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Sample records for als phenotypes identifies

  1. Latent cluster analysis of ALS phenotypes identifies prognostically differing groups.

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    Jeban Ganesalingam

    Full Text Available BACKGROUND: Amyotrophic lateral sclerosis (ALS is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS: Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS: The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001. Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb and time from symptom onset to diagnosis (p<0.00001. CONCLUSION: The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research.

  2. An Effective Method to Identify Heritable Components from Multivariate Phenotypes.

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    Jiangwen Sun

    Full Text Available Multivariate phenotypes may be characterized collectively by a variety of low level traits, such as in the diagnosis of a disease that relies on multiple disease indicators. Such multivariate phenotypes are often used in genetic association studies. If highly heritable components of a multivariate phenotype can be identified, it can maximize the likelihood of finding genetic associations. Existing methods for phenotype refinement perform unsupervised cluster analysis on low-level traits and hence do not assess heritability. Existing heritable component analytics either cannot utilize general pedigrees or have to estimate the entire covariance matrix of low-level traits from limited samples, which leads to inaccurate estimates and is often computationally prohibitive. It is also difficult for these methods to exclude fixed effects from other covariates such as age, sex and race, in order to identify truly heritable components. We propose to search for a combination of low-level traits and directly maximize the heritability of this combined trait. A quadratic optimization problem is thus derived where the objective function is formulated by decomposing the traditional maximum likelihood method for estimating the heritability of a quantitative trait. The proposed approach can generate linearly-combined traits of high heritability that has been corrected for the fixed effects of covariates. The effectiveness of the proposed approach is demonstrated in simulations and by a case study of cocaine dependence. Our approach was computationally efficient and derived traits of higher heritability than those by other methods. Additional association analysis with the derived cocaine-use trait identified genetic markers that were replicated in an independent sample, further confirming the utility and advantage of the proposed approach.

  3. Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data.

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    Jonathan D Mosley

    Full Text Available A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1 non-synonymous SNPs (nsSNPs associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1 thrombosis, evaluated in a population of 1,655 African Americans; and (2 four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs, and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03, driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03 (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005 (KIF25, PINX1. We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.

  4. Integration of curated databases to identify genotype-phenotype associations

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    Li Jianrong

    2006-10-01

    Full Text Available Abstract Background The ability to rapidly characterize an unknown microorganism is critical in both responding to infectious disease and biodefense. To do this, we need some way of anticipating an organism's phenotype based on the molecules encoded by its genome. However, the link between molecular composition (i.e. genotype and phenotype for microbes is not obvious. While there have been several studies that address this challenge, none have yet proposed a large-scale method integrating curated biological information. Here we utilize a systematic approach to discover genotype-phenotype associations that combines phenotypic information from a biomedical informatics database, GIDEON, with the molecular information contained in National Center for Biotechnology Information's Clusters of Orthologous Groups database (NCBI COGs. Results Integrating the information in the two databases, we are able to correlate the presence or absence of a given protein in a microbe with its phenotype as measured by certain morphological characteristics or survival in a particular growth media. With a 0.8 correlation score threshold, 66% of the associations found were confirmed by the literature and at a 0.9 correlation threshold, 86% were positively verified. Conclusion Our results suggest possible phenotypic manifestations for proteins biochemically associated with sugar metabolism and electron transport. Moreover, we believe our approach can be extended to linking pathogenic phenotypes with functionally related proteins.

  5. Identifiable Phenotyping using Constrained Non-Negative Matrix Factorization

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    Joshi, Shalmali; Gunasekar, Suriya; Sontag, David; Ghosh, Joydeep

    2016-01-01

    This work proposes a new algorithm for automated and simultaneous phenotyping of multiple co-occurring medical conditions, also referred as comorbidities, using clinical notes from the electronic health records (EHRs). A basic latent factor estimation technique of non-negative matrix factorization (NMF) is augmented with domain specific constraints to obtain sparse latent factors that are anchored to a fixed set of chronic conditions. The proposed anchoring mechanism ensures a one-to-one iden...

  6. Als2 mRNA splicing variants detected in KO mice rescue severe motor dysfunction phenotype in Als2 knock-down zebrafish.

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    Gros-Louis, Francois; Kriz, Jasna; Kabashi, Edor; McDearmid, Jonathan; Millecamps, Stéphanie; Urushitani, Makoto; Lin, Li; Dion, Patrick; Zhu, Qinzhang; Drapeau, Pierre; Julien, Jean-Pierre; Rouleau, Guy A

    2008-09-01

    Recessive ALS2 mutations are linked to three related but slightly different neurodegenerative disorders: amyotrophic lateral sclerosis, hereditary spastic paraplegia and primary lateral sclerosis. To investigate the function of the ALS2 encoded protein, we generated Als2 knock-out (KO) mice and zAls2 knock-down zebrafish. The Als2(-/-) mice lacking exon 2 and part of exon 3 developed mild signs of neurodegeneration compatible with axonal transport deficiency. In contrast, zAls2 knock-down zebrafish had severe developmental abnormalities, swimming deficits and motor neuron perturbation. We identified, by RT-PCR, northern and western blotting novel Als2 transcripts in mouse central nervous system. These Als2 transcripts were present in Als2 null mice as well as in wild-type littermates and some rescued the zebrafish phenotype. Thus, we speculate that the newly identified Als2 mRNA species prevent the Als2 KO mice from developing severe neurodegenerative disease and might also regulate the severity of the motor neurons phenotype observed in ALS2 patients. PMID:18558633

  7. Identifying novel protein phenotype annotations by hybridizing protein-protein interactions and protein sequence similarities.

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    Chen, Lei; Zhang, Yu-Hang; Huang, Tao; Cai, Yu-Dong

    2016-04-01

    Studies of protein phenotypes represent a central challenge of modern genetics in the post-genome era because effective and accurate investigation of protein phenotypes is one of the most critical procedures to identify functional biological processes in microscale, which involves the analysis of multifactorial traits and has greatly contributed to the development of modern biology in the post genome era. Therefore, we have developed a novel computational method that identifies novel proteins associated with certain phenotypes in yeast based on the protein-protein interaction network. Unlike some existing network-based computational methods that identify the phenotype of a query protein based on its direct neighbors in the local network, the proposed method identifies novel candidate proteins for a certain phenotype by considering all annotated proteins with this phenotype on the global network using a shortest path (SP) algorithm. The identified proteins are further filtered using both a permutation test and their interactions and sequence similarities to annotated proteins. We compared our method with another widely used method called random walk with restart (RWR). The biological functions of proteins for each phenotype identified by our SP method and the RWR method were analyzed and compared. The results confirmed a large proportion of our novel protein phenotype annotation, and the RWR method showed a higher false positive rate than the SP method. Our method is equally effective for the prediction of proteins involving in all the eleven clustered yeast phenotypes with a quite low false positive rate. Considering the universality and generalizability of our supporting materials and computing strategies, our method can further be applied to study other organisms and the new functions we predicted can provide pertinent instructions for the further experimental verifications. PMID:26728152

  8. A review of approaches to identifying patient phenotype cohorts using electronic health records

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    Shivade, Chaitanya; Raghavan, Preethi; Fosler-Lussier, Eric; Embi, Peter J; Elhadad, Noemie; Johnson, Stephen B.; Lai, Albert M.

    2013-01-01

    Objective To summarize literature describing approaches aimed at automatically identifying patients with a common phenotype. Materials and methods We performed a review of studies describing systems or reporting techniques developed for identifying cohorts of patients with specific phenotypes. Every full text article published in (1) Journal of American Medical Informatics Association, (2) Journal of Biomedical Informatics, (3) Proceedings of the Annual American Medical Informatics Associatio...

  9. A simple screen to identify promoters conferring high levels of phenotypic noise.

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    Nikki E Freed

    2008-12-01

    Full Text Available Genetically identical populations of unicellular organisms often show marked variation in some phenotypic traits. To investigate the molecular causes and possible biological functions of this phenotypic noise, it would be useful to have a method to identify genes whose expression varies stochastically on a certain time scale. Here, we developed such a method and used it for identifying genes with high levels of phenotypic noise in Salmonella enterica ssp. I serovar Typhimurium (S. Typhimurium. We created a genomic plasmid library fused to a green fluorescent protein (GFP reporter and subjected replicate populations harboring this library to fluctuating selection for GFP expression using fluorescent-activated cell sorting (FACS. After seven rounds of fluctuating selection, the populations were strongly enriched for promoters that showed a high amount of noise in gene expression. Our results indicate that the activity of some promoters of S. Typhimurium varies on such a short time scale that these promoters can absorb rapid fluctuations in the direction of selection, as imposed during our experiment. The genomic fragments that conferred the highest levels of phenotypic variation were promoters controlling the synthesis of flagella, which are associated with virulence and host-pathogen interactions. This confirms earlier reports that phenotypic noise may play a role in pathogenesis and indicates that these promoters have among the highest levels of noise in the S. Typhimurium genome. This approach can be applied to many other bacterial and eukaryotic systems as a simple method for identifying genes with noisy expression.

  10. Phenotype Similarity Regression for Identifying the Genetic Determinants of Rare Diseases.

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    Greene, Daniel; Richardson, Sylvia; Turro, Ernest

    2016-03-01

    Rare genetic disorders, which can now be studied systematically with affordable genome sequencing, are often caused by high-penetrance rare variants. Such disorders are often heterogeneous and characterized by abnormalities spanning multiple organ systems ascertained with variable clinical precision. Existing methods for identifying genes with variants responsible for rare diseases summarize phenotypes with unstructured binary or quantitative variables. The Human Phenotype Ontology (HPO) allows composite phenotypes to be represented systematically but association methods accounting for the ontological relationship between HPO terms do not exist. We present a Bayesian method to model the association between an HPO-coded patient phenotype and genotype. Our method estimates the probability of an association together with an HPO-coded phenotype characteristic of the disease. We thus formalize a clinical approach to phenotyping that is lacking in standard regression techniques for rare disease research. We demonstrate the power of our method by uncovering a number of true associations in a large collection of genome-sequenced and HPO-coded cases with rare diseases. PMID:26924528

  11. Common genetic variants associated with cognitive performance identified using the proxy-phenotype method

    NARCIS (Netherlands)

    Rietveld, Cornelius A; Esko, Tõnu; Davies, Gail; Pers, Tune H; Turley, Patrick; Benyamin, Beben; Chabris, Christopher F; Emilsson, Valur; Johnson, Andrew D; Lee, James J; de Leeuw, Christiaan; Marioni, Riccardo E; Medland, Sarah E; Miller, Michael B; Rostapshova, Olga; van der Lee, Sven J; Vinkhuyzen, Anna A E; Amin, Najaf; Conley, Dalton; Derringer, Jaime; van Duijn, Cornelia M; Fehrmann, Rudolf; Franke, Lude; Glaeser, Edward L; Hansell, Narelle K; Hayward, Caroline; Iacono, William G; Ibrahim-Verbaas, Carla; Jaddoe, Vincent; Karjalainen, Juha; Laibson, David; Lichtenstein, Paul; Liewald, David C; Magnusson, Patrik K E; Martin, Nicholas G; McGue, Matt; McMahon, George; Pedersen, Nancy L; Pinker, Steven; Porteous, David J; Posthuma, Danielle; Rivadeneira, Fernando; Smith, Blair H; Starr, John M; Tiemeier, Henning; Timpson, Nicholas J; Trzaskowski, Maciej; Uitterlinden, André G; Verhulst, Frank C; Ward, Mary E; Wright, Margaret J; Davey Smith, George; Deary, Ian J; Johannesson, Magnus; Plomin, Robert; Visscher, Peter M; Benjamin, Daniel J; Cesarini, David; Koellinger, Philipp D

    2014-01-01

    We identify common genetic variants associated with cognitive performance using a two-stage approach, which we call the proxy-phenotype method. First, we conduct a genome-wide association study of educational attainment in a large sample (n = 106,736), which produces a set of 69 education-associated

  12. Exploration of methods to identify polymorphisms associated with variation in DNA repair capacity phenotypes

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    Jones, I M; Thomas, C B; Xi, T; Mohrenweiser, H W; Nelson, D O

    2006-07-03

    Elucidating the relationship between polymorphic sequences and risk of common disease is a challenge. For example, although it is clear that variation in DNA repair genes is associated with familial cancer, aging and neurological disease, progress toward identifying polymorphisms associated with elevated risk of sporadic disease has been slow. This is partly due to the complexity of the genetic variation, the existence of large numbers of mostly low frequency variants and the contribution of many genes to variation in susceptibility. There has been limited development of methods to find associations between genotypes having many polymorphisms and pathway function or health outcome. We have explored several statistical methods for identifying polymorphisms associated with variation in DNA repair phenotypes. The model system used was 80 cell lines that had been resequenced to identify variation; 191 single nucleotide substitution polymorphisms (SNPs) are included, of which 172 are in 31 base excision repair pathway genes, 19 in 5 anti-oxidation genes, and DNA repair phenotypes based on single strand breaks measured by the alkaline Comet assay. Univariate analyses were of limited value in identifying SNPs associated with phenotype variation. Of the multivariable model selection methods tested: the easiest that provided reduced error of prediction of phenotype was simple counting of the variant alleles predicted to encode proteins with reduced activity, which led to a genotype including 52 SNPs; the best and most parsimonious model was achieved using a two-step analysis without regard to potential functional relevance: first SNPs were ranked by importance determined by Random Forests Regression (RFR), followed by cross-validation in a second round of RFR modeling that included ever more SNPs in declining order of importance. With this approach 6 SNPs were found to minimize prediction error. The results should encourage research into utilization of multivariate

  13. Refined phenotyping identifies links between preeclampsia and related diseases in a Norwegian preeclampsia family cohort

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    Thomsen, Liv Cecilie Vestrheim; Melton, Philip E.; Tollaksen, Kjersti; Lyslo, Ingvill; Roten, Linda Tømmerdal; Odland, Maria Lisa; Strand, Kristin Melheim; Nygård, Ottar; Sun, Chen; Iversen, Ann-Charlotte; Austgulen, Rigmor; Moses, Eric; Bjørge, Line

    2015-01-01

    Objective: Preeclampsia is a complex genetic disease of pregnancy with a heterogenous presentation, unknown cause and potential severe outcomes for both mother and child. Preeclamptic women have increased risk for atherothrombotic cardiovascular disease. We aimed to identify heritabilities and phenotypic correlations of preeclampsia and related conditions in the Norwegian Preeclampsia Family Biobank. Methods: By applying a variance components model, a total of 493 individuals (from 138 fa...

  14. Tightly congruent bursts of lineage and phenotypic diversification identified in a continental ant radiation.

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    Price, Shauna L; Etienne, Rampal S; Powell, Scott

    2016-04-01

    Adaptive diversification is thought to be shaped by ecological opportunity. A prediction of this ecological process of diversification is that it should result in congruent bursts of lineage and phenotypic diversification, but few studies have found this expected association. Here, we study the relationship between rates of lineage diversification and body size evolution in the turtle ants, a diverse Neotropical clade. Using a near complete, time-calibrated phylogeny we investigated lineage diversification dynamics and body size disparity through model fitting analyses and estimation of per-lineage rates of cladogenesis and phenotypic evolution. We identify an exceptionally high degree of congruence between the high rates of lineage and body size diversification in a young clade undergoing renewed diversification in the ecologically distinct Chacoan biogeographical region of South America. It is likely that the region presented turtle ants with novel ecological opportunity, which facilitated a nested burst of diversification and phenotypic evolution within the group. Our results provide a compelling quantitative example of tight congruence between rates of lineage and phenotypic diversification, meeting the key predicted pattern of adaptive diversification shaped by ecological opportunity. PMID:26935139

  15. Phenotyping and genotyping are both essential to identify and classify a probiotic microorganism

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    Gianfranco Donelli

    2013-03-01

    Full Text Available The use of probiotic products, especially for humans, requires an unequivocal taxonomical definition of their microbial content, in order to assign the probiotic effects to well identified and characterized microbial strains. In the absence of this, the labeling of some marketed probiotics may be misleading, both in terms of microbiological contents and possible beneficial effects. Currently, the ‘polyphasic taxonomy’ based on the integration of phenotypic and genotypic data seems to be the most appropriate approach. In fact, even if phenotypic characters often overlap among genetically different species, the molecular methods alone are frequently not able to establish distinct boundaries among phylogenetically related species. Thus, a valid scheme for the identification of a probiotic strain should be currently based on its morphological, physiological, and biochemical features as well as on aspects of its genetic profile. It is important that the identity of specific probiotic strains appearing on the product label is the result of a carefully selected combination of suitable phenotypic and genotypic analytical methods. Only adoption of such a policy could give the right emphasis to the significance of strain-specificity and thus provide health authorities with accurate tools to better evaluate the health benefits claimed by each probiotic-based product. The most common phenotypic and genotypic methods are briefly reviewed here with the aim of highlighting the suitable techniques which can be used to differentiate among microorganisms of probiotic interest, particularly those claiming beneficial health effects for humans.

  16. Automated local bright feature image analysis of nuclear protein distribution identifies changes in tissue phenotype

    International Nuclear Information System (INIS)

    The organization of nuclear proteins is linked to cell and tissue phenotypes. When cells arrest proliferation, undergo apoptosis, or differentiate, the distribution of nuclear proteins changes. Conversely, forced alteration of the distribution of nuclear proteins modifies cell phenotype. Immunostaining and fluorescence microscopy have been critical for such findings. However, there is an increasing need for quantitative analysis of nuclear protein distribution to decipher epigenetic relationships between nuclear structure and cell phenotype, and to unravel the mechanisms linking nuclear structure and function. We have developed imaging methods to quantify the distribution of fluorescently-stained nuclear protein NuMA in different mammary phenotypes obtained using three-dimensional cell culture. Automated image segmentation of DAPI-stained nuclei was generated to isolate thousands of nuclei from three-dimensional confocal images. Prominent features of fluorescently-stained NuMA were detected using a novel local bright feature analysis technique, and their normalized spatial density calculated as a function of the distance from the nuclear perimeter to its center. The results revealed marked changes in the distribution of the density of NuMA bright features as non-neoplastic cells underwent phenotypically normal acinar morphogenesis. In contrast, we did not detect any reorganization of NuMA during the formation of tumor nodules by malignant cells. Importantly, the analysis also discriminated proliferating non-neoplastic cells from proliferating malignant cells, suggesting that these imaging methods are capable of identifying alterations linked not only to the proliferation status but also to the malignant character of cells. We believe that this quantitative analysis will have additional applications for classifying normal and pathological tissues

  17. Automated local bright feature image analysis of nuclear proteindistribution identifies changes in tissue phenotype

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    Knowles, David; Sudar, Damir; Bator, Carol; Bissell, Mina

    2006-02-01

    The organization of nuclear proteins is linked to cell and tissue phenotypes. When cells arrest proliferation, undergo apoptosis, or differentiate, the distribution of nuclear proteins changes. Conversely, forced alteration of the distribution of nuclear proteins modifies cell phenotype. Immunostaining and fluorescence microscopy have been critical for such findings. However, there is an increasing need for quantitative analysis of nuclear protein distribution to decipher epigenetic relationships between nuclear structure and cell phenotype, and to unravel the mechanisms linking nuclear structure and function. We have developed imaging methods to quantify the distribution of fluorescently-stained nuclear protein NuMA in different mammary phenotypes obtained using three-dimensional cell culture. Automated image segmentation of DAPI-stained nuclei was generated to isolate thousands of nuclei from three-dimensional confocal images. Prominent features of fluorescently-stained NuMA were detected using a novel local bright feature analysis technique, and their normalized spatial density calculated as a function of the distance from the nuclear perimeter to its center. The results revealed marked changes in the distribution of the density of NuMA bright features as non-neoplastic cells underwent phenotypically normal acinar morphogenesis. In contrast, we did not detect any reorganization of NuMA during the formation of tumor nodules by malignant cells. Importantly, the analysis also discriminated proliferating non-neoplastic cells from proliferating malignant cells, suggesting that these imaging methods are capable of identifying alterations linked not only to the proliferation status but also to the malignant character of cells. We believe that this quantitative analysis will have additional applications for classifying normal and pathological tissues.

  18. Candidate gene resequencing to identify rare, pedigree-specific variants influencing healthy aging phenotypes in the long life family study

    DEFF Research Database (Denmark)

    Druley, Todd E; Wang, Lihua; Lin, Shiow J;

    2016-01-01

    BACKGROUND: The Long Life Family Study (LLFS) is an international study to identify the genetic components of various healthy aging phenotypes. We hypothesized that pedigree-specific rare variants at longevity-associated genes could have a similar functional impact on healthy phenotypes. METHODS...... was significantly associated with three phenotypes (GSK3B with the Healthy Aging Index, NOTCH1 with diastolic blood pressure and TP53 with serum HDL). CONCLUSIONS: Sequencing analysis of family-based associations for age-related phenotypes can identify rare or novel variants....

  19. Enu mutagenesis identifies a novel platelet phenotype in a loss-of-function Jak2 allele.

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    Nicole M Anderson

    Full Text Available Utilizing ENU mutagenesis, we identified a mutant mouse with elevated platelets. Genetic mapping localized the mutation to an interval on chromosome 19 that encodes the Jak2 tyrosine kinase. We identified a A3056T mutation resulting in a premature stop codon within exon 19 of Jak2 (Jak2(K915X, resulting in a protein truncation and functionally inactive enzyme. This novel platelet phenotype was also observed in mice bearing a hemizygous targeted disruption of the Jak2 locus (Jak2(+/-. Timed pregnancy experiments revealed that Jak2(K915X/K915X and Jak2(-/- displayed embryonic lethality; however, Jak2(K915X/K915X embryos were viable an additional two days compared to Jak2(-/- embryos. Our data suggest that perturbing JAK2 activation may have unexpected consequences in elevation of platelet number and correspondingly, important implications for treatment of hematological disorders with constitutive Jak2 activity.

