurodegenerative diseases) that were partitioned into training, validation, and independent test cohorts to identify and validate a gene signature. Batch-effect reduction and cross-validation were performed to ensure signature reliability. Finally, functional and pathway enrichment analyses were applied to the signature to identify PD-associated gene networks. A gene signature of 100 probes that mapped to 87 genes, corresponding to 64 upregulated and 23 downregulated genes differentiating between patients with idiopathic PD and controls, was identified with the training cohort and successfully replicated in both an independent validation cohort (area under the curve [AUC] = 0.79, p = 7.13E-6) and a subsequent independent test cohort (AUC = 0.74, p = 4.2E-4). Network analysis of the signature revealed gene enrichment in pathways, including metabolism, oxidation, and ubiquitination/proteasomal activity, and misregulation of mitochondria-localized genes, including downregulation of COX4I1 , ATP5A1 , and VDAC3 . We present a large-scale study of PD gene expression profiling. This work identifies a reliable blood-based PD signature and highlights the importance of large-scale patient cohorts in developing potential PD biomarkers. © 2017 American Academy of Neurology.

Identification of Human Disease Genes from Interactome Network Using Graphlet Interaction

PubMed Central

Yang, Lun; Wei, Dong-Qing; Qi, Ying-Xin; Jiang, Zong-Lai

2014-01-01

Identifying genes related to human diseases, such as cancer and cardiovascular disease, etc., is an important task in biomedical research because of its applications in disease diagnosis and treatment. Interactome networks, especially protein-protein interaction networks, had been used to disease genes identification based on the hypothesis that strong candidate genes tend to closely relate to each other in some kinds of measure on the network. We proposed a new measure to analyze the relationship between network nodes which was called graphlet interaction. The graphlet interaction contained 28 different isomers. The results showed that the numbers of the graphlet interaction isomers between disease genes in interactome networks were significantly larger than random picked genes, while graphlet signatures were not. Then, we designed a new type of score, based on the network properties, to identify disease genes using graphlet interaction. The genes with higher scores were more likely to be disease genes, and all candidate genes were ranked according to their scores. Then the approach was evaluated by leave-one-out cross-validation. The precision of the current approach achieved 90% at about 10% recall, which was apparently higher than the previous three predominant algorithms, random walk, Endeavour and neighborhood based method. Finally, the approach was applied to predict new disease genes related to 4 common diseases, most of which were identified by other independent experimental researches. In conclusion, we demonstrate that the graphlet interaction is an effective tool to analyze the network properties of disease genes, and the scores calculated by graphlet interaction is more precise in identifying disease genes. PMID:24465923

Genes2Networks: connecting lists of gene symbols using mammalian protein interactions databases.

PubMed

Berger, Seth I; Posner, Jeremy M; Ma'ayan, Avi

2007-10-04

In recent years, mammalian protein-protein interaction network databases have been developed. The interactions in these databases are either extracted manually from low-throughput experimental biomedical research literature, extracted automatically from literature using techniques such as natural language processing (NLP), generated experimentally using high-throughput methods such as yeast-2-hybrid screens, or interactions are predicted using an assortment of computational approaches. Genes or proteins identified as significantly changing in proteomic experiments, or identified as susceptibility disease genes in genomic studies, can be placed in the context of protein interaction networks in order to assign these genes and proteins to pathways and protein complexes. Genes2Networks is a software system that integrates the content of ten mammalian interaction network datasets. Filtering techniques to prune low-confidence interactions were implemented. Genes2Networks is delivered as a web-based service using AJAX. The system can be used to extract relevant subnetworks created from "seed" lists of human Entrez gene symbols. The output includes a dynamic linkable three color web-based network map, with a statistical analysis report that identifies significant intermediate nodes used to connect the seed list. Genes2Networks is powerful web-based software that can help experimental biologists to interpret lists of genes and proteins such as those commonly produced through genomic and proteomic experiments, as well as lists of genes and proteins associated with disease processes. This system can be used to find relationships between genes and proteins from seed lists, and predict additional genes or proteins that may play key roles in common pathways or protein complexes.

Inferring causal genomic alterations in breast cancer using gene expression data

PubMed Central

2011-01-01

Background One of the primary objectives in cancer research is to identify causal genomic alterations, such as somatic copy number variation (CNV) and somatic mutations, during tumor development. Many valuable studies lack genomic data to detect CNV; therefore, methods that are able to infer CNVs from gene expression data would help maximize the value of these studies. Results We developed a framework for identifying recurrent regions of CNV and distinguishing the cancer driver genes from the passenger genes in the regions. By inferring CNV regions across many datasets we were able to identify 109 recurrent amplified/deleted CNV regions. Many of these regions are enriched for genes involved in many important processes associated with tumorigenesis and cancer progression. Genes in these recurrent CNV regions were then examined in the context of gene regulatory networks to prioritize putative cancer driver genes. The cancer driver genes uncovered by the framework include not only well-known oncogenes but also a number of novel cancer susceptibility genes validated via siRNA experiments. Conclusions To our knowledge, this is the first effort to systematically identify and validate drivers for expression based CNV regions in breast cancer. The framework where the wavelet analysis of copy number alteration based on expression coupled with the gene regulatory network analysis, provides a blueprint for leveraging genomic data to identify key regulatory components and gene targets. This integrative approach can be applied to many other large-scale gene expression studies and other novel types of cancer data such as next-generation sequencing based expression (RNA-Seq) as well as CNV data. PMID:21806811

Computational gene network study on antibiotic resistance genes of Acinetobacter baumannii.

PubMed

Anitha, P; Anbarasu, Anand; Ramaiah, Sudha

2014-05-01

Multi Drug Resistance (MDR) in Acinetobacter baumannii is one of the major threats for emerging nosocomial infections in hospital environment. Multidrug-resistance in A. baumannii may be due to the implementation of multi-combination resistance mechanisms such as β-lactamase synthesis, Penicillin-Binding Proteins (PBPs) changes, alteration in porin proteins and in efflux pumps against various existing classes of antibiotics. Multiple antibiotic resistance genes are involved in MDR. These resistance genes are transferred through plasmids, which are responsible for the dissemination of antibiotic resistance among Acinetobacter spp. In addition, these resistance genes may also have a tendency to interact with each other or with their gene products. Therefore, it becomes necessary to understand the impact of these interactions in antibiotic resistance mechanism. Hence, our study focuses on protein and gene network analysis on various resistance genes, to elucidate the role of the interacting proteins and to study their functional contribution towards antibiotic resistance. From the search tool for the retrieval of interacting gene/protein (STRING), a total of 168 functional partners for 15 resistance genes were extracted based on the confidence scoring system. The network study was then followed up with functional clustering of associated partners using molecular complex detection (MCODE). Later, we selected eight efficient clusters based on score. Interestingly, the associated protein we identified from the network possessed greater functional similarity with known resistance genes. This network-based approach on resistance genes of A. baumannii could help in identifying new genes/proteins and provide clues on their association in antibiotic resistance. Copyright © 2014 Elsevier Ltd. All rights reserved.