  20. Galactosemia: A strategy to identify new biochemical phenotypes and molecular genotypes

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    Elsas, L.J.; Langley, S.; Steele, E.; Evinger, J.; Brown, A.; Singh, R.; Fernhoff, P.; Hjelm, L.N.; Dembure, P.P.; Fridovich-Keil, J.L. [Emory Univ. School of Medicine, Atlanta, GA (United States)

    1995-03-01

    We describe a stratagem for identifying new mutations in the galactose-1-phosphate uridyl transferase (GALT) gene. GALT enzyme activity and isoforms were defined in erythrocytes from probands and their first-degree relatives. If the biochemical phenotypes segregated in an autosomal recesssive pattern, we screened for common mutations by using multiplex PCR and restriction endonuclease digestions. If common mutant alleles were not present, the 11 exons of the GALT gene were amplified by PCR, and variations from the normal nucleotide sequences were identified by SSCP. The suspected region(s) was then analyzed by direct DNA sequencing. We identified 86 mutant GALT alleles that reduced erythrocyte GALT activity. Seventy-five of these GALT genomes had abnormal SSCP patterns, of which 41 were sequenced, yielding 12 new and 21 previously reported, rare mutations. Among the novel group of 12 new mutations, an unusual biochemical phenotype was found in a family whose newborn proband has classical galactosemia. He had inherited two mutations in cis (N314D-E204K) from his father, whose GALT activity was near normal, and an additional GALT mutation in the splice-acceptor site of intron C (IVSC) from his mother. The substitution of a positively charged E204K mutation created a unique isoform-banding pattern. An asymptomatic sister`s GALT genes carries three mutations (E203K-N314D/N314D) with eight distinct isoform bands. Surprisingly, her erythrocytes have normal GALT activity. We conclude that the synergism of pedigree, biochemical, SSCP, and direct GALT gene analyses is an efficient protocol for identifying new mutations and speculate that E203K and N314D codon changes produce intra-allelic complementation when in cis. 40 refs., 4 figs., 3 tabs.

  1. Anthropometric indices to identify metabolic syndrome and hypertriglyceridemic waist phenotype: a comparison between the three stages of adolescence

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    Patrícia Feliciano Pereira

    2015-06-01

    Full Text Available OBJECTIVE: To determine the prevalence of metabolic syndrome (MS and the hypertriglyceridemic waist phenotype (HW in a representative adolescent sample; as well as to establish which anthropometric indicator better identifies MS and HW, according to gender and adolescent age. METHODS: This cross sectional study had the participation of 800 adolescents (414 girls from 10-19 years old. Anthropometric indicators (body mass index, waist perimeter, waist/stature ratio, waist/hip ratio, and central/peripheral skinfolds were determined by standard protocols. For diagnosis of MS, the criteria proposed by de Ferranti et al. (2004 were used. HW was defined by the simultaneous presence of increased waist perimeter (>75th percentile for age and sex and high triglycerides (>100 mg/dL. The ability of anthropometric indicators was evaluated by Receiver Operating Characteristic curve. RESULTS: The prevalence of MS was identical to HW (6.4%, without differences between genders and the adolescence phases. The waist perimeter showed higher area under the curve for the diagnosis of MS, except for boys with 17-19 years old, for whom the waist/stature ratio exhibited better performance. For diagnosing HW, waist perimeter also showed higher area under the curve, except for boys in initial and final phases, in which the waist/stature ratio obtained larger area under the curve. The central/peripheral skinfolds had the lowest area under the curve for the presence of both MS and HW phenotype. CONCLUSIONS: The waist perimeter and the waist/stature showed a better performance to identify MS and HW in both genders and in all three phases of adolescence.

  2. Phenotypic diversity of toxigenic Vibrio cholerae O1 E1 Tor strains identified in China

    Institute of Scientific and Technical Information of China (English)

    赵璇

    2014-01-01

    Objective To understand the phenotypic diversity of toxigenic Vibrio cholerae O1 E1 Tor strains isolated from different provinces in China during the last 50 years.Methods Traditional biotyping testings including susceptibility to polymyxin B,sensitivity to groupⅣphage,Voges-Proskauer test and haemolysis of sheep erythrocytes were conducted.Results Data from Biotype-specific phenotype analysis revealed that only 133 isolates carried the typical E1 Tor phenotypes while the other 251

  3. Differential analysis of ovarian and endometrial cancers identifies a methylator phenotype.

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    Diana L Kolbe

    Full Text Available Despite improved outcomes in the past 30 years, less than half of all women diagnosed with epithelial ovarian cancer live five years beyond their diagnosis. Although typically treated as a single disease, epithelial ovarian cancer includes several distinct histological subtypes, such as papillary serous and endometrioid carcinomas. To address whether the morphological differences seen in these carcinomas represent distinct characteristics at the molecular level we analyzed DNA methylation patterns in 11 papillary serous tumors, 9 endometrioid ovarian tumors, 4 normal fallopian tube samples and 6 normal endometrial tissues, plus 8 normal fallopian tube and 4 serous samples from TCGA. For comparison within the endometrioid subtype we added 6 primary uterine endometrioid tumors and 5 endometrioid metastases from uterus to ovary. Data was obtained from 27,578 CpG dinucleotides occurring in or near promoter regions of 14,495 genes. We identified 36 locations with significant increases or decreases in methylation in comparisons of serous tumors and normal fallopian tube samples. Moreover, unsupervised clustering techniques applied to all samples showed three major profiles comprising mostly normal samples, serous tumors, and endometrioid tumors including ovarian, uterine and metastatic origins. The clustering analysis identified 60 differentially methylated sites between the serous group and the normal group. An unrelated set of 25 serous tumors validated the reproducibility of the methylation patterns. In contrast, >1,000 genes were differentially methylated between endometrioid tumors and normal samples. This finding is consistent with a generalized regulatory disruption caused by a methylator phenotype. Through DNA methylation analyses we have identified genes with known roles in ovarian carcinoma etiology, whereas pathway analyses provided biological insight to the role of novel genes. Our finding of differences between serous and endometrioid

  4. Phenotype of Children with QT Prolongation Identified Using an Institution-Wide QT Alert System.

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    Anderson, Heather N; Bos, J Martijn; Haugaa, Kristina H; Morlan, Bruce W; Tarrell, Robert F; Caraballo, Pedro J; Ackerman, Michael J

    2015-10-01

    QT prolongation is an independent risk factor for cardiovascular mortality in adults. However, there is little information available on pediatric patients with QT prolongation and their outcomes. Herein, we evaluated the prevalence of QT prolongation in pediatric patients identified by an institution-wide QT alert system, and the spectrum of their phenotype. Patients with documented QT prolongation on an ECG obtained between November 2010 and June 2011 were included. There were 1303 pediatric ECGs, and 68 children had electrographically isolated QT prolongation. Comprehensive review of medical records was performed with particular attention to QT-prolonging clinical, laboratory, and medication data, which were summarized into a pro-QTc score. Overall, 68 (5 %) pediatric patients had isolated QT prolongation. The mean age of this pediatric cohort was 9 ± 6 years, and the average QTc was 494 ± 42 ms. All children had 1 or more QT-prolonging risk factor(s), most commonly QT-prolonging medications. One patient was identified with congenital long QT syndrome (LQTS), which was not previously diagnosed. In one-year follow-up, only one pediatric death (non-cardiac) occurred (1.5 %). Potentially QT-offending/pro-arrhythmic medications were changed in 80 % of pediatric patients after the physician received the QT alert. Children with QT prolongation had very low mortality and minimal polypharmacy. Still, medications and other modifiable conditions were the most common causes of QT prolongation. Children with a prolonged QTc should be evaluated for modifiable QT-prolonging factors. However, if no risk factors are present or the QTc does not attenuate after risk factor modification/removal, the child should be evaluated for congenital LQTS. PMID:25845942

  5. NIH Researchers Identify New Gene Mutation Associated with ALS and Dementia

    Science.gov (United States)

    ... NIH researchers identify new gene mutation associated with ALS and dementia April 7, 2014 A rare mutation ... cell, has been linked with development of familial amyotrophic lateral sclerosis (ALS). This finding, from a research team led ...

  6. Exploiting CpG hypermutability to identify phenotypically significant variation within human protein-coding genes.

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    Ying, Hua; Huttley, Gavin

    2011-01-01

    The CpG dinucleotide is disproportionately represented in human genetic variation due to the hypermutability of 5-methyl-cytosine (5mC). We exploit this hypermutability and a novel codon substitution model to identify candidate functionally important exonic nucleotides. Population genetic theory suggests that codon positions with high cross-species CpG frequency will derive from stronger purifying selection. Using the phylogeny-based maximum likelihood inference framework, we applied codon substitution models with context-dependent parameters to measure the mutagenic and selective processes affecting CpG dinucleotides within exonic sequence. The suitability of these models was validated on >2,000 protein coding genes from a naturally occurring biological control, four yeast species that do not methylate their DNA. As expected, our analyses of yeast revealed no evidence for an elevated CpG transition rate or for substitution suppression affecting CpG-containing codons. Our analyses of >12,000 protein-coding genes from four primate lineages confirm the systemic influence of 5mC hypermutability on the divergence of these genes. After adjusting for confounding influences of mutation and the properties of the encoded amino acids, we confirmed that CpG-containing codons are under greater purifying selection in primates. Genes with significant evidence of enhanced suppression of nonsynonymous CpG changes were also shown to be significantly enriched in Online Mendelian Inheritance in Man. We developed a method for ranking candidate phenotypically influential CpG positions in human genes. Application of this method indicates that of the ∼1 million exonic CpG dinucleotides within humans, ∼20% are strong candidates for both hypermutability and disease association. PMID:21398426

  7. Genome-wide Association Study Identifies Loci for the Polled Phenotype in Yak

    Science.gov (United States)

    Wu, Xiaoyun; Wang, Kun; Ding, Xuezhi; Wang, Mingcheng; Chu, Min; Xie, Xiuyue; Qiu, Qiang; Yan, Ping

    2016-01-01

    The absence of horns, known as the polled phenotype, is an economically important trait in modern yak husbandry, but the genomic structure and genetic basis of this phenotype have yet to be discovered. Here, we conducted a genome-wide association study with a panel of 10 horned and 10 polled yaks using whole genome sequencing. We mapped the POLLED locus to a 200-kb interval, which comprises three protein-coding genes. Further characterization of the candidate region showed recent artificial selection signals resulting from the breeding process. We suggest that expressional variations rather than structural variations in protein probably contribute to the polled phenotype. Our results not only represent the first and important step in establishing the genomic structure of the polled region in yak, but also add to our understanding of the polled trait in bovid species. PMID:27389700

  8. Use of phylogenetic and phenotypic analyses to identify nonhemolytic streptococci isolated from bacteremic patients

    DEFF Research Database (Denmark)

    Hoshino, T; Fujivwara, T; Kilian, Mogens

    2005-01-01

    The aim of this study was to evaluate molecular and phenotypic methods for the identification of nonhemolytic streptococci. A collection of 148 strains consisting of 115 clinical isolates from cases of infective endocarditis, septicemia, and meningitis and 33 reference strains, including type...

  9. Rapid-throughput skeletal phenotyping of 100 knockout mice identifies 9 new genes that determine bone strength.

    Directory of Open Access Journals (Sweden)

    J H Duncan Bassett

    Full Text Available Osteoporosis is a common polygenic disease and global healthcare priority but its genetic basis remains largely unknown. We report a high-throughput multi-parameter phenotype screen to identify functionally significant skeletal phenotypes in mice generated by the Wellcome Trust Sanger Institute Mouse Genetics Project and discover novel genes that may be involved in the pathogenesis of osteoporosis. The integrated use of primary phenotype data with quantitative x-ray microradiography, micro-computed tomography, statistical approaches and biomechanical testing in 100 unselected knockout mouse strains identified nine new genetic determinants of bone mass and strength. These nine new genes include five whose deletion results in low bone mass and four whose deletion results in high bone mass. None of the nine genes have been implicated previously in skeletal disorders and detailed analysis of the biomechanical consequences of their deletion revealed a novel functional classification of bone structure and strength. The organ-specific and disease-focused strategy described in this study can be applied to any biological system or tractable polygenic disease, thus providing a general basis to define gene function in a system-specific manner. Application of the approach to diseases affecting other physiological systems will help to realize the full potential of the International Mouse Phenotyping Consortium.

  10. Phenotypic transition of microglia into astrocyte-like cells associated with disease onset in a model of inherited ALS

    OpenAIRE

    Emiliano eTrias; Pablo eDíaz-Amarilla; Silvia eOlivera-Bravo; Eugenia eIsasi; Drechsel, Derek A.; Nathan eLopez; Charles Samuel Bradford; Kyle Edward Ireton; Beckman, Joseph S; Luis Hector Barbeito

    2013-01-01

    Microglia and reactive astrocytes accumulate in the spinal cord of rats expressing the Amyotrophic lateral sclerosis (ALS)-linked SOD1 G93A mutation. We previously reported that the rapid progression of paralysis in ALS rats is associated with the appearance of proliferative astrocyte-like cells that surround motor neurons. These cells, designated as Aberrant Astrocytes (AbA cells) because of their atypical astrocytic phenotype, exhibit high toxicity to motor neurons. However, the cellular or...

  11. Sqstm1 knock-down causes a locomotor phenotype ameliorated by rapamycin in a zebrafish model of ALS/FTLD.

    Science.gov (United States)

    Lattante, Serena; de Calbiac, Hortense; Le Ber, Isabelle; Brice, Alexis; Ciura, Sorana; Kabashi, Edor

    2015-03-15

    Mutations in SQSTM1, encoding for the protein SQSTM1/p62, have been recently reported in 1-3.5% of patients with amyotrophic lateral sclerosis and frontotemporal lobar degeneration (ALS/FTLD). Inclusions positive for SQSTM1/p62 have been detected in patients with neurodegenerative disorders, including ALS/FTLD. In order to investigate the pathogenic mechanisms induced by SQSTM1 mutations in ALS/FTLD, we developed a zebrafish model. Knock-down of the sqstm1 zebrafish ortholog, as well as impairment of its splicing, led to a specific phenotype, consisting of behavioral and axonal anomalies. Here, we report swimming deficits associated with shorter motor neuronal axons that could be rescued by the overexpression of wild-type human SQSTM1. Interestingly, no rescue of the loss-of-function phenotype was observed when overexpressing human SQSTM1 constructs carrying ALS/FTLD-related mutations. Consistent with its role in autophagy regulation, we found increased mTOR levels upon knock-down of sqstm1. Furthermore, treatment of zebrafish embryos with rapamycin, a known inhibitor of the mTOR pathway, yielded an amelioration of the locomotor phenotype in the sqstm1 knock-down model. Our results suggest that loss-of-function of SQSTM1 causes phenotypic features characterized by locomotor deficits and motor neuron axonal defects that are associated with a misregulation of autophagic processes. PMID:25410659

  12. Combining phenotypic and proteomic approaches to identify membrane targets in a ‘triple negative’ breast cancer cell type

    Directory of Open Access Journals (Sweden)

    Rust Steven

    2013-02-01

    Full Text Available Abstract Background The continued discovery of therapeutic antibodies, which address unmet medical needs, requires the continued discovery of tractable antibody targets. Multiple protein-level target discovery approaches are available and these can be used in combination to extensively survey relevant cell membranomes. In this study, the MDA-MB-231 cell line was selected for membranome survey as it is a ‘triple negative’ breast cancer cell line, which represents a cancer subtype that is aggressive and has few treatment options. Methods The MDA-MB-231 breast carcinoma cell line was used to explore three membranome target discovery approaches, which were used in parallel to cross-validate the significance of identified antigens. A proteomic approach, which used membrane protein enrichment followed by protein identification by mass spectrometry, was used alongside two phenotypic antibody screening approaches. The first phenotypic screening approach was based on hybridoma technology and the second was based on phage display technology. Antibodies isolated by the phenotypic approaches were tested for cell specificity as well as internalisation and the targets identified were compared to each other as well as those identified by the proteomic approach. An anti-CD73 antibody derived from the phage display-based phenotypic approach was tested for binding to other ‘triple negative’ breast cancer cell lines and tested for tumour growth inhibitory activity in a MDA-MB-231 xenograft model. Results All of the approaches identified multiple cell surface markers, including integrins, CD44, EGFR, CD71, galectin-3, CD73 and BCAM, some of which had been previously confirmed as being tractable to antibody therapy. In total, 40 cell surface markers were identified for further study. In addition to cell surface marker identification, the phenotypic antibody screening approaches provided reagent antibodies for target validation studies. This is illustrated

  13. HCS-Neurons: identifying phenotypic changes in multi-neuron images upon drug treatments of high-content screening

    OpenAIRE

    Charoenkwan, Phasit; Hwang, Eric; Cutler, Robert W; Lee, Hua-Chin; Ko, Li-Wei; Huang, Hui-Ling; Ho, Shinn-Ying

    2013-01-01

    Background High-content screening (HCS) has become a powerful tool for drug discovery. However, the discovery of drugs targeting neurons is still hampered by the inability to accurately identify and quantify the phenotypic changes of multiple neurons in a single image (named multi-neuron image) of a high-content screen. Therefore, it is desirable to develop an automated image analysis method for analyzing multi-neuron images. Results We propose an automated analysis method with novel descript...

  14. Leveraging Comparative Genomics to Identify and Functionally Characterize Genes Associated with Sperm Phenotypes in Python bivittatus (Burmese Python)

    OpenAIRE

    Irizarry, Kristopher J. L.; Josep Rutllant

    2016-01-01

    Comparative genomics approaches provide a means of leveraging functional genomics information from a highly annotated model organism's genome (such as the mouse genome) in order to make physiological inferences about the role of genes and proteins in a less characterized organism's genome (such as the Burmese python). We employed a comparative genomics approach to produce the functional annotation of Python bivittatus genes encoding proteins associated with sperm phenotypes. We identify 129 g...

  15. Leveraging Comparative Genomics to Identify and Functionally Characterize Genes Associated with Sperm Phenotypes in Python bivittatus (Burmese Python)

    Science.gov (United States)

    Rutllant, Josep

    2016-01-01

    Comparative genomics approaches provide a means of leveraging functional genomics information from a highly annotated model organism's genome (such as the mouse genome) in order to make physiological inferences about the role of genes and proteins in a less characterized organism's genome (such as the Burmese python). We employed a comparative genomics approach to produce the functional annotation of Python bivittatus genes encoding proteins associated with sperm phenotypes. We identify 129 gene-phenotype relationships in the python which are implicated in 10 specific sperm phenotypes. Results obtained through our systematic analysis identified subsets of python genes exhibiting associations with gene ontology annotation terms. Functional annotation data was represented in a semantic scatter plot. Together, these newly annotated Python bivittatus genome resources provide a high resolution framework from which the biology relating to reptile spermatogenesis, fertility, and reproduction can be further investigated. Applications of our research include (1) production of genetic diagnostics for assessing fertility in domestic and wild reptiles; (2) enhanced assisted reproduction technology for endangered and captive reptiles; and (3) novel molecular targets for biotechnology-based approaches aimed at reducing fertility and reproduction of invasive reptiles. Additional enhancements to reptile genomic resources will further enhance their value. PMID:27200191

  16. Identifying A Molecular Phenotype for Bone Marrow Stromal Cells With In Vivo Bone Forming Capacity

    DEFF Research Database (Denmark)

    Larsen, Kenneth H; Frederiksen, Casper M; Burns, Jorge S;

    2009-01-01

    Abstract The ability of bone marrow stromal cells (BMSCs) to differentiate into osteoblasts is being exploited in cell-based therapy for repair of bone defects. However, the phenotype of ex vivo cultured BMSCs predicting their bone forming capacity is not known. Thus, we employed DNA microarrays...... comparing two human bone marrow stromal cell (hBMSC) populations: one is capable of in vivo heterotopic bone formation (hBMSC-TERT(+Bone)) and the other is not (hBMSC-TERT(-Bone)). Compared to hBMSC-TERT(-Bone), the hBMSC-TERT(+Bone) cells had an increased over-representation of extracellular matrix genes...... (17% versus 5%) and a larger percentage of genes with predicted SP3 transcription factor binding sites in their promoter region (21% versus 8%). On the other hand, hBMSC-TERT(-Bone) cells expressed a larger number of immune-response related genes (26% versus 8%). In order to test for the predictive...

  17. Phenotypic consequences of a mosaic marker chromosome identified by fluorescence in situ hybridization (FISH) as being derived from chromosome 16

    Energy Technology Data Exchange (ETDEWEB)

    Ray, J.H.; Zhou, X.; Pletcher, B.A. [Cornell Univ. Medical College, Manhasset, NY (United States)] [and others

    1994-09-01

    De novo marker chromosomes are detected in 1 in 2500 amniotic fluid samples and are associated with a 10-15% risk for phenotypic abnormality. FISH can be utilized as a research tool to identify the origins of marker chromosomes. The phenotypic consequences of a marker chromosome derived from the short arm of chromosome 16 are described. A 26-year-old woman underwent amniocentesis at 28 weeks gestation because of a prenatally diagnosed tetralogy of Fallot. Follow-up ultrasounds also showed ventriculomegaly and cleft lip and palate. 32 of 45 cells had the karyotype 47,XY,+mar; the remaining cells were 46,XY. The de novo marker chromosome was C-band positive and non-satellited and failed to stain with distamycin A/DAPI. At birth the ultrasound findings were confirmed and dysmorphic features and cryptorchidism were noted. Although a newborn blood sample contained only normal cells, mosaicism was confirmed in 2 skin biopsies. FISH using whole-chromosome painting and alpha-satellite DNA probes showed that the marker chromosome had originated from chromosome 16. As proximal 16q is distamycin A/DAPI positive, the marker is apparently derived from proximal 16p. At 15 months of age, this child is hypotonic, globally delayed and is gavage-fed. His physical examination is significant for microbrachycephaly, a round face, sparse scalp hair, ocular hypertelorism, exotropia, a flat, wide nasal bridge and tip, mild micrognathia, and tapered fingers with lymphedema of hands and feet. Inguinal hernias have been repaired. His features are consistent with those described for patients trisomic for most or all of the short arm of chromosome 16. Marker chromosomes derived from the short arm of chromosome 16 appear to have phenotypic consequences. As the origin of more marker chromosomes are identified using FISH, their karyotype/phenotype correlations will become more apparent, which will permit more accurate genetic counseling.

  18. What makes the lac-pathway switch: identifying the fluctuations that trigger phenotype switching in gene regulatory systems.

    Science.gov (United States)

    Bhogale, Prasanna M; Sorg, Robin A; Veening, Jan-Willem; Berg, Johannes

    2014-10-01

    Multistable gene regulatory systems sustain different levels of gene expression under identical external conditions. Such multistability is used to encode phenotypic states in processes including nutrient uptake and persistence in bacteria, fate selection in viral infection, cell-cycle control and development. Stochastic switching between different phenotypes can occur as the result of random fluctuations in molecular copy numbers of mRNA and proteins arising in transcription, translation, transport and binding. However, which component of a pathway triggers such a transition is generally not known. By linking single-cell experiments on the lactose-uptake pathway in E. coli to molecular simulations, we devise a general method to pinpoint the particular fluctuation driving phenotype switching and apply this method to the transition between the uninduced and induced states of the lac-genes. We find that the transition to the induced state is not caused only by the single event of lac-repressor unbinding, but depends crucially on the time period over which the repressor remains unbound from the lac-operon. We confirm this notion in strains with a high expression level of the lac-repressor (leading to shorter periods over which the lac-operon remains unbound), which show a reduced switching rate. Our techniques apply to multistable gene regulatory systems in general and allow to identify the molecular mechanisms behind stochastic transitions in gene regulatory circuits. PMID:25245949

  19. Temporal expression profiling identifies pathways mediating effect of causal variant on phenotype.

    Directory of Open Access Journals (Sweden)

    Saumya Gupta

    2015-06-01

    Full Text Available Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants' effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage

  20. Systems Biology in Animal Breeding: Identifying relationships among markers, genes, and phenotypes

    Science.gov (United States)

    The Breeding and Genetics Symposium titled “Systems Biology in Animal Breeding: Identifying relationships among markers, genes, and phenotypes” was held at the Joint Annual Meeting of the American Dairy Science Association and the American Society of Animal Science in Phoenix, AZ, July 15 to 19, 201...

  1. Identifying genetic marker sets associated with phenotypes via an efficient adaptive score test

    KAUST Repository

    Cai, T.

    2012-06-25

    In recent years, genome-wide association studies (GWAS) and gene-expression profiling have generated a large number of valuable datasets for assessing how genetic variations are related to disease outcomes. With such datasets, it is often of interest to assess the overall effect of a set of genetic markers, assembled based on biological knowledge. Genetic marker-set analyses have been advocated as more reliable and powerful approaches compared with the traditional marginal approaches (Curtis and others, 2005. Pathways to the analysis of microarray data. TRENDS in Biotechnology 23, 429-435; Efroni and others, 2007. Identification of key processes underlying cancer phenotypes using biologic pathway analysis. PLoS One 2, 425). Procedures for testing the overall effect of a marker-set have been actively studied in recent years. For example, score tests derived under an Empirical Bayes (EB) framework (Liu and others, 2007. Semiparametric regression of multidimensional genetic pathway data: least-squares kernel machines and linear mixed models. Biometrics 63, 1079-1088; Liu and others, 2008. Estimation and testing for the effect of a genetic pathway on a disease outcome using logistic kernel machine regression via logistic mixed models. BMC bioinformatics 9, 292-2; Wu and others, 2010. Powerful SNP-set analysis for case-control genome-wide association studies. American Journal of Human Genetics 86, 929) have been proposed as powerful alternatives to the standard Rao score test (Rao, 1948. Large sample tests of statistical hypotheses concerning several parameters with applications to problems of estimation. Mathematical Proceedings of the Cambridge Philosophical Society, 44, 50-57). The advantages of these EB-based tests are most apparent when the markers are correlated, due to the reduction in the degrees of freedom. In this paper, we propose an adaptive score test which up- or down-weights the contributions from each member of the marker-set based on the Z-scores of

  2. Phenotypic assays to identify agents that induce reactive gliosis: a counter-screen to prioritize compounds for preclinical animal studies.

    Science.gov (United States)

    Beckerman, Samuel R; Jimenez, Joaquin E; Shi, Yan; Al-Ali, Hassan; Bixby, John L; Lemmon, Vance P

    2015-09-01

    Astrocyte phenotypes change in a process called reactive gliosis after traumatic central nervous system (CNS) injury. Astrogliosis is characterized by expansion of the glial fibrillary acidic protein (GFAP) cytoskeleton, adoption of stellate morphologies, and differential expression of some extracellular matrix molecules. The astrocytic response immediately after injury is beneficial, but in the chronic injury phase, reactive astrocytes produce inhibitory factors (i.e., chondroitin sulfate proteoglycans [CSPGs]) that limit the regrowth of injured axons. There are no drugs that promote axon regeneration or functional recovery after CNS trauma in humans. To develop novel therapeutics for the injured CNS, we screened various libraries in a phenotypic assay to identify compounds that promote neurite outgrowth. However, the effects these compounds have on astrocytes are unknown. Specifically, we were interested in whether compounds could alter astrocytes in a manner that mimics the glial reaction to injury. To test this hypothesis, we developed cell-based phenotypic bioassays to measure changes in (1) GFAP morphology/localization and (2) CSPG expression/immunoreactivity from primary astrocyte cultures. These assays were optimized for six-point dose-response experiments in 96-well plates. The GFAP morphology assay is suitable for counter-screening with a Z-factor of 0.44±0.03 (mean±standard error of the mean; N=3 biological replicates). The CSPG assay is reproducible and informative, but does not satisfy common metrics for a "screenable" assay. As proof of principle, we tested a small set of hit compounds from our neurite outgrowth bioassay and identified one that can enhance axon growth without exacerbating the deleterious characteristics of reactive gliosis. PMID:26230074

  3. Gravimetric phenotyping of whole plant transpiration responses to atmospheric vapour pressure deficit identifies genotypic variation in water use efficiency.

    Science.gov (United States)

    Ryan, Annette C; Dodd, Ian C; Rothwell, Shane A; Jones, Ros; Tardieu, Francois; Draye, Xavier; Davies, William J

    2016-10-01

    There is increasing interest in rapidly identifying genotypes with improved water use efficiency, exemplified by the development of whole plant phenotyping platforms that automatically measure plant growth and water use. Transpirational responses to atmospheric vapour pressure deficit (VPD) and whole plant water use efficiency (WUE, defined as the accumulation of above ground biomass per unit of water used) were measured in 100 maize (Zea mays L.) genotypes. Using a glasshouse based phenotyping platform with naturally varying VPD (1.5-3.8kPa), a 2-fold variation in WUE was identified in well-watered plants. Regression analysis of transpiration versus VPD under these conditions, and subsequent whole plant gas exchange at imposed VPDs (0.8-3.4kPa) showed identical responses in specific genotypes. Genotype response of transpiration versus VPD fell into two categories: 1) a linear increase in transpiration rate with VPD with low (high WUE) or high (low WUE) transpiration rate at all VPDs, 2) a non-linear response with a pronounced change point at low VPD (high WUE) or high VPD (low WUE). In the latter group, high WUE genotypes required a significantly lower VPD before transpiration was restricted, and had a significantly lower rate of transpiration in response to VPD after this point, when compared to low WUE genotypes. Change point values were significantly positively correlated with stomatal sensitivity to VPD. A change point in stomatal response to VPD may explain why some genotypes show contradictory WUE rankings according to whether they are measured under glasshouse or field conditions. Furthermore, this novel use of a high throughput phenotyping platform successfully reproduced the gas exchange responses of individuals measured in whole plant chambers, accelerating the identification of plants with high WUE. PMID:27593468

  4. Biogeographic Ancestry, Self-Identified Race, and Admixture-Phenotype Associations in the Heart SCORE Study

    OpenAIRE

    Halder, Indrani; Kip, Kevin E.; Mulukutla, Suresh R.; Aiyer, Aryan N.; Marroquin, Oscar C; Huggins, Gordon S.; Reis, Steven E.

    2012-01-01

    Large epidemiologic studies examining differences in cardiovascular disease (CVD) risk factor profiles between European Americans and African Americans have exclusively used self-identified race (SIR) to classify individuals. Recent genetic epidemiology studies of some CVD risk factors have suggested that biogeographic ancestry (BGA) may be a better predictor of CVD risk than SIR. This hypothesis was investigated in 464 African Americans and 771 European Americans enrolled in the Heart Strate...

  5. Broadening of cohesinopathies: exome sequencing identifies mutations in ANKRD11 in two patients with Cornelia de Lange-overlapping phenotype.

    Science.gov (United States)

    Parenti, I; Gervasini, C; Pozojevic, J; Graul-Neumann, L; Azzollini, J; Braunholz, D; Watrin, E; Wendt, K S; Cereda, A; Cittaro, D; Gillessen-Kaesbach, G; Lazarevic, D; Mariani, M; Russo, S; Werner, R; Krawitz, P; Larizza, L; Selicorni, A; Kaiser, F J

    2016-01-01

    Cornelia de Lange syndrome (CdLS) and KBG syndrome are two distinct developmental pathologies sharing common features such as intellectual disability, psychomotor delay, and some craniofacial and limb abnormalities. Mutations in one of the five genes NIPBL, SMC1A, SMC3, HDAC8 or RAD21, were identified in at least 70% of the patients with CdLS. Consequently, additional causative genes, either unknown or responsible of partially merging entities, possibly account for the remaining 30% of the patients. In contrast, KBG has only been associated with mutations in ANKRD11. By exome sequencing we could identify heterozygous loss-of-function mutations in ANKRD11 in two patients with the clinical diagnosis of CdLS. Both patients show features reminiscent of CdLS such as characteristic facies as well as a small head circumference which is not described for KBG syndrome. Patient A, who carries the mutation in a mosaic state, is a 4-year-old girl with features reminiscent of CdLS. Patient B, a 15-year-old boy, shows a complex phenotype which resembled CdLS during infancy, but has developed to a more KBG overlapping phenotype during childhood. These findings point out the importance of screening ANKRD11 in young CdLS patients who were found to be negative for mutations in the five known CdLS genes. PMID:25652421

  6. Integrating Diverse Types of Genomic Data to Identify Genes that Underlie Adverse Pregnancy Phenotypes.

    Directory of Open Access Journals (Sweden)

    Jibril Hirbo

    Full Text Available Progress in understanding complex genetic diseases has been bolstered by synthetic approaches that overlay diverse data types and analyses to identify functionally important genes. Pre-term birth (PTB, a major complication of pregnancy, is a leading cause of infant mortality worldwide. A major obstacle in addressing PTB is that the mechanisms controlling parturition and birth timing remain poorly understood. Integrative approaches that overlay datasets derived from comparative genomics with function-derived ones have potential to advance our understanding of the genetics of birth timing, and thus provide insights into the genes that may contribute to PTB. We intersected data from fast evolving coding and non-coding gene regions in the human and primate lineage with data from genes expressed in the placenta, from genes that show enriched expression only in the placenta, as well as from genes that are differentially expressed in four distinct PTB clinical subtypes. A large fraction of genes that are expressed in placenta, and differentially expressed in PTB clinical subtypes (23-34% are fast evolving, and are associated with functions that include adhesion neurodevelopmental and immune processes. Functional categories of genes that express fast evolution in coding regions differ from those linked to fast evolution in non-coding regions. Finally, there is a surprising lack of overlap between fast evolving genes that are differentially expressed in four PTB clinical subtypes. Integrative approaches, especially those that incorporate evolutionary perspectives, can be successful in identifying potential genetic contributions to complex genetic diseases, such as PTB.

  7. Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors.

    Science.gov (United States)

    Figueres-Oñate, Maria; López-Mascaraque, Laura

    2016-01-01

    Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

  8. Biogeographic ancestry, self-identified race, and admixture-phenotype associations in the Heart SCORE Study.

    Science.gov (United States)

    Halder, Indrani; Kip, Kevin E; Mulukutla, Suresh R; Aiyer, Aryan N; Marroquin, Oscar C; Huggins, Gordon S; Reis, Steven E

    2012-07-15

    Large epidemiologic studies examining differences in cardiovascular disease (CVD) risk factor profiles between European Americans and African Americans have exclusively used self-identified race (SIR) to classify individuals. Recent genetic epidemiology studies of some CVD risk factors have suggested that biogeographic ancestry (BGA) may be a better predictor of CVD risk than SIR. This hypothesis was investigated in 464 African Americans and 771 European Americans enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) Study in March and April 2010. Individual West African and European BGA were ascertained by means of a panel of 1,595 genetic ancestry informative markers. Individual BGA varied significantly among African Americans and to a lesser extent among European Americans. In the total cohort, BGA was not found to be a better predictor of CVD risk factors than SIR. Both measures predicted differences in the presence of the metabolic syndrome, waist circumference, triglycerides, body mass index, very low density lipoprotein cholesterol, lipoprotein A, and systolic and diastolic blood pressure between European Americans and African Americans. These results suggest that for most nongenetic cardiovascular epidemiology studies, SIR is sufficient for predicting CVD risk factor differences between European Americans and African Americans. However, higher body mass index and diastolic blood pressure were significantly associated with West African BGA among African Americans, suggesting that BGA should be considered in genetic cardiovascular epidemiology studies carried out among African Americans. PMID:22771727

  9. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS

    OpenAIRE

    Liao, Bing; Zhao, Weihua; Beers, David R.; Henkel, Jenny S; Appel, Stanley H.

    2012-01-01

    Neuroinflammation is a prominent pathological feature in the spinal cords of patients with amyotrophic lateral sclerosis (ALS), as well as in transgenic mouse models of inherited ALS, and is characterized by activated microglia. Earlier studies showed that activated microglia play important roles in both motoneuron protection and injury. More recent studies investigating the pathoprogression of disease in ALS mice have demonstrated that the in vivo activation states of microglia, including th...

  10. A High-Content, Phenotypic Screen Identifies Fluorouridine as an Inhibitor of Pyoverdine Biosynthesis and Pseudomonas aeruginosa Virulence.

    Science.gov (United States)

    Kirienko, Daniel R; Revtovich, Alexey V; Kirienko, Natalia V

    2016-01-01

    Pseudomonas aeruginosa is an opportunistic pathogen that causes severe health problems. Despite intensive investigation, many aspects of microbial virulence remain poorly understood. We used a high-throughput, high-content, whole-organism, phenotypic screen to identify small molecules that inhibit P. aeruginosa virulence in Caenorhabditis elegans. Approximately half of the hits were known antimicrobials. A large number of hits were nonantimicrobial bioactive compounds, including the cancer chemotherapeutic 5-fluorouracil. We determined that 5-fluorouracil both transiently inhibits bacterial growth and reduces pyoverdine biosynthesis. Pyoverdine is a siderophore that regulates the expression of several virulence determinants and is critical for pathogenesis in mammals. We show that 5-fluorouridine, a downstream metabolite of 5-fluorouracil, is responsible for inhibiting pyoverdine biosynthesis. We also show that 5-fluorouridine, in contrast to 5-fluorouracil, is a genuine antivirulence compound, with no bacteriostatic or bactericidal activity. To our knowledge, this is the first report utilizing a whole-organism screen to identify novel compounds with antivirulent properties effective against P. aeruginosa. IMPORTANCE Despite intense research effort from scientists and the advent of the molecular age of biomedical research, many of the mechanisms that underlie pathogenesis are still understood poorly, if at all. The opportunistic human pathogen Pseudomonas aeruginosa causes a variety of soft tissue infections and is responsible for over 50,000 hospital-acquired infections per year. In addition, P. aeruginosa exhibits a striking degree of innate and acquired antimicrobial resistance, complicating treatment. It is increasingly important to understand P. aeruginosa virulence. In an effort to gain this information in an unbiased fashion, we used a high-throughput phenotypic screen to identify small molecules that disrupted bacterial pathogenesis and increased host

  11. Genome-wide Association Study Identifies HLA 8.1 Ancestral Haplotype Alleles as Major Genetic Risk Factors for Myositis Phenotypes

    OpenAIRE

    Miller, Frederick W.; Chen, Wei; O’Hanlon, Terrance P.; Cooper, Robert G.; Vencovsky, Jiri; Rider, Lisa G; Danko, Katalin; Wedderburn, Lucy R; Lundberg, Ingrid E; Pachman, Lauren M.; Reed, Ann M.; Ytterberg, Steven R.; Padyukov, Leonid; Selva-O’Callaghan, Albert; Radstake, Timothy R.

    2015-01-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis; 473 juvenile dermatomyositis; 532 polymyositis; and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl tRN...

  12. A broad phenotypic screen identifies novel phenotypes driven by a single mutant allele in Huntington's disease CAG knock-in mice.

    Directory of Open Access Journals (Sweden)

    Sabine M Hölter

    Full Text Available Huntington's disease (HD is an autosomal dominant neurodegenerative disorder caused by the expansion of a CAG trinucleotide repeat in the HTT gene encoding huntingtin. The disease has an insidious course, typically progressing over 10-15 years until death. Currently there is no effective disease-modifying therapy. To better understand the HD pathogenic process we have developed genetic HTT CAG knock-in mouse models that accurately recapitulate the HD mutation in man. Here, we describe results of a broad, standardized phenotypic screen in 10-46 week old heterozygous HdhQ111 knock-in mice, probing a wide range of physiological systems. The results of this screen revealed a number of behavioral abnormalities in HdhQ111/+ mice that include hypoactivity, decreased anxiety, motor learning and coordination deficits, and impaired olfactory discrimination. The screen also provided evidence supporting subtle cardiovascular, lung, and plasma metabolite alterations. Importantly, our results reveal that a single mutant HTT allele in the mouse is sufficient to elicit multiple phenotypic abnormalities, consistent with a dominant disease process in patients. These data provide a starting point for further investigation of several organ systems in HD, for the dissection of underlying pathogenic mechanisms and for the identification of reliable phenotypic endpoints for therapeutic testing.

  13. Differential neuronal vulnerability identifies IGF-2 as a protective factor in ALS.

    Science.gov (United States)

    Allodi, Ilary; Comley, Laura; Nichterwitz, Susanne; Nizzardo, Monica; Simone, Chiara; Benitez, Julio Aguila; Cao, Ming; Corti, Stefania; Hedlund, Eva

    2016-01-01

    The fatal disease amyotrophic lateral sclerosis (ALS) is characterized by the loss of somatic motor neurons leading to muscle wasting and paralysis. However, motor neurons in the oculomotor nucleus, controlling eye movement, are for unknown reasons spared. We found that insulin-like growth factor 2 (IGF-2) was maintained in oculomotor neurons in ALS and thus could play a role in oculomotor resistance in this disease. We also showed that IGF-1 receptor (IGF-1R), which mediates survival pathways upon IGF binding, was highly expressed in oculomotor neurons and on extraocular muscle endplate. The addition of IGF-2 induced Akt phosphorylation, glycogen synthase kinase-3β phosphorylation and β-catenin levels while protecting ALS patient motor neurons. IGF-2 also rescued motor neurons derived from spinal muscular atrophy (SMA) patients from degeneration. Finally, AAV9::IGF-2 delivery to muscles of SOD1(G93A) ALS mice extended life-span by 10%, while preserving motor neurons and inducing motor axon regeneration. Thus, our studies demonstrate that oculomotor-specific expression can be utilized to identify candidates that protect vulnerable motor neurons from degeneration. PMID:27180807

  14. Exome sequencing identified mutations in CASK and MYBPC3 as the cause of a complex dilated cardiomyopathy phenotype.

    Science.gov (United States)

    Reinstein, Eyal; Tzur, Shay; Bormans, Concetta; Behar, Doron M

    2016-01-01

    Whole-exome sequencing for clinical applications is now an integral part of medical genetics practice. Though most studies are performed in order to establish diagnoses in individuals with rare and clinically unrecognizable disorders, due to the constantly decreasing costs and commercial availability, whole-exome sequencing has gradually become the initial tool to study patients with clinically recognized disorders when more than one gene is responsible for the phenotype or in complex phenotypes, when variants in more than one gene can be the cause for the disease. Here we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations, and a second variant, in MYBPC3, that is associated with hereditary cardiomyopathy. We conclude that although the potential for co-occurrence of rare diseases is higher when analyzing undefined phenotypes in consanguineous families, it should also be given consideration in the genetic evaluation of complex phenotypes in non-consanguineous families. PMID:27173948

  15. GENOME-WIDE LINKAGE ANALYSIS TO IDENTIFY CHROMOSOMAL REGIONS AFFECTING PHENOTYPIC TRAITS IN THE CHICKEN. IV. SKELETAL INTEGRITY

    Science.gov (United States)

    Two unique chicken F2 populations generated from a broiler breeder male line and two genetically distinct inbred (greater than 99%) chicken lines (Leghom and Fayoumi), were used for whole genome QTL analysis. Twelve phenotypic skeletal integrity traits (6 absolute and 6 relative traits) were measure...

  16. Can the genotype or phenotype of two polymorphic drug metabolising cytochrome P450-enzymes identify oral lichenoid drug eruptions?

    DEFF Research Database (Denmark)

    Kragelund, Camilla; Hansen, Claus; Reibel, Jesper;

    2010-01-01

    Lichenoid drug eruptions (LDE) in the oral cavity are adverse drug reactions (ADR) that are impossible to differentiate from oral lichen planus (OLP) as no phenotypic criteria exist. Impaired function of polymorphic cytochrome 450-enzymes (CYPs) may cause increased plasma concentration of some dr...

  17. Novel Phenotypic Outcomes Identified for a Public Collection of Approved Drugs from a Publicly Accessible Panel of Assays.

    Directory of Open Access Journals (Sweden)

    Jonathan A Lee

    Full Text Available Phenotypic assays have a proven track record for generating leads that become first-in-class therapies. Whole cell assays that inform on a phenotype or mechanism also possess great potential in drug repositioning studies by illuminating new activities for the existing pharmacopeia. The National Center for Advancing Translational Sciences (NCATS pharmaceutical collection (NPC is the largest reported collection of approved small molecule therapeutics that is available for screening in a high-throughput setting. Via a wide-ranging collaborative effort, this library was analyzed in the Open Innovation Drug Discovery (OIDD phenotypic assay modules publicly offered by Lilly. The results of these tests are publically available online at www.ncats.nih.gov/expertise/preclinical/pd2 and via the PubChem Database (https://pubchem.ncbi.nlm.nih.gov/ (AID 1117321. Phenotypic outcomes for numerous drugs were confirmed, including sulfonylureas as insulin secretagogues and the anti-angiogenesis actions of multikinase inhibitors sorafenib, axitinib and pazopanib. Several novel outcomes were also noted including the Wnt potentiating activities of rotenone and the antifolate class of drugs, and the anti-angiogenic activity of cetaben.

  18. Genetic diversity of color phenotypes in the koi (Cyprinus carpio L.) as identified by molecular markers

    OpenAIRE

    Dani Bercovich; Sigal Korem; Lior Shauder; Gad Degani

    2012-01-01

    The common carp (Cyprinus carpio) has a large variety of strains. The more popular are the koi (Japanese ornamental carp), which are still bred today to generate creative colors and patterns, giving rise to multiple phenotypes. Since koi are in great demand, there is a challenge to determine the genetics defining their quality. Two methods: 1) direct sequencing of five candidate gene regions, i.e., mitochondrial (cytochrome b&l...

  19. Fast forward genetics to identify mutations causing a high light tolerant phenotype in Chlamydomonas reinhardtii by whole-genome-sequencing

    OpenAIRE

    Schierenbeck, Lisa; Ries, David; Rogge, Kristin; Grewe, Sabrina; Weisshaar, Bernd; Kruse, Olaf

    2015-01-01

    Background: High light tolerance of microalgae is a desired phenotype for efficient cultivation in large scale production systems under fluctuating outdoor conditions. Outdoor cultivation requires the use of either wild-type or non-GMO derived mutant strains due to safety concerns. The identification and molecular characterization of such mutants derived from untagged forward genetics approaches was limited previously by the tedious and time-consuming methods involving techniques such as ...

  20. Defining Disease Phenotypes in Primary Care Electronic Health Records by a Machine Learning Approach: A Case Study in Identifying Rheumatoid Arthritis

    OpenAIRE

    Zhou, Shang-Ming; Fernandez-Gutierrez, Fabiola; Kennedy, Jonathan; Cooksey, Roxanne; Atkinson, Mark; Denaxas, Spiros; Siebert, Stefan; Dixon, William G.; O’Neill, Terence W; Choy, Ernest; Sudlow, Cathie; ,; Brophy, Sinead

    2016-01-01

    Objectives 1) To use data-driven method to examine clinical codes (risk factors) of a medical condition in primary care electronic health records (EHRs) that can accurately predict a diagnosis of the condition in secondary care EHRs. 2) To develop and validate a disease phenotyping algorithm for rheumatoid arthritis using primary care EHRs. Methods This study linked routine primary and secondary care EHRs in Wales, UK. A machine learning based scheme was used to identify patients with rheumat...

  1. Defining disease phenotypes in primary care electronic health records by a machine learning approach: a case study in identifying rheumatoid arthritis

    OpenAIRE

    Pappalardo, Francesco; Zhou, Shang; Fernandez-Gutierrez, Fabiola; Kennedy, Jonathan; Cooksey, Roxanne; Atkinson, Mark; Denaxas, Spiros; Siebert, Stefan; Dixon, William; O’Neill, Terence; Choy, Ernest; Sudlow, Cathie; Brophy, Sinead

    2016-01-01

    Objectives: 1) To use data-driven method to examine clinical codes (risk factors) of a medical condition in primary care electronic health records (EHRs) that can accurately predict a diagnosis of the condition in secondary care EHRs. 2) To develop and validate a disease phenotyping algorithm for rheumatoid arthritis using primary care EHRs. Methods: This study linked routine primary and secondary care EHRs in Wales, UK. A machine learning based scheme was used to identify patie...

  2. Defining disease phenotypes in primary care electronic health records by a machine learning approach:A case study in identifying rheumatoid arthritis

    OpenAIRE

    Zhou, Shang Ming; Fernandez-Gutierrez, Fabiola; Kennedy, Jonathan; Cooksey, Roxanne; Atkinson, Mark; Denaxas, Spiros; Siebert, Stefan; Dixon, William G.; O'Neill, Terence W.; Choy, Ernest; Sudlow, Cathie; Brophy, Sinead; Danesh, John; Allen, Naomi; Blaveri, Ekaterini

    2016-01-01

    Objectives: 1) To use data-driven method to examine clinical codes (risk factors) of a medical condition in primary care electronic health records (EHRs) that can accurately predict a diagnosis of the condition in secondary care EHRs. 2) To develop and validate a disease phenotyping algorithm for rheumatoid arthritis using primary care EHRs. Methods: This study linked routine primary and secondary care EHRs in Wales, UK. A machine learning based scheme was used to identify patients with rheum...

  3. Phenotypic and functional characteristic of a newly identified CD8+Foxp3−CD103+ regulatory T cells

    OpenAIRE

    Liu, Ya; Lan, Qin; Lu, Ling; Chen, Maogen; Xia, Zanxian; Ma, Jilin; Wang, Julie; Fan, Huimin; Shen, Yi; Ryffel, Bernhard; Brand, David; Quismorio, Francisco; Liu, Zhongmin; Horwitz, David A.; Xu, Anping

    2013-01-01

    TGF-β and Foxp3 expressions are crucial for the induction and functional activity of CD4+Foxp3+ regulatory T (iTreg) cells. Here, we demonstrate that although TGF-β-primed CD8+ cells display much lower Foxp3 expression, their suppressive capacity is equivalent to that of CD4+ iTreg cells, and both Foxp3− and Foxp3+ CD8+ subsets have suppressive activities in vitro and in vivo. CD8+Foxp3− iTreg cells produce little IFN-γ but almost no IL-2, and display a typical anergic phenotype. Among phenot...

  4. Genome-wide association study identifies HLA 8.1 ancestral haplotype alleles as major genetic risk factors for myositis phenotypes.

    Science.gov (United States)

    Miller, F W; Chen, W; O'Hanlon, T P; Cooper, R G; Vencovsky, J; Rider, L G; Danko, K; Wedderburn, L R; Lundberg, I E; Pachman, L M; Reed, A M; Ytterberg, S R; Padyukov, L; Selva-O'Callaghan, A; Radstake, T R; Isenberg, D A; Chinoy, H; Ollier, W E R; Scheet, P; Peng, B; Lee, A; Byun, J; Lamb, J A; Gregersen, P K; Amos, C I

    2015-10-01

    Autoimmune muscle diseases (myositis) comprise a group of complex phenotypes influenced by genetic and environmental factors. To identify genetic risk factors in patients of European ancestry, we conducted a genome-wide association study (GWAS) of the major myositis phenotypes in a total of 1710 cases, which included 705 adult dermatomyositis, 473 juvenile dermatomyositis, 532 polymyositis and 202 adult dermatomyositis, juvenile dermatomyositis or polymyositis patients with anti-histidyl-tRNA synthetase (anti-Jo-1) autoantibodies, and compared them with 4724 controls. Single-nucleotide polymorphisms showing strong associations (PAH8.1) defined essentially all the genetic risk in the phenotypes studied. Although the HLA DRB1*03:01 allele showed slightly stronger associations with adult and juvenile dermatomyositis, and HLA B*08:01 with polymyositis and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for the full risk effects. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. PMID:26291516

  5. Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats.

    Science.gov (United States)

    Nikodemova, Maria; Small, Alissa L; Smith, Stephanie M C; Mitchell, Gordon S; Watters, Jyoti J

    2014-09-01

    Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1(G93A) rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed no differences in microglial number or phenotype in presymptomatic rats compared to wild-type controls. Although after disease onset there was no macrophage infiltration, there were significant increases in microglial numbers in the spinal cord, but not cortex. At disease end-stage, microglia were characterized by high expression of galectin-3, osteopontin and VEGF, and concomitant downregulated expression of TNFα, IL-6, BDNF and arginase-1. Flow cytometry revealed the presence of at least two phenotypically distinct microglial populations in the spinal cord. Immunohistochemistry showed that galectin-3/osteopontin positive microglia were restricted to the ventral horns of the spinal cord, regions with severe motor neuron degeneration. End-stage SOD1(G93A) microglia from the cortex, a less affected region, displayed similar gene expression profiles to microglia from wild-type rats, and displayed normal responses to systemic inflammation induced by LPS. On the other hand, end-stage SOD1(G93A) spinal microglia had blunted responses to systemic LPS suggesting that in addition to their phenotypic changes, they may also be functionally impaired. Thus, after disease onset, microglia acquired unique characteristics that do not conform to typical M1 (inflammatory) or M2 (anti-inflammatory) phenotypes. This transformation was observed only in the most affected CNS regions, suggesting that overexpression of mutated hSOD1 is not sufficient to trigger these changes in microglia. These

  6. Integrative Functional Genomics Analysis of Sustained Polyploidy Phenotypes in Breast Cancer Cells Identifies an Oncogenic Profile for GINS2

    Directory of Open Access Journals (Sweden)

    Juha K. Rantala

    2010-11-01

    Full Text Available Aneuploidy is among the most obvious differences between normal and cancer cells. However, mechanisms contributing to development and maintenance of aneuploid cell growth are diverse and incompletely understood. Functional genomics analyses have shown that aneuploidy in cancer cells is correlated with diffuse gene expression signatures and aneuploidy can arise by a variety of mechanisms, including cytokinesis failures, DNA endoreplication, and possibly through polyploid intermediate states. To identify molecular processes contributing to development of aneuploidy, we used a cell spot microarray technique to identify genes inducing polyploidy and/or allowing maintenance of polyploid cell growth in breast cancer cells. Of 5760 human genes screened, 177 were found to induce severe DNA content alterations on prolonged transient silencing. Association with response to DNA damage stimulus and DNA repair was found to be the most enriched cellular processes among the candidate genes. Functional validation analysis of these genes highlighted GINS2 as the highest ranking candidate inducing polyploidy, accumulation of endogenous DNA damage, and impairing cell proliferation on inhibition. The cell growth inhibition and induction of polyploidy by suppression of GINS2 was verified in a panel of breast cancer cell lines. Bioinformatic analysis of published gene expression and DNA copy number studies of clinical breast tumors suggested GINS2 to be associated with the aggressive characteristics of a subgroup of breast cancers in vivo. In addition, nuclear GINS2 protein levels distinguished actively proliferating cancer cells suggesting potential use of GINS2 staining as a biomarker of cell proliferation as well as a potential therapeutic target.

  7. Genomic and Transcriptomic Associations Identify a New Insecticide Resistance Phenotype for the Selective Sweep at the Cyp6g1 Locus of Drosophila melanogaster.

    Science.gov (United States)

    Battlay, Paul; Schmidt, Joshua M; Fournier-Level, Alexandre; Robin, Charles

    2016-01-01

    Scans of the Drosophila melanogaster genome have identified organophosphate resistance loci among those with the most pronounced signature of positive selection. In this study, the molecular basis of resistance to the organophosphate insecticide azinphos-methyl was investigated using the Drosophila Genetic Reference Panel, and genome-wide association. Recently released full transcriptome data were used to extend the utility of the Drosophila Genetic Reference Panel resource beyond traditional genome-wide association studies to allow systems genetics analyses of phenotypes. We found that both genomic and transcriptomic associations independently identified Cyp6g1, a gene involved in resistance to DDT and neonicotinoid insecticides, as the top candidate for azinphos-methyl resistance. This was verified by transgenically overexpressing Cyp6g1 using natural regulatory elements from a resistant allele, resulting in a 6.5-fold increase in resistance. We also identified four novel candidate genes associated with azinphos-methyl resistance, all of which are involved in either regulation of fat storage, or nervous system development. In Cyp6g1, we find a demonstrable resistance locus, a verification that transcriptome data can be used to identify variants associated with insecticide resistance, and an overlap between peaks of a genome-wide association study, and a genome-wide selective sweep analysis. PMID:27317781

  8. Genome sequencing of the Trichoderma reesei QM9136 mutant identifies a truncation of the transcriptional regulator XYR1 as the cause for its cellulase-negative phenotype

    Energy Technology Data Exchange (ETDEWEB)

    Lichius, Alexander; Bidard, Frederique; Buchholz, Franziska; Le Crom, Stphane; Martin, Joel X.; Schackwitz, Wendy; Austerlitz, Tina; Grigoriev, Igor V.; Baker, Scott E.; Margeot, Antoine; Seiboth, Bernhard; Kubicek, Christian P.

    2015-12-01

    Background: Trichoderma reesei is the main industrial source of cellulases and hemicellulases required for the hydrolysis of biomass to simple sugars, which can then be used in the production of biofuels and biorefineries. The highly productive strains in use today were generated by classical mutagenesis. As byproducts of this procedure, mutants were generated that turned out to be unable to produce cellulases. In order to identify the mutations responsible for this inability, we sequenced the genome of one of these strains, QM9136, and compared it to that of its progenitor T. reesei QM6a. Results: In QM9136, we detected a surprisingly low number of mutagenic events in the promoter and coding regions of genes, i.e. only eight indels and six single nucleotide variants. One of these indels led to a frame-shift in the Zn2Cys6 transcription factor XYR1, the general regulator of cellulase and xylanase expression, and resulted in its C-terminal truncation by 140 amino acids. Retransformation of strain QM9136 with the wild-type xyr1 allele fully recovered the ability to produce cellulases, and is thus the reason for the cellulase-negative phenotype. Introduction of an engineered xyr1 allele containing the truncating point mutation into the moderate producer T. reesei QM9414 rendered this strain also cellulase-negative. The correspondingly truncated XYR1 protein was still able to enter the nucleus, but failed to be expressed over the basal constitutive level. Conclusion: The missing 140 C-terminal amino acids of XYR1 are therefore responsible for its previously observed auto-regulation which is essential for cellulases to be expressed. Our data present a working example of the use of genome sequencing leading to a functional explanation of the QM9136 cellulase-negative phenotype.

  9. Optimizing the phenotyping of rodent ASD models: enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features

    Directory of Open Access Journals (Sweden)

    Buxbaum Joseph D

    2012-02-01

    Full Text Available Abstract Background There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitutes useful phenotypes in ASD models. Methods To address this, we made use of a list of 112 disease genes etiologically involved in ASD to survey, on a large scale and with unbiased methods as well as expert review, phenotypes associated with a targeted disruption of these genes in mice, using the Mammalian Phenotype Ontology database. In addition, we compared the results with similar analyses for human phenotypes. Findings We observed four classes of neurobiological phenotypes associated with disruption of a large proportion of ASD genes, including: (1 Changes in brain and neuronal morphology; (2 electrophysiological changes; (3 neurological changes; and (4 higher-order behavioral changes. Alterations in brain and neuronal morphology represent quantitative measures that can be more widely adopted in models of ASD to understand cellular and network changes. Interestingly, the electrophysiological changes differed across different genes, indicating that excitation/inhibition imbalance hypotheses for ASD would either have to be so non-specific as to be not falsifiable, or, if specific, would not be supported by the data. Finally, it was significant that in analyses of both mouse and human databases, many of the behavioral alterations were neurological changes, encompassing sensory alterations, motor abnormalities, and seizures, as opposed to higher-order behavioral changes in learning and memory and social behavior paradigms. Conclusions The results indicated that mutations

  10. Optimizing the phenotyping of rodent ASD models: Enrichment analysis of mouse and human neurobiological phenotypes associated with high-risk autism genes identifies morphological, electrophysiological, neurological, and behavioral features.

    OpenAIRE

    Buxbaum Joseph D; Betancur Catalina; Bozdagi Ozlem; Dorr Nate P; Elder Gregory A; Hof Patrick R

    2012-01-01

    Abstract Background There is interest in defining mouse neurobiological phenotypes useful for studying autism spectrum disorders (ASD) in both forward and reverse genetic approaches. A recurrent focus has been on high-order behavioral analyses, including learning and memory paradigms and social paradigms. However, well-studied mouse models, including for example Fmr1 knockout mice, do not show dramatic deficits in such high-order phenotypes, raising a question as to what constitutes useful ph...

  11. β-N-methylamino-l-alanine causes neurological and pathological phenotypes mimicking Amyotrophic Lateral Sclerosis (ALS): the first step towards an experimental model for sporadic ALS.

    Science.gov (United States)

    de Munck, Estefanía; Muñoz-Sáez, Emma; Miguel, Begoña G; Solas, M Teresa; Ojeda, Irene; Martínez, Ana; Gil, Carmen; Arahuetes, Rosa Ma

    2013-09-01

    β-N-methylamino-l-alanine (L-BMAA) is a neurotoxic amino acid that has been related to various neurodegenerative diseases. The aim of this work was to analyze the biotoxicity produced by L-BMAA in vivo in rats, trying to elucidate its physiopathological mechanisms and to search for analogies between the found effects and pathologies like Amyotrophic Lateral Sclerosis (ALS). Our data demonstrated that the neurotoxic effects in vivo were dosage-dependent. For evaluating the state of the animals, a neurological evaluation scale was developed as well as a set of functional tests. Ultrastructural cell analysis of spinal motoneurons has revealed alterations both in endoplasmic reticulum and mitochondria. Since GSK3β could play a role in some neuropathological processes, we analyzed the alterations occurring in GSK3β levels in L-BMAA treated rats, we have observed an increase in the active form of GSK3β levels in lumbar spinal cord and motor cerebral cortex. On the other hand, (TAR)-DNA-binding protein 43 (TDP-43) increased in L-BMAA treated animals. Our results indicated that N-acetylaspartate (NAA) declined in animals treated with L-BMAA, and the ratio of N-acetylaspartate/choline (NAA/Cho), N-acetylaspartate/creatine (NAA/Cr) and N-acetylaspartate/choline+creatine (NAA/Cho+Cr) tended to decrease in lumbar spinal cord and motor cortex. This project offers some encouraging results that could help establishing the progress in the development of an animal model of sporadic ALS and L-BMAA could be a useful tool for this purpose. PMID:23688553

  12. Defining Disease Phenotypes in Primary Care Electronic Health Records by a Machine Learning Approach: A Case Study in Identifying Rheumatoid Arthritis

    Science.gov (United States)

    Zhou, Shang-Ming; Fernandez-Gutierrez, Fabiola; Kennedy, Jonathan; Cooksey, Roxanne; Atkinson, Mark; Denaxas, Spiros; Siebert, Stefan; Dixon, William G.; O’Neill, Terence W.; Choy, Ernest; Sudlow, Cathie; Brophy, Sinead

    2016-01-01

    Objectives 1) To use data-driven method to examine clinical codes (risk factors) of a medical condition in primary care electronic health records (EHRs) that can accurately predict a diagnosis of the condition in secondary care EHRs. 2) To develop and validate a disease phenotyping algorithm for rheumatoid arthritis using primary care EHRs. Methods This study linked routine primary and secondary care EHRs in Wales, UK. A machine learning based scheme was used to identify patients with rheumatoid arthritis from primary care EHRs via the following steps: i) selection of variables by comparing relative frequencies of Read codes in the primary care dataset associated with disease case compared to non-disease control (disease/non-disease based on the secondary care diagnosis); ii) reduction of predictors/associated variables using a Random Forest method, iii) induction of decision rules from decision tree model. The proposed method was then extensively validated on an independent dataset, and compared for performance with two existing deterministic algorithms for RA which had been developed using expert clinical knowledge. Results Primary care EHRs were available for 2,238,360 patients over the age of 16 and of these 20,667 were also linked in the secondary care rheumatology clinical system. In the linked dataset, 900 predictors (out of a total of 43,100 variables) in the primary care record were discovered more frequently in those with versus those without RA. These variables were reduced to 37 groups of related clinical codes, which were used to develop a decision tree model. The final algorithm identified 8 predictors related to diagnostic codes for RA, medication codes, such as those for disease modifying anti-rheumatic drugs, and absence of alternative diagnoses such as psoriatic arthritis. The proposed data-driven method performed as well as the expert clinical knowledge based methods. Conclusion Data-driven scheme, such as ensemble machine learning methods, has

  13. Genome-wide association study identifies chromosome 10q24.32 variants associated with arsenic metabolism and toxicity phenotypes in Bangladesh.

    Directory of Open Access Journals (Sweden)

    Brandon L Pierce

    Full Text Available Arsenic contamination of drinking water is a major public health issue in many countries, increasing risk for a wide array of diseases, including cancer. There is inter-individual variation in arsenic metabolism efficiency and susceptibility to arsenic toxicity; however, the basis of this variation is not well understood. Here, we have performed the first genome-wide association study (GWAS of arsenic-related metabolism and toxicity phenotypes to improve our understanding of the mechanisms by which arsenic affects health. Using data on urinary arsenic metabolite concentrations and approximately 300,000 genome-wide single nucleotide polymorphisms (SNPs for 1,313 arsenic-exposed Bangladeshi individuals, we identified genome-wide significant association signals (P<5×10(-8 for percentages of both monomethylarsonic acid (MMA and dimethylarsinic acid (DMA near the AS3MT gene (arsenite methyltransferase; 10q24.32, with five genetic variants showing independent associations. In a follow-up analysis of 1,085 individuals with arsenic-induced premalignant skin lesions (the classical sign of arsenic toxicity and 1,794 controls, we show that one of these five variants (rs9527 is also associated with skin lesion risk (P = 0.0005. Using a subset of individuals with prospectively measured arsenic (n = 769, we show that rs9527 interacts with arsenic to influence incident skin lesion risk (P = 0.01. Expression quantitative trait locus (eQTL analyses of genome-wide expression data from 950 individual's lymphocyte RNA suggest that several of our lead SNPs represent cis-eQTLs for AS3MT (P = 10(-12 and neighboring gene C10orf32 (P = 10(-44, which are involved in C10orf32-AS3MT read-through transcription. This is the largest and most comprehensive genomic investigation of arsenic metabolism and toxicity to date, the only GWAS of any arsenic-related trait, and the first study to implicate 10q24.32 variants in both arsenic metabolism and arsenical

  14. Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations

    OpenAIRE

    Mackay, Donna S.; Borman, Arundhati Dev; Sui, Ruifang; van den Born, L. Ingeborgh; Berson, Eliot L.; Ocaka, Louise A.; Davidson, Alice E.; Heckenlively, John R.; Branham, Kari; Ren, Huanan; Lopez, Irma; Maria, Maleeha; Azam, Maleeha; Henkes, Arjen; Blokland, Ellen

    2013-01-01

    To investigate the prevalence of sequence variants in LCA5 in patients with Leber congenital amaurosis (LCA), early onset rod-cone dystrophy (EORD) and autosomal recessive retinitis pigmentosa (RP), to delineate the ocular phenotypes, and to provide an overview of all published LCA5 variants in an online database._Patients underwent standard ophthalmic evaluations after providing informed consent. In selected patients, optical coherence tomography (OCT) and fundus autoflu...

  15. Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system.

    OpenAIRE

    Staropoli, John F.; Haliw, Larissa; Biswas, Sunita; Garrett, Lillian; Hölter, Sabine M.; Becker, Lore; Skosyrski, Sergej; Da Silva-Buttkus, Patricia; Calzada-Wack, Julia; Neff, Frauke; Rathkolb, Birgit; Rozman, Jan; Schrewe, Anja; Adler, Thure; Puk, Oliver

    2012-01-01

    Cln3(Δex7/8) mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3(Δex7/8) mice. Homozygous Cln3(Δex7/8) mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10-14 wee...

  16. Large-Scale Phenotyping of an Accurate Genetic Mouse Model of JNCL Identifies Novel Early Pathology Outside the Central Nervous System

    OpenAIRE

    Staropoli, John F.; Haliw, Larissa; Biswas, Sunita; Garrett, Lillian; Hölter, Sabine M.; Becker, Lore; Skosyrski, Sergej; Da Silva-Buttkus, Patricia; Calzada-Wack, Julia; Neff, Frauke; Rathkolb, Birgit; Rozman, Jan; Schrewe, Anja; Adler, Thure; Puk, Oliver

    2012-01-01

    Cln3Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL), an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3Δex7/8 mice. Homozygous Cln3Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10–14 weeks of ...

  17. Large-scale phenotyping of an accurate genetic mouse model of JNCL identifies novel early pathology outside the central nervous system.

    Directory of Open Access Journals (Sweden)

    John F Staropoli

    Full Text Available Cln3(Δex7/8 mice harbor the most common genetic defect causing juvenile neuronal ceroid lipofuscinosis (JNCL, an autosomal recessive disease involving seizures, visual, motor and cognitive decline, and premature death. Here, to more thoroughly investigate the manifestations of the common JNCL mutation, we performed a broad phenotyping study of Cln3(Δex7/8 mice. Homozygous Cln3(Δex7/8 mice, congenic on a C57BL/6N background, displayed subtle deficits in sensory and motor tasks at 10-14 weeks of age. Homozygous Cln3(Δex7/8 mice also displayed electroretinographic changes reflecting cone function deficits past 5 months of age and a progressive decline of retinal post-receptoral function. Metabolic analysis revealed increases in rectal body temperature and minimum oxygen consumption in 12-13 week old homozygous Cln3(Δex7/8 mice, which were also seen to a lesser extent in heterozygous Cln3(Δex7/8 mice. Heart weight was slightly increased at 20 weeks of age, but no significant differences were observed in cardiac function in young adults. In a comprehensive blood analysis at 15-16 weeks of age, serum ferritin concentrations, mean corpuscular volume of red blood cells (MCV, and reticulocyte counts were reproducibly increased in homozygous Cln3(Δ (ex7/8 mice, and male homozygotes had a relative T-cell deficiency, suggesting alterations in hematopoiesis. Finally, consistent with findings in JNCL patients, vacuolated peripheral blood lymphocytes were observed in homozygous Cln3(Δ (ex7/8 neonates, and to a greater extent in older animals. Early onset, severe vacuolation in clear cells of the epididymis of male homozygous Cln3(Δ (ex7/8 mice was also observed. These data highlight additional organ systems in which to study CLN3 function, and early phenotypes have been established in homozygous Cln3(Δ (ex7/8 mice that merit further study for JNCL biomarker development.

  18. Meta-analysis of archived DNA microarrays identifies genes regulated by hypoxia and involved in a metastatic phenotype in cancer cells

    International Nuclear Information System (INIS)

    Metastasis is a major cancer-related cause of death. Recent studies have described metastasis pathways. However, the exact contribution of each pathway remains unclear. Another key feature of a tumor is the presence of hypoxic areas caused by a lack of oxygen at the center of the tumor. Hypoxia leads to the expression of pro-metastatic genes as well as the repression of anti-metastatic genes. As many Affymetrix datasets about metastasis and hypoxia are publicly available and not fully exploited, this study proposes to re-analyze these datasets to extract new information about the metastatic phenotype induced by hypoxia in different cancer cell lines. Affymetrix datasets about metastasis and/or hypoxia were downloaded from GEO and ArrayExpress. AffyProbeMiner and GCRMA packages were used for pre-processing and the Window Welch t test was used for processing. Three approaches of meta-analysis were eventually used for the selection of genes of interest. Three complementary approaches were used, that eventually selected 183 genes of interest. Out of these 183 genes, 99, among which the well known JUNB, FOS and TP63, have already been described in the literature to be involved in cancer. Moreover, 39 genes of those, such as SERPINE1 and MMP7, are known to regulate metastasis. Twenty-one genes including VEGFA and ID2 have also been described to be involved in the response to hypoxia. Lastly, DAVID classified those 183 genes in 24 different pathways, among which 8 are directly related to cancer while 5 others are related to proliferation and cell motility. A negative control composed of 183 random genes failed to provide such results. Interestingly, 6 pathways retrieved by DAVID with the 183 genes of interest concern pathogen recognition and phagocytosis. The proposed methodology was able to find genes actually known to be involved in cancer, metastasis and hypoxia and, thus, we propose that the other genes selected based on the same methodology are of prime interest in

  19. Genome-wide linkage analysis to identify chromosomal regions affecting phenotypic traits in the chicken. I. Growth and average daily gain

    Science.gov (United States)

    A genome scan was used to detect chromosomal regions and QTL that control quantitative traits of economic importance in chickens. Two unique F2 crosses generated from a commercial broiler male line and 2 genetically distinct inbred lines (Leghorn and Fayoumi) were used to identify QTL affecting BW a...

  20. Optically confined polarized resonance Raman studies in identifying crystalline orientation of sub-diffraction limited AlGaN nanostructure

    International Nuclear Information System (INIS)

    An optical characterization tool of Raman spectroscopy with extremely weak scattering cross section tool is not popular to analyze scattered signal from a single nanostructure in the sub-diffraction regime. In this regard, plasmonic assisted characterization tools are only relevant in spectroscopic studies of nanoscale object in the sub-diffraction limit. We have reported polarized resonance Raman spectroscopic (RRS) studies with strong electron-phonon coupling to understand the crystalline orientation of a single AlGaN nanowire of diameter ∼100 nm. AlGaN nanowire is grown by chemical vapor deposition technique using the catalyst assisted vapor-liquid-solid process. The results are compared with the high resolution transmission electron microscopic analysis. As a matter of fact, optical confinement effect due to the dielectric contrast of nanowire with respect to that of surrounding media assisted with electron-phonon coupling of RRS is useful for the spectroscopic analysis in the sub-diffraction limit of 325 nm (λ/2N.A.) using an excitation wavelength (λ) of 325 nm and near ultraviolet 40× far field objective with a numerical aperture (N.A.) value of 0.50

  1. Extreme-phenotype genome-wide association study (XP-GWAS): a method for identifying trait-associated variants by sequencing pools of individuals selected from a diversity panel.

    Science.gov (United States)

    Yang, Jinliang; Jiang, Haiying; Yeh, Cheng-Ting; Yu, Jianming; Jeddeloh, Jeffrey A; Nettleton, Dan; Schnable, Patrick S

    2015-11-01

    Although approaches for performing genome-wide association studies (GWAS) are well developed, conventional GWAS requires high-density genotyping of large numbers of individuals from a diversity panel. Here we report a method for performing GWAS that does not require genotyping of large numbers of individuals. Instead XP-GWAS (extreme-phenotype GWAS) relies on genotyping pools of individuals from a diversity panel that have extreme phenotypes. This analysis measures allele frequencies in the extreme pools, enabling discovery of associations between genetic variants and traits of interest. This method was evaluated in maize (Zea mays) using the well-characterized kernel row number trait, which was selected to enable comparisons between the results of XP-GWAS and conventional GWAS. An exome-sequencing strategy was used to focus sequencing resources on genes and their flanking regions. A total of 0.94 million variants were identified and served as evaluation markers; comparisons among pools showed that 145 of these variants were statistically associated with the kernel row number phenotype. These trait-associated variants were significantly enriched in regions identified by conventional GWAS. XP-GWAS was able to resolve several linked QTL and detect trait-associated variants within a single gene under a QTL peak. XP-GWAS is expected to be particularly valuable for detecting genes or alleles responsible for quantitative variation in species for which extensive genotyping resources are not available, such as wild progenitors of crops, orphan crops, and other poorly characterized species such as those of ecological interest. PMID:26386250

  2. Can We Identify Patients with High Risk of Osteoarthritis Progression Who Will Respond to Treatment? A Focus on Epidemiology and Phenotype of Osteoarthritis

    OpenAIRE

    Bruyère, Olivier; Cooper, Cyrus; Arden, Nigel; Branco, Jaime; Brandi, Maria Luisa; Herrero-Beaumont, Gabriel; Berenbaum, Francis; Dennison, Elaine; Devogelaer, Jean-Pierre; Hochberg, Marc; Kanis, John; Laslop, Andrea; McAlindon, Tim; Reiter, Susanne; Richette, Pascal

    2015-01-01

    Osteoarthritis is a syndrome affecting a variety of patient profiles. A European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the European Union Geriatric Medicine Society working meeting explored the possibility of identifying different patient profiles in osteoarthritis. The risk factors for the development of osteoarthritis include systemic factors (e.g., age, sex, obesity, genetics, race, and bone density) and local biomechanical factors (e.g., obesity,...

  3. Exome sequencing of extreme clopidogrel response phenotypes identifies B4GALT2 as a determinant of on-treatment platelet reactivity.

    Science.gov (United States)

    Scott, S A; Collet, J-P; Baber, U; Yang, Y; Peter, I; Linderman, M; Sload, J; Qiao, W; Kini, A S; Sharma, S K; Desnick, R J; Fuster, V; Hajjar, R J; Montalescot, G; Hulot, J-S

    2016-09-01

    Interindividual variability in platelet aggregation is common among patients treated with clopidogrel and both high on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) increase risks for adverse clinical outcomes. CYP2C19 influences clopidogrel response but only accounts for ∼12% of the variability in platelet reactivity. To identify novel variants implicated in on-treatment platelet reactivity, patients with coronary artery disease (CAD) with extreme pharmacodynamic responses to clopidogrel and wild-type CYP2C19 were subjected to exome sequencing. Candidate variants that clustered in the LTPR subgroup subsequently were genotyped across the discovery cohort (n = 636). Importantly, carriers of B4GALT2 c.909C>T had lower on-treatment P2Y12 reaction units (PRUs; P = 0.0077) and residual platelet aggregation (P = 0.0008) compared with noncarriers, which remained significant after adjusting for CYP2C19 and other clinical variables in both the discovery (P = 0.0298) and replication (n = 160; PRU: P = 0.0001) cohorts. B4GALT2 is a platelet-expressed galactosyltransferase, indicating that B4GALT2 c.909C>T may influence clopidogrel sensitivity through atypical cell-surface glycoprotein processing and platelet adhesion. PMID:27213804

  4. Spinal but not cortical microglia acquire an atypical phenotype with high VEGF, galectin-3 and osteopontin, and blunted inflammatory responses in ALS rats

    OpenAIRE

    Nikodemova, Maria; Small, Alissa L.; Smith, Stephanie M.C.; Mitchell, Gordon S.; Watters, Jyoti J.

    2013-01-01

    Activation of microglia, CNS resident immune cells, is a pathological hallmark of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting motor neurons. Despite evidence that microglia contribute to disease progression, the exact role of these cells in ALS pathology remains unknown. We immunomagnetically isolated microglia from different CNS regions of SOD1G93A rats at three different points in disease progression: presymptomatic, symptom onset and end-stage. We observed n...

  5. Retraction: "Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells" by Bao et al.

    Science.gov (United States)

    2016-08-01

    The above article, published online on April 18, 2011 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the second author that found Figures 1C and 4C to be inappropriately re-used and re-labeled. REFERENCE Bao B, Wang Z, Ali S, Kong D, Banerjee S, Ahmad A, Li Y, Azmi AS, Miele L, Sarkar FH. 2011. Over-expression of FoxM1 leads to epithelial-mesenchymal transition and cancer stem cell phenotype in pancreatic cancer cells. J Cell Biochem 112:2296-2306; doi: 10.1002/jcb.23150. PMID:27301890

  6. The exome sequencing identified the mutation in YARS2 encoding the mitochondrial tyrosyl-tRNA synthetase as a nuclear modifier for the phenotypic manifestation of Leber's hereditary optic neuropathy-associated mitochondrial DNA mutation.

    Science.gov (United States)

    Jiang, Pingping; Jin, Xiaofen; Peng, Yanyan; Wang, Meng; Liu, Hao; Liu, Xiaoling; Zhang, Zengjun; Ji, Yanchun; Zhang, Juanjuan; Liang, Min; Zhao, Fuxin; Sun, Yan-Hong; Zhang, Minglian; Zhou, Xiangtian; Chen, Ye; Mo, Jun Qin; Huang, Taosheng; Qu, Jia; Guan, Min-Xin

    2016-02-01

    Leber's hereditary optic neuropathy (LHON) is the most common mitochondrial disorder. Nuclear modifier genes are proposed to modify the phenotypic expression of LHON-associated mitochondrial DNA (mtDNA) mutations. By using an exome sequencing approach, we identified a LHON susceptibility allele (c.572G>T, p.191Gly>Val) in YARS2 gene encoding mitochondrial tyrosyl-tRNA synthetase, which interacts with m.11778G>A mutation to cause visual failure. We performed functional assays by using lymphoblastoid cell lines derived from members of Chinese families (asymptomatic individuals carrying m.11778G>A mutation, or both m.11778G>A and heterozygous p.191Gly>Val mutations and symptomatic subjects harboring m.11778G>A and homozygous p.191Gly>Val mutations) and controls lacking these mutations. The 191Gly>Val mutation reduced the YARS2 protein level in the mutant cells. The aminoacylated efficiency and steady-state level of tRNA(Tyr) were markedly decreased in the cell lines derived from patients both carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The failure in tRNA(Tyr) metabolism impaired mitochondrial translation, especially for polypeptides with high content of tyrosine codon such as ND4, ND5, ND6 and COX2 in cells lines carrying homozygous YARS2 p.191Gly>Val and m.11778G>A mutations. The YARS2 p.191Gly>Val mutation worsened the respiratory phenotypes associated with m.11778G>A mutation, especially reducing activities of complexes I and IV. The respiratory deficiency altered the efficiency of mitochondrial ATP synthesis and increased the production of reactive oxygen species. Thus, mutated YARS2 aggravates mitochondrial dysfunctions associated with the m.11778G>A mutation, exceeding the threshold for the expression of blindness phenotype. Our findings provided new insights into the pathophysiology of LHON that were manifested by interaction between mtDNA mutation and mutated nuclear-modifier YARS2. PMID:26647310

  7. Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

    Directory of Open Access Journals (Sweden)

    Cyro José de Moraes Martins

    Full Text Available The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH, endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR, adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity.

  8. Circulating Endocannabinoids and the Polymorphism 385C>A in Fatty Acid Amide Hydrolase (FAAH) Gene May Identify the Obesity Phenotype Related to Cardiometabolic Risk: A Study Conducted in a Brazilian Population of Complex Interethnic Admixture.

    Science.gov (United States)

    Martins, Cyro José de Moraes; Genelhu, Virginia; Pimentel, Marcia Mattos Gonçalves; Celoria, Bruno Miguel Jorge; Mangia, Rogerio Fabris; Aveta, Teresa; Silvestri, Cristoforo; Di Marzo, Vincenzo; Francischetti, Emilio Antonio

    2015-01-01

    The dysregulation of the endocannabinoid system is associated with cardiometabolic complications of obesity. Allelic variants in coding genes for this system components may contribute to differences in the susceptibility to obesity and related health hazards. These data have mostly been shown in Caucasian populations and in severely obese individuals. We investigated a multiethnic Brazilian population to study the relationships among the polymorphism 385C>A in an endocannabinoid degrading enzyme gene (FAAH), endocannabinoid levels and markers of cardiometabolic risk. Fasting plasma levels of endocannabinoids and congeners (anandamide, 2-arachidonoylglycerol, N-oleoylethanolamide and N-palmitoylethanolamide) were measured by liquid chromatography-mass spectrometry in 200 apparently healthy individuals of both genders with body mass indices from 22.5 ± 1.8 to 35.9 ± 5.5 kg/m2 (mean ± 1 SD) and ages between 18 and 60 years. All were evaluated for anthropometric parameters, blood pressure, metabolic variables, homeostatic model assessment of insulin resistance (HOMA-IR), adiponectin, leptin, C-reactive protein, and genotyping. The endocannabinoid levels increased as a function of obesity and insulin resistance. The homozygous genotype AA was associated with higher levels of anandamide and lower levels of adiponectin versus wild homozygous CC and heterozygotes combined. The levels of anandamide were independent and positively associated with the genotype AA position 385 of FAAH, C-reactive protein levels and body mass index. Our findings provide evidence for an endocannabinoid-related phenotype that may be identified by the combination of circulating anandamide levels with genotyping of the FAAH 385C>A; this phenotype is not exclusive to mono-ethnoracial populations nor to individuals with severe obesity. PMID:26561012

  9. A case of severe proximal focal femoral deficiency with overlapping phenotypes of Al-Awadi-Raas-Rothschild syndrome and Fuhrmann syndrome.

    Science.gov (United States)

    Matsushita, Masaki; Kitoh, Hiroshi; Mishima, Kenichi; Nishida, Yoshihiro; Ishiguro, Naoki

    2014-12-01

    Proximal focal femoral deficiency (PFFD) is a heterogeneous disorder characterized by various degrees of femoral deficiencies and associated anomalies of the pelvis and lower limbs. The etiology of the disease has not been determined. We report on a 3-year-old boy with severe PFFD, who showed almost completely absent femora and fibulae, malformed pelvis and ectrodactyly of the left foot. These features were partially overlapped with those of Al-Awadi-Raas-Rothschild syndrome or Fuhrmann syndrome, both of which are caused by WNT7A mutations. Molecular analysis of our case, however, demonstrated no disease-causing mutations in the WNT7A gene. PMID:24839142

  10. An overlapping phenotype of Osteogenesis imperfecta and Ehlers-Danlos syndrome due to a heterozygous mutation in COL1A1 and biallelic missense variants in TNXB identified by whole exome sequencing.

    Science.gov (United States)

    Mackenroth, Luisa; Fischer-Zirnsak, Björn; Egerer, Johannes; Hecht, Jochen; Kallinich, Tilmann; Stenzel, Werner; Spors, Birgit; von Moers, Arpad; Mundlos, Stefan; Kornak, Uwe; Gerhold, Kerstin; Horn, Denise

    2016-04-01

    Osteogenesis imperfecta (OI) and Ehlers-Danlos syndrome (EDS) are variable genetic disorders that overlap in different ways [Cole 1993; Grahame 1999]. Here, we describe a boy presenting with severe muscular hypotonia, multiple fractures, and joint hyperflexibility, features that are compatible with mild OI and hypermobility type EDS, respectively. By whole exome sequencing, we identified both a COL1A1 mutation (c.4006-1G > A) inherited from the patient's mildly affected mother and biallelic missense variants in TNXB (p.Val1213Ile, p.Gly2592Ser). Analysis of cDNA showed that the COL1A1 splice site mutation led to intron retention causing a frameshift (p.Phe1336Valfs*72). Type 1 collagen secretion by the patient's skin fibroblasts was reduced. Immunostaining of a muscle biopsy obtained from the patient revealed a clear reduction of tenascin-X in the extracellular matrix compared to a healthy control. These findings imply that the combination of the COL1A1 mutation with the TNXB variants might cause the patient's unique phenotype. PMID:26799614

  11. Deciphering amyotrophic lateral sclerosis: What phenotype, neuropathology and genetics are telling us about pathogenesis

    Science.gov (United States)

    Ravits, John; Appel, Stanley; Baloh, Robert H.; Barohn, Richard; Brooks, Benjamin Rix; Elman, Lauren; Floeter, Mary Kay; Henderson, Christopher; Lomen-Hoerth, Catherine; Macklis, Jeffrey D.; Mccluskey, Leo; Mitsumoto, Hiroshi; Przedborski, Serge; Rothstein, Jeffrey; Trojanowski, John Q.; Van Den Berg, Leonard H.; Ringel, Steven

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant cognitive and behavioral involvement. These phenotypes can be so distinctive that they would seem to have differing biology. However, they cannot be distinguished, at least neuropathologically or genetically. In sporadic ALS (SALS), they are mostly characterized by ubiquitinated cytoplasmic inclusions of TDP-43. In familial ALS (FALS), where phenotypes are indistinguishable from SALS and similarly heterogeneous, each mutated gene has its own genetic and molecular signature. Overall, since the same phenotypes can have multiple causes including different gene mutations, there must be multiple molecular mechanisms causing ALS – and ALS is a syndrome. Since, however, multiple phenotypes can be caused by one single gene mutation, a single molecular mechanism can cause heterogeneity. What the mechanisms are remain unknown, but active propagation of the pathology neuroanatomically seems to be a principal component. Leading candidate mechanisms include RNA processing, cell-cell interactions between neurons and non-neuronal neighbors, focal seeding from a misfolded protein that has prion-like propagation, and fatal errors introduced during neurodevelopment of the motor system. If fundamental mechanisms could be identified and understood, ALS therapy could rationally target progression and stop the disease – a goal that seems increasingly achievable. PMID:23678876

  12. Emerging molecular phenotypes of asthma.

    Science.gov (United States)

    Ray, Anuradha; Oriss, Timothy B; Wenzel, Sally E

    2015-01-15

    Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease. PMID:25326577

  13. Micro X-ray diffraction using X-ray area detector and identifying multiple phases in Zr2TiAl alloy system

    International Nuclear Information System (INIS)

    The birth of X-ray diffraction technique and its evolution has catalyzed the development of solid state science and further our understanding of material properties. The first single crystal X-ray diffraction pattern recorded was of Copper Sulphate Hydrate on a photographic film by Laue, and his co-workers Friedrich and Knipping, in 1912, for which he was awarded the Nobel prize. The actual diffraction pattern obtained was pretty awful with vague smudges instead of sharp diffraction spots (1). Development of X-ray detection technology has been playing an important role in advancing the development of new X-ray diffraction and imaging techniques. For instance, developments in electronics in the 1960's to 80's enabled advent of point detectors (eg. Nal scintillation detector) and line detectors (e.g gas filled single wire detector). These led to faster and more sensitive detection of X-rays leading to good XRD patterns. However, important information about microstructural details, defects, etc that are manifest well in the two dimensional map of the reciprocal space could be obtained reliably using area detectors (e.g X-ray films) (2). In the 1990's new developments in 2D X-ray area detectors such as Charge coupled devices (CCD), Imaging Plate Systems (IPS) and Multiwire proportional counters (MPC) led to replacement of the slower and low sensitive X-ray films with extremely sensitive 2D detection technology. This presentation will discuss these 2D detection techniques and their underlying mechanism. Recently the structure of multiple phases in Zr2TiAl alloy system could be identified using micro-XRD and 2D detection technique. Result of this study will be presented. (author)

  14. Identifying postmenopausal women at risk for cognitive decline within a healthy cohort using a panel of clinical metabolic indicators: potential for detecting an at-Alzheimer's risk metabolic phenotype.

    Science.gov (United States)

    Rettberg, Jamaica R; Dang, Ha; Hodis, Howard N; Henderson, Victor W; St John, Jan A; Mack, Wendy J; Brinton, Roberta Diaz

    2016-04-01

    Detecting at-risk individuals within a healthy population is critical for preventing or delaying Alzheimer's disease. Systems biology integration of brain and body metabolism enables peripheral metabolic biomarkers to serve as reporters of brain bioenergetic status. Using clinical metabolic data derived from healthy postmenopausal women in the Early versus Late Intervention Trial with Estradiol (ELITE), we conducted principal components and k-means clustering analyses of 9 biomarkers to define metabolic phenotypes. Metabolic clusters were correlated with cognitive performance and analyzed for change over 5 years. Metabolic biomarkers at baseline generated 3 clusters, representing women with healthy, high blood pressure, and poor metabolic phenotypes. Compared with healthy women, poor metabolic women had significantly lower executive, global and memory cognitive performance. Hormone therapy provided metabolic benefit to women in high blood pressure and poor metabolic phenotypes. This panel of well-established clinical peripheral biomarkers represents an initial step toward developing an affordable, rapidly deployable, and clinically relevant strategy to detect an at-risk phenotype of late-onset Alzheimer's disease. PMID:26973115

  15. Multivariate Analysis of Genotype-Phenotype Association.

    Science.gov (United States)

    Mitteroecker, Philipp; Cheverud, James M; Pavlicev, Mihaela

    2016-04-01

    With the advent of modern imaging and measurement technology, complex phenotypes are increasingly represented by large numbers of measurements, which may not bear biological meaning one by one. For such multivariate phenotypes, studying the pairwise associations between all measurements and all alleles is highly inefficient and prevents insight into the genetic pattern underlying the observed phenotypes. We present a new method for identifying patterns of allelic variation (genetic latent variables) that are maximally associated-in terms of effect size-with patterns of phenotypic variation (phenotypic latent variables). This multivariate genotype-phenotype mapping (MGP) separates phenotypic features under strong genetic control from less genetically determined features and thus permits an analysis of the multivariate structure of genotype-phenotype association, including its dimensionality and the clustering of genetic and phenotypic variables within this association. Different variants of MGP maximize different measures of genotype-phenotype association: genetic effect, genetic variance, or heritability. In an application to a mouse sample, scored for 353 SNPs and 11 phenotypic traits, the first dimension of genetic and phenotypic latent variables accounted for >70% of genetic variation present in all 11 measurements; 43% of variation in this phenotypic pattern was explained by the corresponding genetic latent variable. The first three dimensions together sufficed to account for almost 90% of genetic variation in the measurements and for all the interpretable genotype-phenotype association. Each dimension can be tested as a whole against the hypothesis of no association, thereby reducing the number of statistical tests from 7766 to 3-the maximal number of meaningful independent tests. Important alleles can be selected based on their effect size (additive or nonadditive effect on the phenotypic latent variable). This low dimensionality of the genotype-phenotype map

  16. Quasicrystalline d-AlCuCo identified as random tiling by ion channeling combined with particle induced X-ray emission

    OpenAIRE

    Zeger, Gabriele; Plachke, Dieter; Carstanjen, Heinz Dieter; Trebin, Hans-Rainer

    1999-01-01

    In a model quasicrystal for decagonal AlCuCo the phason disorder was gradually increased and the channeling PIXE yields were computed for 3 MeV He ions by Monte Carlo simulations. For large phason disorder good agreement with experimental data was obtained. Thus we conclude that the sample of d-AlCuCo used in the measurements is a random tiling. One remaining discrepancy, namely that the PIXE yields of the simulations are approximately the same for Cu and Co, is eliminated by optimization of ...

  17. Comment on "Evolutionary trade-offs, Pareto optimality, and the geometry of phenotype space".

    Science.gov (United States)

    Edelaar, Pim

    2013-02-15

    Shoval et al. (Reports, 1 June 2012, p. 1157) showed how configurations of phenotypes may identify tasks that trade off with each other, using randomizations assuming independence of data points. I argue that this assumption may not be correct for most and possibly all examples and led to pseudoreplication and inflated significance levels. Improved statistical testing is necessary to assess how the theory applies to empirical data. PMID:23413338

  18. Semiparametric Allelic Tests for Mapping Multiple Phenotypes: Binomial Regression and Mahalanobis Distance.

    Science.gov (United States)

    Majumdar, Arunabha; Witte, John S; Ghosh, Saurabh

    2015-12-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors and genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g., MultiPhen (O'Reilly et al. []), have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. In this article, we explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (Binomial regression-based Association of Multivariate Phenotypes [BAMP]), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a single-nucleotide polymorphism (Distance-based Association of Multivariate Phenotypes [DAMP]). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association is compared with the genotype-level test MultiPhen's. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found to be substantially more powerful. All three tests are applied to two different real data and the results offer some support for the simulation study. We propose a hybrid approach for testing multivariate association that implements MultiPhen when Hardy-Weinberg Equilibrium (HWE) is violated and BAMP otherwise, because the allelic approaches assume HWE

  19. Use of Arrott plots to identify Néel temperature (TN) in metamagnetic Ni48Co6Mn26Al20 polycrystalline ribbons

    International Nuclear Information System (INIS)

    (Ni48Co6)Mn26Al20 polycrystalline ribbons with B2 structure at room temperature are investigated. Considering the presence of competing magnetic interactions, Arrott-plot analysis gives TN ∼ 170 K. A broad ferromagnetic-paramagnetic transition (TC) is observed at ∼200 K. H-T phase-diagram is used to validate the presence of competing exchange interactions that persist till very close to TC. Based on Néel theory, a cluster model is used to explain the presence of ferromagnetic and antiferromagnetic clusters in the sample. Formation of ferromagnetic clusters can be understood in terms of positive exchange interactions among the Mn atoms that are neighboring Co atoms located at Ni sites

  20. Phenotypic heterogeneity of Streptococcus mutans in dentin.

    Science.gov (United States)

    Rupf, S; Hannig, M; Breitung, K; Schellenberger, W; Eschrich, K; Remmerbach, T; Kneist, S

    2008-12-01

    Information concerning phenotypic heterogeneity of Streptococcus mutans in carious dentin is sparse. Matrix-assisted laser-desorption/ionization-time-of-flight mass-spectrometry (MALDI-TOF-MS) facilitates the phenotypic differentiation of bacteria to the subspecies level. To verify a supposed influence of restorative treatment on the phenotypic heterogeneity of S. mutans, we isolated and compared a total of 222 S. mutans strains from dentin samples of 21 human deciduous molars during caries excavation (T(1)) and 8 wks (T(2)) after removal of the temporary restoration. Phenotypic heterogeneity was determined by MALDI-TOF-MS and hierarchical clustering. Thirty-six distinct S. mutans phenotypes could be identified. Although indistinguishable phenotypes were found in the same teeth at T(1) and T(2), as well as in different teeth of individual participants, the phenotypic heterogeneity increased significantly, from 1.4 phenotypes per S. mutans-positive dentin sample at T(1) to 2.2 phenotypes at T(2). We attribute this to an adaptation of S. mutans to the modified environment under the restoration following caries excavation. PMID:19029088

  1. Identifying spectrometric signatures of phosphate deposits and enclosing sediments in Al-Awabed area, Northern Palmyrides, Central Syria, by the use of statistical factor analysis

    International Nuclear Information System (INIS)

    In previous published research, a factor analysis approach has been applied to airborne spectrometric data of Al-Awabed area, Northern Palmyrides, Syria. A model of four factors (F1, F2, F3 and F4) has proven to be sufficient to represent the acquired data, where 94% of the total data variance is explained. A powerful tool for direct differentiation of various rocks units is obtained through the mapping of these four factors, where a scored lithological map including 11 radiometric units is established. Ninty nine rock samples have been taken according to the four factors to be analyzed by the γ-spectrometry technique in order to determine their content of eU, eTh and K%. The analysis of 65 samples according to F1 indicates that uranium concentration varies between 2.74 and 123.3 ppm with an average of 58.85 ppm and a standard deviation of 32.53 ppm. The analysis of 18 samples taken according to F2 indicates that K% concentration varies between 0.001 and 0.324 with an average of 0.145 and a standard deviation of 0.122. The analysis of 16 samples taken according to F3 indicates that K% concentration varies between 0.024 and 0.558 with an average of 0.227 and a standard deviation of 0.133. These γ-results are expected and fit very well with the results obtained by the factor analysis approach. Therefore, the validity and efficacy of the factor analysis approach, to be widely used as a guide in exploration and smart sampling for mining programs, are well demonstrated. The established phosphate maps show a width extension and distribution, and clearly indicate the potential of the research area, and it merits to be followed by economic exploration

  2. Identifying spectrometric signatures of phosphate deposits and enclosing sediments in Al-Awabed area, Northern Palmyrides, Central Syria, by the use of statistical factor analysis

    International Nuclear Information System (INIS)

    In previous published research, a factor analysis approach has been applied to airborne spectrometric data of Al-Awabed area, Northern Palmyrides, Syria. A model of four factors (F1, F2, F3 and F4) has proven to be sufficient to represent the acquired data, where 94% of the total data variance is explained. A powerful tool for direct differentiation of various rocks units is obtained through the mapping of these four factors, where a scored lithological map including 11 radiometric units is established. Ninety nine rock samples have been taken according to the four factors to be analyzed by the gamma spectrometry technique in order to determine their content of e U, e Th and K%. The analysis of 65 samples according to F1 indicates that uranium concentration varies between 2.74 and 123.3 ppm with an average of 58.85 ppm and a standard deviation of 32.53 ppm. The analysis of 18 samples taken according to F2 indicates that K% concentration varies between 0.001 and 0.324 with an average of 0.145 and a standard deviation of 0.122. The analysis of 16 samples taken according to F3 indicates that K% concentration varies between 0.024 and 0.558 with an average of 0.227 and a standard deviation of 0.133. These gamma-results are expected and fit very well with the results obtained by the factor analysis approach. Therefore, the validity and efficacy of the factor analysis approach, to be widely used as a guide in exploration and smart sampling for mining programs, are well demonstrated. The established phosphate maps show a width extension and distribution, and clearly indicate the potential of the research area, and it merits to be followed by economic exploration

  3. Hemogoblin phenotypes in Murgese horse

    OpenAIRE

    Carmela Bottiglieri; Rosario Rullo; Aldo Di Luccia; Elisa Pieragostini

    2010-01-01

    In this note we describe two new equine hemoglobin phenotypes found during a survey of the Murgese horse, a rare  Apulian native breed, among whose ancestors the Arabian surely plays an important role. To date we have analysed about  300 individual hemolysates by different chromatographic analyses (PAGIF, IPG, CMC). The results pointed out two unusu-  al patterns where the ratio of the α24Phe60Gln band to the α24Phe60Lys band was 93:7 and 70:30 rather than 60:40&nbs...

  4. A new mutation in MC1R explains a coat color phenotype in 2 "old" breeds: Saluki and Afghan hound.

    Science.gov (United States)

    Dreger, Dayna L; Schmutz, Sheila M

    2010-01-01

    Melanocortin 1 Receptor (MC1R) has been studied in a wide variety of domestic animals (Klungland et al. 1995; Marklund et al. 1996; Våge et al. 1997; Kijas et al. 1998; Newton et al. 2000; Våge et al. 2003), and also several wild animals (Robbins et al. 1993; Ritland et al. 2001; Eizirik et al. 2003; Nachman et al. 2003; McRobie et al. 2009) in relation to coat color variation. A variety of phenotypic changes have been reported including coat colors from pure black to pure red, as well as some phenotypes with hairs with red and black bands. One phenotype, called grizzle in Salukis and domino in Afghan Hounds, appears to be unique to these 2 old dog breeds. This pattern is characterized by a pale face with a widow's peak above the eyes. The body hairs on the dorsal surface of Salukis and Afghan Hounds have both phaeomelanin and eumelanin portions, even though they had an a(t)/a(t) genotype at ASIP. In addition, all had at least one copy of a newly identified mutation in MC1R, g.233G>T, resulting in p.Gly78Val. This new allele, that we suggest be designated as E(G), is dominant to the E and e (p.Arg306ter) alleles at MC1R but recessive to the E(M) (p.Met264Val) allele. The K(B) allele (p.Gly23del) at DEFB103 and the a(y) allele (p.Ala82Ser and p.Arg83His) of ASIP are epistatic to grizzle and domino. PMID:20525767

  5. Advanced phenotyping and phenotype data analysis for the study of plant growth and development.

    Science.gov (United States)

    Rahaman, Md Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

    2015-01-01

    Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germplasm with high performance characteristics in resource-limited environments. Recently, plant phenomics has offered and integrated a suite of new technologies, and we are on a path to improve the description of complex plant phenotypes. High-throughput phenotyping platforms have also been developed that capture phenotype data from plants in a non-destructive manner. In this review, we discuss recent developments of high-throughput plant phenotyping infrastructure including imaging techniques and corresponding principles for phenotype data analysis. PMID:26322060

  6. Deciphering Amyotrophic Lateral Sclerosis: What Phenotype, Neuropathology and Genetics Are Telling Us about Pathogenesis

    OpenAIRE

    Ravits, John; Appel, Stanley; Baloh, Robert H.; Barohn, Richard; Brooks, Benjamin Rix; Elman, Lauen; Floeter, Mary Kay; Macklis, Jeffrey Daniel; Henderson, Christopher; Lomen-Hoerth, Catherine; McCluskey, Leo; Mitsumoto, Hiroshi; Prezedborski, Serge; Rothstein, Jeffrey; Trojanowski, John

    2013-01-01

    Amyotrophic lateral sclerosis (ALS) is characterized phenotypically by progressive weakness and neuropathologically by loss of motor neurons. Phenotypically, there is marked heterogeneity. Typical ALS has mixed upper motor neuron (UMN) and lower motor neuron (LMN) involvement. Primary lateral sclerosis has predominant UMN involvement. Progressive muscular atrophy has predominant LMN involvement. Bulbar and limb ALS have predominant regional involvement. Frontotemporal dementia has significant...

  7. Atypical disease phenotypes in pediatric ulcerative colitis

    DEFF Research Database (Denmark)

    Levine, Arie; de Bie, Charlotte I; Turner, Dan; Cucchiara, Salvatore; Sladek, Malgorzata; Murphy, M Stephen; Escher, Johanna C; Pærregaard, Anders

    2013-01-01

    Definitive diagnosis of pediatric ulcerative colitis (UC) may be particularly challenging since isolated colitis with overlapping features is common in pediatric Crohn's disease (CD), while atypical phenotypes of UC are not uncommon. The Paris classification allows more accurate phenotyping of...... atypical inflammatory bowel disease (IBD) patients. Our aim was to identify the prevalence of atypical disease patterns in new-onset pediatric UC using the Paris classification....

  8. Deciphering the Galaxy Guppy phenotype

    Directory of Open Access Journals (Sweden)

    Philip Shaddock

    2011-01-01

    Full Text Available Animal breeding hobbyists have been useful to science because they identify and isolate colorcoat mutations that geneticists can in turn use in their studies of the development and differentiation ofcolor cells. This paper discusses a very interesting color mutant, the Japanese Galaxy, tracing its creationfrom back to a self-educated genetics hobbyist, Hoskiki Tsutsui. The paper discusses a constituent genepreviously studied by Dr. Violet Phang, the snakeskin gene (the linked body and fin genes Ssb and Sst.And it discusses a gene previously unknown to science, the Schimmelpfennig Platinum gene (Sc.Through crossing experiments, the author determines that the combination of these two genes producesan intermediate phenotype, the Medusa. Incorporating the Grass (Gr, another gene unknown to sciencegene into the Medusa through a crossover produces the Galaxy phenotype. Microscope studies of thesnakeskin pattern in Galaxies and snakeskins reveals some parallels with similar studies made of theZebrafish Danio.

  9. Semi-parametric Allelic Tests For Mapping Multiple Phenotypes: Binomial Regression And Mahalanobis Distance

    Science.gov (United States)

    Majumdar, Arunabha; Witte, John S.; Ghosh, Saurabh

    2016-01-01

    Binary phenotypes commonly arise due to multiple underlying quantitative precursors. Genetic variants may impact multiple traits in a pleiotropic manner. Hence, simultaneously analyzing such correlated traits may be more powerful than analyzing individual traits. Various genotype-level methods, e.g. MultiPhen [O'Reilly et al., 2012], have been developed to identify genetic factors underlying a multivariate phenotype. For univariate phenotypes, the usefulness and applicability of allele-level tests have been investigated. The test of allele frequency difference among cases and controls is commonly used for mapping case-control association. However, allelic methods for multivariate association mapping have not been studied much. We explore two allelic tests of multivariate association: one using a Binomial regression model based on inverted regression of genotype on phenotype (BAMP), and the other employing the Mahalanobis distance between two sample means of the multivariate phenotype vector for two alleles at a SNP (DAMP). These methods can incorporate both discrete and continuous phenotypes. Some theoretical properties for BAMP are studied. Using simulations, the power of the methods for detecting multivariate association are compared with the genotype-level test MultiPhen. The allelic tests yield marginally higher power than MultiPhen for multivariate phenotypes. For one/two binary traits under recessive mode of inheritance, allelic tests are found substantially more powerful. All three tests are applied to two real data and the results offer some support for the simulation study. Since the allelic approaches assume Hardy-Weinberg Equilibrium (HWE), we propose a hybrid approach for testing multivariate association that implements MultiPhen when HWE is violated and BAMP otherwise. PMID:26493781

  10. Large phenotype jumps in biomolecular evolution

    CERN Document Server

    Bardou, F

    2003-01-01

    By defining the phenotype of a biopolymer by its active three-dimensional shape, and its genotype by its primary sequence, we propose a model that predicts and characterizes the statistical distribution of a population of biopolymers with a specific phenotype, that originated from a given genotypic sequence by a single mutational event. Depending on the ratio g0 that characterizes the spread of potential energies of the mutated population with respect to temperature, three different statistical regimes have been identified. We suggest that biopolymers found in nature are in a critical regime with g0 in the range 1-6, corresponding to a broad, but not too broad, phenotypic distribution resembling a truncated Levy flight. Thus the biopolymer phenotype can be considerably modified in just a few mutations.

  11. Statistical models for trisomic phenotypes

    Energy Technology Data Exchange (ETDEWEB)

    Lamb, N.E.; Sherman, S.L.; Feingold, E. [Emory Univ., Atlanta, GA (United States)

    1996-01-01

    Certain genetic disorders are rare in the general population but more common in individuals with specific trisomies, which suggests that the genes involved in the etiology of these disorders may be located on the trisomic chromosome. As with all aneuploid syndromes, however, a considerable degree of variation exists within each phenotype so that any given trait is present only among a subset of the trisomic population. We have previously presented a simple gene-dosage model to explain this phenotypic variation and developed a strategy to map genes for such traits. The mapping strategy does not depend on the simple model but works in theory under any model that predicts that affected individuals have an increased likelihood of disomic homozygosity at the trait locus. This paper explores the robustness of our mapping method by investigating what kinds of models give an expected increase in disomic homozygosity. We describe a number of basic statistical models for trisomic phenotypes. Some of these are logical extensions of standard models for disomic phenotypes, and some are more specific to trisomy. Where possible, we discuss genetic mechanisms applicable to each model. We investigate which models and which parameter values give an expected increase in disomic homozygosity in individuals with the trait. Finally, we determine the sample sizes required to identify the increased disomic homozygosity under each model. Most of the models we explore yield detectable increases in disomic homozygosity for some reasonable range of parameter values, usually corresponding to smaller trait frequencies. It therefore appears that our mapping method should be effective for a wide variety of moderately infrequent traits, even though the exact mode of inheritance is unlikely to be known. 21 refs., 8 figs., 1 tab.

  12. Retraction: "Activated K-Ras and INK4a/Arf Deficiency Promote Aggressiveness of Pancreatic Cancer by Induction of EMT Consistent With Cancer Stem Cell Phenotype" by Wang et al.

    Science.gov (United States)

    2016-10-01

    The above article, published online on November 23, 2012 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor in Chief, Gary S. Stein, and Wiley Periodicals, Inc. The retraction has been agreed following an investigation from Wayne State University involving the first author and the corresponding author that found Figure 4B and C to be inappropriately manipulated and re-labeled. Literature Cited Wang Z, Ali S, Banerjee S, Bao B, Li Y, Azmi AS, Korc M, Sarkar FH. 2013. Activated K-Ras and INK4a/Arf deficiency promote aggressiveness of pancreatic cancer by induction of EMT consistent with cancer stem cell phenotype. J Cell Physiol 228:556-562; doi: 10.1002/jcp.24162. PMID:27315162

  13. Hemogoblin phenotypes in Murgese horse

    Directory of Open Access Journals (Sweden)

    Carmela Bottiglieri

    2010-01-01

    Full Text Available In this note we describe two new equine hemoglobin phenotypes found during a survey of the Murgese horse, a rare  Apulian native breed, among whose ancestors the Arabian surely plays an important role. To date we have analysed about  300 individual hemolysates by different chromatographic analyses (PAGIF, IPG, CMC. The results pointed out two unusu-  al patterns where the ratio of the α24Phe60Gln band to the α24Phe60Lys band was 93:7 and 70:30 rather than 60:40  which would have been expected of BII homozygote. Given that the three horses exhibiting the unusual patterns shared  a common ancestor and that none of the possible combinations of the known haplotypes can account for 7-8%  α24Phe60Lys, reasonably a triplicated arrangement has to be postulated. 

  14. Serum Biochemical Phenotypes in the Domestic Dog

    Science.gov (United States)

    Chang, Yu-Mei; Hadox, Erin; Szladovits, Balazs; Garden, Oliver A.

    2016-01-01

    The serum or plasma biochemical profile is essential in the diagnosis and monitoring of systemic disease in veterinary medicine, but current reference intervals typically take no account of breed-specific differences. Breed-specific hematological phenotypes have been documented in the domestic dog, but little has been published on serum biochemical phenotypes in this species. Serum biochemical profiles of dogs in which all measurements fell within the existing reference intervals were retrieved from a large veterinary database. Serum biochemical profiles from 3045 dogs were retrieved, of which 1495 had an accompanying normal glucose concentration. Sixty pure breeds plus a mixed breed control group were represented by at least 10 individuals. All analytes, except for sodium, chloride and glucose, showed variation with age. Total protein, globulin, potassium, chloride, creatinine, cholesterol, total bilirubin, ALT, CK, amylase, and lipase varied between sexes. Neutering status significantly impacted all analytes except albumin, sodium, calcium, urea, and glucose. Principal component analysis of serum biochemical data revealed 36 pure breeds with distinctive phenotypes. Furthermore, comparative analysis identified 23 breeds with significant differences from the mixed breed group in all biochemical analytes except urea and glucose. Eighteen breeds were identified by both principal component and comparative analysis. Tentative reference intervals were generated for breeds with a distinctive phenotype identified by comparative analysis and represented by at least 120 individuals. This is the first large-scale analysis of breed-specific serum biochemical phenotypes in the domestic dog and highlights potential genetic components of biochemical traits in this species. PMID:26919479

  15. Mixed phenotype acute leukemia

    Institute of Scientific and Technical Information of China (English)

    Ye Zixing; Wang Shujie

    2014-01-01

    Objective To highlight the current understanding of mixed phenotype acute leukemia (MPAL).Data sources We collected the relevant articles in PubMed (from 1985 to present),using the terms "mixed phenotype acute leukemia","hybrid acute leukemia","biphenotypic acute leukemia",and "mixed lineage leukemia".We also collected the relevant studies in WanFang Data base (from 2000 to present),using the terms "mixed phenotype acute leukemia" and "hybrid acute leukemia".Study selection We included all relevant studies concerning mixed phenotype acute leukemia in English and Chinese version,with no limitation of research design.The duplicated articles are excluded.Results MPAL is a rare subgroup of acute leukemia which expresses the myeloid and lymphoid markers simultaneously.The clinical manifestations of MPAL are similar to other acute leukemias.The World Health Organization classification and the European Group for Immunological classification of Leukaemias 1998 cdteria are most widely used.MPAL does not have a standard therapy regimen.Its treatment depends mostly on the patient's unique immunophenotypic and cytogenetic features,and also the experience of individual physician.The lack of effective treatment contributes to an undesirable prognosis.Conclusion Our understanding about MPAL is still limited.The diagnostic criteria have not been unified.The treatment of MPAL remains to be investigated.The prognostic factor is largely unclear yet.A better diagnostic cdteria and targeted therapeutics will improve the therapy effect and a subsequently better prognosis.

  16. Phenotypic Resistance to Antibiotics

    Directory of Open Access Journals (Sweden)

    Jose L. Martinez

    2013-04-01

    Full Text Available The development of antibiotic resistance is usually associated with genetic changes, either to the acquisition of resistance genes, or to mutations in elements relevant for the activity of the antibiotic. However, in some situations resistance can be achieved without any genetic alteration; this is called phenotypic resistance. Non-inherited resistance is associated to specific processes such as growth in biofilms, a stationary growth phase or persistence. These situations might occur during infection but they are not usually considered in classical susceptibility tests at the clinical microbiology laboratories. Recent work has also shown that the susceptibility to antibiotics is highly dependent on the bacterial metabolism and that global metabolic regulators can modulate this phenotype. This modulation includes situations in which bacteria can be more resistant or more susceptible to antibiotics. Understanding these processes will thus help in establishing novel therapeutic approaches based on the actual susceptibility shown by bacteria during infection, which might differ from that determined in the laboratory. In this review, we discuss different examples of phenotypic resistance and the mechanisms that regulate the crosstalk between bacterial metabolism and the susceptibility to antibiotics. Finally, information on strategies currently under development for diminishing the phenotypic resistance to antibiotics of bacterial pathogens is presented.

  17. Undiagnosed genetic muscle disease in the north of England: an in depth phenotype analysis.

    Science.gov (United States)

    Harris, Elizabeth; Laval, Steve; Hudson, Judith; Barresi, Rita; De Waele, Liesbeth; Straub, Volker; Lochmüller, Hanns; Bushby, Kate; Sarkozy, Anna

    2013-01-01

    Advances in the molecular characterisation of genetic muscle disease has been rapid, as demonstrated by a recent analysis of these conditions in the north of England by Norwood et al (2009), in which a genetic diagnosis was achieved for 75.7% of patients. However, there remain many patients with suspected genetic muscle disease in who a diagnosis is not obtained, often despite considerable diagnostic effort, and these patients are now being considered for the application of new technologies such as next generation sequencing. This study aimed to provide an in-depth phenotype analysis of undiagnosed patients referred to the Northern region muscle clinic with suspected genetic muscle disease, with the intention of gaining insight into these conditions, identifing cases with a shared phenotype who may be amenable to collective diagnostic testing or research, and evaluating the strengths and limitations of our current diagnostic strategy. We used two approaches: a review of clinical findings in patients with undiagnosed muscle disease, and a hierarchical cluster analysis to provide an unbiased interpretation of the phenotype data. These joint approaches identified a correlation of phenotypic features according to the age of disease onset and also delineated several interesting groups of patients, as well as highlighting areas of frequent diagnostic difficulty that could benefit from the use of new high-throughput diagnostic techniques. Correspondence to: anna.sarkozy@ncl.ac.uk. PMID:23788081

  18. Determining Which Phenotypes Underlie a Pleiotropic Signal.

    Science.gov (United States)

    Majumdar, Arunabha; Haldar, Tanushree; Witte, John S

    2016-07-01

    Discovering pleiotropic loci is important to understand the biological basis of seemingly distinct phenotypes. Most methods for assessing pleiotropy only test for the overall association between genetic variants and multiple phenotypes. To determine which specific traits are pleiotropic, we evaluate via simulation and application three different strategies. The first is model selection techniques based on the inverse regression of genotype on phenotypes. The second is a subset-based meta analysis ASSET [Bhattacharjee et al., ], which provides an optimal subset of nonnull traits. And the third is a modified Benjamini-Hochberg (B-H) procedure of controlling the expected false discovery rate [Benjamini and Hochberg, ] in the framework of phenome-wide association study. From our simulations we see that an inverse regression-based approach MultiPhen [O'Reilly et al., ] is more powerful than ASSET for detecting overall pleiotropic association, except for when all the phenotypes are associated and have genetic effects in the same direction. For determining which specific traits are pleiotropic, the modified B-H procedure performs consistently better than the other two methods. The inverse regression-based selection methods perform competitively with the modified B-H procedure only when the phenotypes are weakly correlated. The efficiency of ASSET is observed to lie below and in between the efficiency of the other two methods when the traits are weakly and strongly correlated, respectively. In our application to a large GWAS, we find that the modified B-H procedure also performs well, indicating that this may be an optimal approach for determining the traits underlying a pleiotropic signal. PMID:27238845

  19. Covert Genetic Selections to Optimize Phenotypes

    OpenAIRE

    Wu, Di; Townsley, Elizabeth; Tartakoff, Alan Michael

    2007-01-01

    In many high complexity systems (cells, organisms, institutions, societies, economies, etc.), it is unclear which components should be regulated to affect overall performance. To identify and prioritize molecular targets which impact cellular phenotypes, we have developed a selection procedure (“SPI”–single promoting/inhibiting target identification) which monitors the abundance of ectopic cDNAs. We have used this approach to identify growth regulators. For this purpose, complex pools of S. c...

  20. Describing the phenotype in Rett syndrome using a population database

    OpenAIRE

    Colvin, L; Fyfe, S.; Leonard, S.; Schiavello, T; ELLAWAY, C; N de Klerk; Christodoulou, J.; Msall, M; Leonard, H

    2003-01-01

    Background: Mutations in the MECP2 gene have been recently identified as the cause of Rett syndrome, prompting research into genotype-phenotype relations. However, despite these genetic advances there has been little descriptive epidemiology of the full range of phenotypes.

  1. hnRNPA2B1 and hnRNPA1 mutations are rare in patients with "multisystem proteinopathy" and frontotemporal lobar degeneration phenotypes.

    Science.gov (United States)

    Le Ber, Isabelle; Van Bortel, Inge; Nicolas, Gael; Bouya-Ahmed, Kawtar; Camuzat, Agnès; Wallon, David; De Septenville, Anne; Latouche, Morwena; Lattante, Serena; Kabashi, Edor; Jornea, Ludmila; Hannequin, Didier; Brice, Alexis

    2014-04-01

    hnRNPA2B1 and hnRNPA1 mutations have been recently identified by exome sequencing in three families presenting with multisystem proteinopathy (MSP), a rare complex phenotype associating frontotemporal lobar degeneration (FTLD), Paget disease of bone (PDB), inclusion body myopathy (IBM), and amyotrophic lateral sclerosis (ALS). No study has evaluated the exact frequency of these genes in cohorts of MSP or FTD patients so far. We sequenced both genes in 17 patients with MSP phenotypes, and in 60 patients with FTLD and FTLD-ALS to test whether mutations could be implicated in the pathogenesis of these disorders. No disease-causing mutation was identified. We conclude that hnRNPA2B1 and hnRNPA1 mutations are rare in MSP and FTLD spectrum of diseases, although further investigations in larger populations are needed. PMID:24119545

  2. Phenotypic Switching in Fungi

    OpenAIRE

    Jain, Neena; Hasan, Fahmi; Fries, Bettina C.

    2008-01-01

    Over the past three decades new fungal diseases have emerged that now constitute a major threat, especially for patients with chronic diseases and/or underlying immune defi ciencies. Despite the epidemiologic data, the emergence of stable drug-resistant or hyper-virulent fungal strains in human disease has not been demonstrated as seen in emerging viral and bacterial infections. Fungi are eukaryotic microbes that capitalize on a sophisticated built-in ability to generate phenotypic variabilit...

  3. Phenotypic and genetic consequences of protein damage.

    Directory of Open Access Journals (Sweden)

    Anita Krisko

    Full Text Available Although the genome contains all the information necessary for maintenance and perpetuation of life, it is the proteome that repairs, duplicates and expresses the genome and actually performs most cellular functions. Here we reveal strong phenotypes of physiological oxidative proteome damage at the functional and genomic levels. Genome-wide mutations rates and biosynthetic capacity were monitored in real time, in single Escherichia coli cells with identical levels of reactive oxygen species and oxidative DNA damage, but with different levels of irreversible oxidative proteome damage (carbonylation. Increased protein carbonylation correlates with a mutator phenotype, whereas reducing it below wild type level produces an anti-mutator phenotype identifying proteome damage as the leading cause of spontaneous mutations. Proteome oxidation elevates also UV-light induced mutagenesis and impairs cellular biosynthesis. In conclusion, protein damage reduces the efficacy and precision of vital cellular processes resulting in high mutation rates and functional degeneracy akin to cellular aging.

  4. Predicting phenotypic diversity and the underlying quantitative molecular transitions.

    Directory of Open Access Journals (Sweden)

    Claudiu A Giurumescu

    2009-04-01

    Full Text Available During development, signaling networks control the formation of multicellular patterns. To what extent quantitative fluctuations in these complex networks may affect multicellular phenotype remains unclear. Here, we describe a computational approach to predict and analyze the phenotypic diversity that is accessible to a developmental signaling network. Applying this framework to vulval development in C. elegans, we demonstrate that quantitative changes in the regulatory network can render approximately 500 multicellular phenotypes. This phenotypic capacity is an order-of-magnitude below the theoretical upper limit for this system but yet is large enough to demonstrate that the system is not restricted to a select few outcomes. Using metrics to gauge the robustness of these phenotypes to parameter perturbations, we identify a select subset of novel phenotypes that are the most promising for experimental validation. In addition, our model calculations provide a layout of these phenotypes in network parameter space. Analyzing this landscape of multicellular phenotypes yielded two significant insights. First, we show that experimentally well-established mutant phenotypes may be rendered using non-canonical network perturbations. Second, we show that the predicted multicellular patterns include not only those observed in C. elegans, but also those occurring exclusively in other species of the Caenorhabditis genus. This result demonstrates that quantitative diversification of a common regulatory network is indeed demonstrably sufficient to generate the phenotypic differences observed across three major species within the Caenorhabditis genus. Using our computational framework, we systematically identify the quantitative changes that may have occurred in the regulatory network during the evolution of these species. Our model predictions show that significant phenotypic diversity may be sampled through quantitative variations in the regulatory network

  5. Identification of distinct phenotypes of locally advanced pancreatic adenocarcinoma.

    LENUS (Irish Health Repository)

    Teo, Minyuen

    2013-03-01

    A significant number of pancreatic ductal adenocarcinoma present as locally advanced disease. Optimal treatment remains controversial. We sought to analyze the clinical course of locally advanced pancreatic adenocarcinoma (LAPC) in order to identify potential distinct clinical phenotypes.

  6. Evolution and diversity of the mechanisms endowing resistance to herbicides inhibiting acetolactate-synthase (ALS) in corn poppy (Papaver rhoeas L.)

    OpenAIRE

    Delye, Christophe; Pernin, Fanny; Scarabel, Laura

    2011-01-01

    We investigated the diversity of mechanisms conferring resistance to herbicides inhibiting acetolactate synthase (ALS) in corn poppy (Papaver rhoeas L.) and the processes underlying the selection for resistance. Six mutant ALS alleles, Arg197, His197, Leu197, Ser197, Thr197 and Leu574 were identified in five Italian populations. Different alleles were found in a same population or a same plant. Comparison of individual plant phenotype (herbicide sensitivity) and genotype (amino-acid substitu...

  7. Covert genetic selections to optimize phenotypes.

    Directory of Open Access Journals (Sweden)

    Di Wu

    Full Text Available In many high complexity systems (cells, organisms, institutions, societies, economies, etc., it is unclear which components should be regulated to affect overall performance. To identify and prioritize molecular targets which impact cellular phenotypes, we have developed a selection procedure ("SPI"-single promoting/inhibiting target identification which monitors the abundance of ectopic cDNAs. We have used this approach to identify growth regulators. For this purpose, complex pools of S. cerevisiae cDNA transformants were established and we quantitated the evolution of the spectrum of cDNAs which was initially present. These data emphasized the importance of translation initiation and ER-Golgi traffic for growth. SPI provides functional insight into the stability of cellular phenotypes under circumstances in which established genetic approaches cannot be implemented. It provides a functional "synthetic genetic signature" for each state of the cell (i.e. genotype and environment by surveying complex genetic libraries, and does not require specialized arrays of cDNAs/shRNAs, deletion strains, direct assessment of clonal growth or even a conditional phenotype. Moreover, it establishes a hierarchy of importance of those targets which can contribute, either positively or negatively, to modify the prevailing phenotype. Extensions of these proof-of-principle experiments to other cell types should provide a novel and powerful approach to analyze multiple aspects of the basic biology of yeast and animal cells as well as clinically-relevant issues.

  8. COPD: Definition and Phenotypes

    DEFF Research Database (Denmark)

    Vestbo, J.

    2014-01-01

    Chronic obstructive pulmonary disease (COPD) is currently defined as a common preventable and treatable disease that is characterized by persistent airflow limitation that is usually progressive and associated with an enhanced chronic inflammatory response in the airways and the lung to noxious...... particles or gases. Exacerbations and comorbidities contribute to the overall severity in individual patients. The evolution of this definition and the diagnostic criteria currently in use are discussed. COPD is increasingly divided in subgroups or phenotypes based on specific features and association with...

  9. ALS Association

    Science.gov (United States)

    ... toward a world without ALS! Walk to Defeat ALS® Walk to Defeat ALS® draws people of all ... We need your help. I Will Advocate National ALS Registry The National ALS Registry is a congressionally ...

  10. Phenotypic approaches to drought in cassava: review.

    Science.gov (United States)

    Okogbenin, Emmanuel; Setter, Tim L; Ferguson, Morag; Mutegi, Rose; Ceballos, Hernan; Olasanmi, Bunmi; Fregene, Martin

    2013-01-01

    Cassava is an important crop in Africa, Asia, Latin America, and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12-18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance breeding. PMID

  11. Phenotypic Approaches to Drought in Cassava: Review

    Directory of Open Access Journals (Sweden)

    Emmanuel eOkogbenin

    2013-05-01

    Full Text Available Cassava is an important crop in Africa, Asia, Latin America and the Caribbean. Cassava can be produced adequately in drought conditions making it the ideal food security crop in marginal environments. Although cassava can tolerate drought stress, it can be genetically improved to enhance productivity in such environments. Drought adaptation studies in over three decades in cassava have identified relevant mechanisms which have been explored in conventional breeding. Drought is a quantitative trait and its multigenic nature makes it very challenging to effectively manipulate and combine genes in breeding for rapid genetic gain and selection process. Cassava has a long growth cycle of 12 - 18 months which invariably contributes to a long breeding scheme for the crop. Modern breeding using advances in genomics and improved genotyping, is facilitating the dissection and genetic analysis of complex traits including drought tolerance, thus helping to better elucidate and understand the genetic basis of such traits. A beneficial goal of new innovative breeding strategies is to shorten the breeding cycle using minimized, efficient or fast phenotyping protocols. While high throughput genotyping have been achieved, this is rarely the case for phenotyping for drought adaptation. Some of the storage root phenotyping in cassava are often done very late in the evaluation cycle making selection process very slow. This paper highlights some modified traits suitable for early-growth phase phenotyping that may be used to reduce drought phenotyping cycle in cassava. Such modified traits can significantly complement the high throughput genotyping procedures to fast track breeding of improved drought tolerant varieties. The need for metabolite profiling, improved phenomics to take advantage of next generation sequencing technologies and high throughput phenotyping are basic steps for future direction to improve genetic gain and maximize speed for drought tolerance

  12. The common bipolar phenotype in young people

    OpenAIRE

    Rock, Philippa L; Chandler, Rebecca A.; Harmer, Catherine J.; Rogers, Robert D.; Goodwin, Guy M.

    2013-01-01

    Background Mood elevation is common in adolescents and young adults. The aim of this study was to investigate the prevalence of a bipolar diagnosis and co-morbidity in individuals identified by online screening for experience of (hypo)manic symptoms in order to better define the common bipolar phenotype in young people. Methods Survey data regarding experience of (hypo)manic symptoms and occurrence of co-morbidities were analysed for 106 students satisfying criteria for probable bipolar syndr...

  13. Gene networks underlying convergent and pleiotropic phenotypes in a large and systematically-phenotyped cohort with heterogeneous developmental disorders.

    Directory of Open Access Journals (Sweden)

    Tallulah Andrews

    2015-03-01

    Full Text Available Readily-accessible and standardised capture of genotypic variation has revolutionised our understanding of the genetic contribution to disease. Unfortunately, the corresponding systematic capture of patient phenotypic variation needed to fully interpret the impact of genetic variation has lagged far behind. Exploiting deep and systematic phenotyping of a cohort of 197 patients presenting with heterogeneous developmental disorders and whose genomes harbour de novo CNVs, we systematically applied a range of commonly-used functional genomics approaches to identify the underlying molecular perturbations and their phenotypic impact. Grouping patients into 408 non-exclusive patient-phenotype groups, we identified a functional association amongst the genes disrupted in 209 (51% groups. We find evidence for a significant number of molecular interactions amongst the association-contributing genes, including a single highly-interconnected network disrupted in 20% of patients with intellectual disability, and show using microcephaly how these molecular networks can be used as baits to identify additional members whose genes are variant in other patients with the same phenotype. Exploiting the systematic phenotyping of this cohort, we observe phenotypic concordance amongst patients whose variant genes contribute to the same functional association but note that (i this relationship shows significant variation across the different approaches used to infer a commonly perturbed molecular pathway, and (ii that the phenotypic similarities detected amongst patients who share the same inferred pathway perturbation result from these patients sharing many distinct phenotypes, rather than sharing a more specific phenotype, inferring that these pathways are best characterized by their pleiotropic effects.

  14. AL Amyloidosis

    Directory of Open Access Journals (Sweden)

    Desport Estelle

    2012-08-01

    /or immunofluorescence. Due to the systemic nature of the disease, non-invasive biopsies such as abdominal fat aspiration should be considered before taking biopsies from involved organs, in order to reduce the risk of bleeding complications. Differential diagnosis Systemic AL amyloidosis should be distinguished from other diseases related to deposition of monoclonal LC, and from other forms of systemic amyloidosis. When pathological studies have failed to identify the nature of amyloid deposits, genetic studies should be performed to diagnose hereditary amyloidosis. Management Treatment of AL amyloidosis is based on chemotherapy, aimed at controlling the underlying plasma clone that produces amyloidogenic LC. The hematological response should be carefully checked by serial measurements of serum free LC. The association of an alkylating agent with high-dose dexamethasone has proven to be effective in two thirds of patients and is considered as the current reference treatment. New agents used in the treatment of multiple myeloma are under investigation and appear to increase hematological response rates. Symptomatic measures and supportive care is necessary in patients with organ failure. Noticeably, usual treatments for cardiac failure (i.e. calcium inhibitors, β-blockers, angiotensin converting enzyme inhibitors are inefficient or even dangerous in patients with amyloid heart disease, that should be managed using diuretics. Amiodarone and pace maker implantation should be considered in patients with rhythm or conduction abnormalities. In selected cases, heart and kidney transplantation may be associated with prolonged patient and graft survival. Prognosis Survival in AL amyloidosis depends on the spectrum of organ involvement (amyloid heart disease being the main prognosis factor, the severity of individual organs involved and haematological response to treatment.

  15. Pseudomonas Aeruginosa Resistance Phenotypes and Phenotypic Highlighting Methods

    Science.gov (United States)

    BĂLĂŞOIU, MARIA; BĂLĂŞOIU, A.T.; MĂNESCU, RODICA; AVRAMESCU, CARMEN; IONETE, OANA

    2014-01-01

    Pseudomonas aeruginosa genus bacteria are well known for their increased drug resistance (phenotypic ang genotypic resistance). The most important resistance mechanisms are: enzyme production, reduction of pore expression, reduction of the external membrane proteins expression, efflux systems, topoisomerase mutations. These mechanisms often accumulate and lead to multidrug ressitance strains emergence. The most frequent acquired resistance mechanisms are betalactamase-type enzyme production (ESBLs, AmpC, carbapenemases), which determine variable phenotypes of betalactamines resistance, phenotypes which are associated with aminoglycosides and quinolones resistance. The nonenzymatic drug resistance mechanisms are caused by efflux systems, pore reduction and penicillin-binding proteins (PBP) modification, which are often associated to other resistance mechanisms. Phenotypic methods used for testing these mechanisms are based on highlighting these phenotypes using Kirby Bauer antibiogram, clinical breakpoints, and “cut off” values recommended by EUCAST 2013 standard, version 3.1. PMID:25729587

  16. Sex hormone binding globulin phenotypes

    DEFF Research Database (Denmark)

    Cornelisse, M M; Bennett, Patrick; Christiansen, M;

    1994-01-01

    Human sex hormone binding globulin (SHBG) is encoded by a normal and a variant allele. The resulting SHBG phenotypes (the homozygous normal SHBG, the heterozygous SHBG and the homozygous variant SHBG phenotype) can be distinguished by their electrophoretic patterns. We developed a novel detection...

  17. Phenotypic extremes in rare variant study designs.

    Science.gov (United States)

    Peloso, Gina M; Rader, Daniel J; Gabriel, Stacey; Kathiresan, Sekar; Daly, Mark J; Neale, Benjamin M

    2016-06-01

    Currently, next-generation sequencing studies aim to identify rare and low-frequency variation that may contribute to disease. For a given effect size, as the allele frequency decreases, the power to detect genes or variants of interest also decreases. Although many methods have been proposed for the analysis of such data, study design and analytic issues still persist in data interpretation. In this study we present sequencing data for ABCA1 that has known rare variants associated with high-density lipoprotein cholesterol (HDL-C). We contrast empirical findings from two study designs: a phenotypic extreme sample and a population-based random sample. We found differing strengths of association with HDL-C across the two study designs (P=0.0006 with n=701 phenotypic extremes vs P=0.03 with n=1600 randomly sampled individuals). To explore this apparent difference in evidence for association, we performed a simulation study focused on the impact of phenotypic selection on power. We demonstrate that the power gain for an extreme phenotypic selection study design is much greater in rare variant studies than for studies of common variants. Our study confirms that studying phenotypic extremes is critical in rare variant studies because it boosts power in two ways: the typical increases from extreme sampling and increasing the proportion of relevant functional variants ascertained and thereby tested for association. Furthermore, we show that when combining statistical evidence through meta-analysis from an extreme-selected sample and a second separate population-based random sample, power is lower when a traditional sample size weighting is used compared with weighting by the noncentrality parameter. PMID:26350511

  18. Deciphering the Mechanisms of Developmental Disorders (DMDD): a new programme for phenotyping embryonic lethal mice.

    Science.gov (United States)

    Mohun, Timothy; Adams, David J; Baldock, Richard; Bhattacharya, Shoumo; Copp, Andrew J; Hemberger, Myriam; Houart, Corinne; Hurles, Matt E; Robertson, Elizabeth; Smith, James C; Weaver, Tom; Weninger, Wolfgang

    2013-05-01

    International efforts to test gene function in the mouse by the systematic knockout of each gene are creating many lines in which embryonic development is compromised. These homozygous lethal mutants represent a potential treasure trove for the biomedical community. Developmental biologists could exploit them in their studies of tissue differentiation and organogenesis; for clinical researchers they offer a powerful resource for investigating the origins of developmental diseases that affect newborns. Here, we outline a new programme of research in the UK aiming to kick-start research with embryonic lethal mouse lines. The 'Deciphering the Mechanisms of Developmental Disorders' (DMDD) programme has the ambitious goal of identifying all embryonic lethal knockout lines made in the UK over the next 5 years, and will use a combination of comprehensive imaging and transcriptomics to identify abnormalities in embryo structure and development. All data will be made freely available, enabling individual researchers to identify lines relevant to their research. The DMDD programme will coordinate its work with similar international efforts through the umbrella of the International Mouse Phenotyping Consortium [see accompanying Special Article (Adams et al., 2013)] and, together, these programmes will provide a novel database for embryonic development, linking gene identity with molecular profiles and morphology phenotypes. PMID:23519034

  19. Deciphering the Mechanisms of Developmental Disorders (DMDD: a new programme for phenotyping embryonic lethal mice

    Directory of Open Access Journals (Sweden)

    Timothy Mohun

    2013-05-01

    International efforts to test gene function in the mouse by the systematic knockout of each gene are creating many lines in which embryonic development is compromised. These homozygous lethal mutants represent a potential treasure trove for the biomedical community. Developmental biologists could exploit them in their studies of tissue differentiation and organogenesis; for clinical researchers they offer a powerful resource for investigating the origins of developmental diseases that affect newborns. Here, we outline a new programme of research in the UK aiming to kick-start research with embryonic lethal mouse lines. The ‘Deciphering the Mechanisms of Developmental Disorders’ (DMDD programme has the ambitious goal of identifying all embryonic lethal knockout lines made in the UK over the next 5 years, and will use a combination of comprehensive imaging and transcriptomics to identify abnormalities in embryo structure and development. All data will be made freely available, enabling individual researchers to identify lines relevant to their research. The DMDD programme will coordinate its work with similar international efforts through the umbrella of the International Mouse Phenotyping Consortium [see accompanying Special Article (Adams et al., 2013] and, together, these programmes will provide a novel database for embryonic development, linking gene identity with molecular profiles and morphology phenotypes.

  20. Plant Phenotype Characterization System

    Energy Technology Data Exchange (ETDEWEB)

    Daniel W McDonald; Ronald B Michaels

    2005-09-09

    This report is the final scientific report for the DOE Inventions and Innovations Project: Plant Phenotype Characterization System, DE-FG36-04GO14334. The period of performance was September 30, 2004 through July 15, 2005. The project objective is to demonstrate the viability of a new scientific instrument concept for the study of plant root systems. The root systems of plants are thought to be important in plant yield and thus important to DOE goals in renewable energy sources. The scientific study and understanding of plant root systems is hampered by the difficulty in observing root activity and the inadequacy of existing root study instrumentation options. We have demonstrated a high throughput, non-invasive, high resolution technique for visualizing plant root systems in-situ. Our approach is based upon low-energy x-ray radiography and the use of containers and substrates (artificial soil) which are virtually transparent to x-rays. The system allows us to germinate and grow plant specimens in our containers and substrates and to generate x-ray images of the developing root system over time. The same plant can be imaged at different times in its development. The system can be used for root studies in plant physiology, plant morphology, plant breeding, plant functional genomics and plant genotype screening.

  1. Endothelial and Epithelial Cell Transition to a Mesenchymal Phenotype Was Delineated by Nestin Expression.

    Science.gov (United States)

    Chabot, Andréanne; Hertig, Vanessa; Boscher, Elena; Nguyen, Quang Trinh; Boivin, Benoît; Chebli, Jasmine; Bissonnette, Lyse; Villeneuve, Louis; Brochiero, Emmanuelle; Dupuis, Jocelyn; Calderone, Angelino

    2016-07-01

    Cover: The cover image, by Angelino Calderone et al., is based on the Original Research Article Endothelial and Epithelial Cell Transition to a Mesenchymal Phenotype Was Delineated by Nestin Expression, DOI: 10.1002/jcp.25257. PMID:26995059

  2. Expanding the phenotype of mosaic trisomy 20.

    Science.gov (United States)

    Willis, Mary J H; Bird, Lynne M; Dell'Aquilla, Marie; Jones, Marilyn C

    2008-02-01

    Mosaic trisomy 20 is one of the more common cytogenetic abnormalities found on amniocentesis or chorionic villus sampling. Studies have shown that outcome is normal in 90-93% of prenatally diagnosed cases. There are however, reports in the literature of children with mosaic trisomy 20 described as having an assortment of dysmorphic features and varying levels of developmental delay. Unfortunately, the literature has not defined a specific phenotype for this entity. Here we report on three patients with mosaic trisomy 20, two of whom were identified prenatally. Over a number of years of follow-up it has become apparent that there are some striking similarities among the three. Comparison between our patients and the literature cases indicates a more consistent phenotype than has previously been suggested. Recurring features include; spinal abnormalities (including spinal stenosis, vertebral fusion, and kyphosis), hypotonia, lifelong constipation, sloped shoulders, and significant learning disabilities despite normal intelligence. These findings may be overlooked on routine history and physical exam or assumed to be standard pediatric problems. It is not our intention to suggest that there is a distinctive face for this entity but to suggest that a subtle phenotype does exist. We have attempted to identify a set of findings for which any child diagnosed with mosaic trisomy 20 should be assessed or followed even in the presence of an apparently normal physical exam at birth. PMID:18203170

  3. Phenotypic heterogeneity of monogenic frontotemporal dementia

    Directory of Open Access Journals (Sweden)

    Barbara Borroni

    2015-09-01

    Full Text Available Frontotemporal dementia (FTD is a genetically and pathologically heterogeneous disorder characterized by personality changes, language impairment and deficits of executive functions associated with frontal and temporal lobe degeneration. Different phenotypes have been defined on the basis of presenting clinical symptoms, i.e. the behavioral variant of FTD (bvFTD, the agrammatic variant of Primary Progressive Aphasia (avPPA and the semantic variant of PPA (svPPA. Some patients have an associated movement disorder, either parkinsonism, as in Progressive Supranuclear Palsy (PSP and Corticobasal Syndrome (CBS, or motor neuron disease (FTD-MND. A family history of dementia is found in 40% of cases of FTD and about 10% have a clear autosomal dominant inheritance. Genetic studies have identified several genes associated to monogenic FTD: microtubule-associated protein tau (MAPT, progranulin (GRN, TAR DNA-binding protein 43 (TARBDP, valosin-containing protein (VCP, charged multivesicular body protein 2B (CHMP2B, fused in sarcoma (FUS and the hexanucleotide repeat expansion in intron 1 of the chromosome 9 open reading frame 72 (C9orf72. Patients often present with an extensive phenotypic variability, even among different members of the same kindred carrying an identical disease mutation. The objective of the present work is to review and evaluate available literature data in order to highlight recent advances in clinical, biological and neuroimaging features of monogenic frontotemporal lobar degeneration and try to identify different mechanisms underlying the extreme phenotypic heterogeneity that characterizes this disease.

  4. Dissecting Phenotypic Variation in Pigmentation using Forward and Reverse Genetics

    OpenAIRE

    Hellström, Anders R.

    2010-01-01

    Coat color and patterning phenotypes have been extensively studied as a model for advancing our understanding of the relationship between genetic and phenotypic variation. In this thesis, genes of relevance for pigment cell biology were investigated. The dissertation is divided in two parts. Forward genetics was used in the first part (Paper I and II) to identify the genes controlling the Silver and Sex-linked barring loci in chicken. In the second part, reverse genetics was employed to creat...

  5. Identification of Candida spp. by phenotypic tests and PCR

    OpenAIRE

    Sandra Aparecida Marinho; Alice Becker Teixeira; Otávio Silveira Santos; Ricardo Flores Cazanova; Carlos Alexandre Sanchez Ferreira; Karen Cherubini; Sílvia Dias de Oliveira

    2010-01-01

    The correct identification of Candida species is of great importance, as it presents prognostic and therapeutical significance, allowing an early and appropriate antifungical therapy. The purpose of this study was to identify isolates of Candida spp. from oral mucosa of 38 patients with oral candidosis evaluated in 2004 by phenotypic methods and PCR, discriminating C. albicans from the other Candida species. The tests used for phenotypic analysis were germ-tube and chlamydoconidia production,...

  6. RDH12 retinopathy: novel mutations and phenotypic description

    OpenAIRE

    Mackay, D. S.; Borman, A. D.; Moradi, P; Henderson, R. H.; Li, Z.; Wright, G. A.; Waseem, N; M. Gandra; Thompson, D.A.; Bhattacharya, S S; Holder, G E; Webster, A. R.; Moore, A T

    2011-01-01

    Purpose: To identify patients with autosomal recessive retinal dystrophy caused by mutations in the gene, retinal dehydrogenase 12 (RDH12), and to report the associated phenotype.Methods: After giving informed consent, all patients underwent full clinical evaluation. Patients were selected for mutation analysis based upon positive results from the Asper Ophthalmics Leber congenital amaurosis arrayed primer extansion (APEX) microarray screening, linkage analysis, or their clinical phenotype. A...

  7. The behavioral phenotype of FMR1 mutations.

    Science.gov (United States)

    Boyle, Lia; Kaufmann, Walter E

    2010-11-15

    The purpose of this article is to provide an overview of the behavioral phenotype of FMR1 mutations, including fragile X syndrome (FXS) in order to better understand the clinical involvement of individuals affected by mutations in this gene. FXS is associated with a wide range of intellectual and behavioral problems, some relatively mild and others quite severe. FXS is the most common cause of inherited intellectual disability and one of the most prevalent genetic causes of autism spectrum disorder. Learning difficulties, attentional problems, anxiety, aggressive behavior, stereotypies, and mood disorders are also frequent in FXS. Recent studies of children and adults have identified associations between FMR1 premutation and many of the same disorders. We examine the neurobehavioral phenotypes of FXS and FMR1 premutation as they manifest across the lifespan of the individual. PMID:20981777

  8. Diagnosis, assessment, and phenotyping of COPD

    DEFF Research Database (Denmark)

    Lange, Peter; Halpin, David M; O'Donnell, Denis E;

    2016-01-01

    COPD is now widely recognized as a complex heterogeneous syndrome, having both pulmonary and extrapulmonary features. In clinical practice, the diagnosis of COPD is based on the presence of chronic airflow limitation, as assessed by post-bronchodilator spirometry. The severity of the airflow...... limitation, as measured by percent predicted FEV1, provides important information to the physician to enable optimization of management. However, in order to accurately assess the complexity of COPD, there need to be other measures made beyond FEV1. At present, there is a lack of reliable and simple blood...... biomarkers to confirm and further assess the diagnosis of COPD. However, it is possible to identify patients who display different phenotypic characteristics of COPD that relate to clinically relevant outcomes. Currently, validated phenotypes of COPD include alpha-1 antitrypsin deficiency, and "frequent...

  9. Deletion of ALS5, ALS6 or ALS7 increases adhesion of Candida albicans to human vascular endothelial and buccal epithelial cells

    OpenAIRE

    Zhao, Xiaomin; Oh, Soon-Hwan; Hoyer, Lois L.

    2007-01-01

    C. albicans yeast forms deleted for ALS5, ALS6 or ALS7 are more adherent than a relevant control strain to human vascular endothelial cell monolayers and buccal epithelial cells. In the buccal and vaginal reconstituted human epithelium (RHE) disease models, however, mutant and control strains caused a similar degree of tissue destruction. Deletion of ALS5 or ALS6 significantly slowed growth of the mutant strain; this phenotype was not affected by addition of excess uridine to the culture medi...

  10. Tools to identify the men with prostate cancer most appropriate for active surveillance?

    Directory of Open Access Journals (Sweden)

    Robert H Getzenberg

    2014-02-01

    Full Text Available A great deal of effort is underway in order to identify those men with prostate cancer felicitous for active surveillance with greater precision than that afforded to us today. In the manuscript by Irshad et al. the authors evaluate a novel set of genes associated with senescence and aging as tools that can provide guidance regarding the indolent nature of an individual's prostate cancer with validation using both mRNA and protein analyses. While additional studies are required to understand the full impact of these findings, the innovative approach taken enhances our understanding of distinct phenotypes of prostate cancer.

  11. Phenotypic plasticity, costs of phenotypes, and costs of plasticity

    DEFF Research Database (Denmark)

    Callahan, Hilary S; Maughan, Heather; Steiner, Uli

    2008-01-01

    Why are some traits constitutive and others inducible? The term costs often appears in work addressing this issue but may be ambiguously defined. This review distinguishes two conceptually distinct types of costs: phenotypic costs and plasticity costs. Phenotypic costs are assessed from patterns of...... covariation, typically between a focal trait and a separate trait relevant to fitness. Plasticity costs, separable from phenotypic costs, are gauged by comparing the fitness of genotypes with equivalent phenotypes within two environments but differing in plasticity and fitness. Subtleties associated with both...... types of costs are illustrated by a body of work addressing predator-induced plasticity. Such subtleties, and potential interplay between the two types of costs, have also been addressed, often in studies involving genetic model organisms. In some instances, investigators have pinpointed the mechanistic...

  12. Length of normal alleles of C9ORF72 GGGGCC repeat do not influence disease phenotype

    Science.gov (United States)

    Rutherford, Nicola J.; Heckman, Michael G.; DeJesus-Hernandez, Mariely; Baker, Matt C.; Soto-Ortolaza, Alexandra I.; Rayaprolu, Sruti; Stewart, Heather; Finger, Elizabeth; Volkening, Kathryn; Seeley, William W.; Hatanpaa, Kimmo J.; Lomen-Hoerth, Catherine; Kertesz, Andrew; Bigio, Eileen H.; Lippa, Carol; Knopman, David S.; Kretzschmar, Hans A.; Neumann, Manuela; Caselli, Richard J.; White, Charles L.; Mackenzie, Ian R.; Petersen, Ronald C.; Strong, Michael J.; Miller, Bruce L.; Boeve, Bradley F.; Uitti, Ryan J.; Boylan, Kevin; Wszolek, Zbigniew K.; Graff-Radford, Neill R.; Dickson, Dennis W.; Ross, Owen A.; Rademakers, Rosa

    2012-01-01

    Expansions of the non-coding GGGGCC hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene were recently identified as the long sought-after cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) on chromosome 9p. In this study we aimed to determine whether the length of the normal - unexpanded - allele of the GGGGCC repeat in C9ORF72 plays a role in the presentation of disease or affects age at onset in C9ORF72 mutation carriers. We also studied whether the GGGGCC repeat length confers risk or affects age at onset in FTD and ALS patients without C9ORF72 repeat expansions. C9ORF72 genotyping was performed in 580 FTD, 995 ALS and 160 FTD-ALS patients and 1444 controls, leading to the identification of 211 patients with pathogenic C9ORF72 repeat expansions and an accurate quantification of the length of the normal alleles in all patients and controls. No meaningful association between the repeat length of the normal alleles of the GGGGCC repeat in C9ORF72 and disease phenotype or age at onset was observed in C9ORF72 mutation carriers or non-mutation carriers. PMID:22840558

  13. ALS-linked protein disulfide isomerase variants cause motor dysfunction.

    Science.gov (United States)

    Woehlbier, Ute; Colombo, Alicia; Saaranen, Mirva J; Pérez, Viviana; Ojeda, Jorge; Bustos, Fernando J; Andreu, Catherine I; Torres, Mauricio; Valenzuela, Vicente; Medinas, Danilo B; Rozas, Pablo; Vidal, Rene L; Lopez-Gonzalez, Rodrigo; Salameh, Johnny; Fernandez-Collemann, Sara; Muñoz, Natalia; Matus, Soledad; Armisen, Ricardo; Sagredo, Alfredo; Palma, Karina; Irrazabal, Thergiory; Almeida, Sandra; Gonzalez-Perez, Paloma; Campero, Mario; Gao, Fen-Biao; Henny, Pablo; van Zundert, Brigitte; Ruddock, Lloyd W; Concha, Miguel L; Henriquez, Juan P; Brown, Robert H; Hetz, Claudio

    2016-04-15

    Disturbance of endoplasmic reticulum (ER) proteostasis is a common feature of amyotrophic lateral sclerosis (ALS). Protein disulfide isomerases (PDIs) areERfoldases identified as possibleALSbiomarkers, as well as neuroprotective factors. However, no functional studies have addressed their impact on the disease process. Here, we functionally characterized fourALS-linked mutations recently identified in two majorPDIgenes,PDIA1 andPDIA3/ERp57. Phenotypic screening in zebrafish revealed that the expression of thesePDIvariants induce motor defects associated with a disruption of motoneuron connectivity. Similarly, the expression of mutantPDIs impaired dendritic outgrowth in motoneuron cell culture models. Cellular and biochemical studies identified distinct molecular defects underlying the pathogenicity of thesePDImutants. Finally, targetingERp57 in the nervous system led to severe motor dysfunction in mice associated with a loss of neuromuscular synapses. This study identifiesERproteostasis imbalance as a risk factor forALS, driving initial stages of the disease. PMID:26869642

  14. Epigenetics in heart failure phenotypes.

    Science.gov (United States)

    Berezin, Alexander

    2016-12-01

    Chronic heart failure (HF) is a leading clinical and public problem posing a higher risk of morbidity and mortality in different populations. HF appears to be in both phenotypic forms: HF with reduced left ventricular ejection fraction (HFrEF) and HF with preserved left ventricular ejection fraction (HFpEF). Although both HF phenotypes can be distinguished through clinical features, co-morbidity status, prediction score, and treatment, the clinical outcomes in patients with HFrEF and HFpEF are similar. In this context, investigation of various molecular and cellular mechanisms leading to the development and progression of both HF phenotypes is very important. There is emerging evidence that epigenetic regulation may have a clue in the pathogenesis of HF. This review represents current available evidence regarding the implication of epigenetic modifications in the development of different HF phenotypes and perspectives of epigenetic-based therapies of HF. PMID:27335803

  15. Capturing phenotypes for precision medicine.

    Science.gov (United States)

    Robinson, Peter N; Mungall, Christopher J; Haendel, Melissa

    2015-10-01

    Deep phenotyping followed by integrated computational analysis of genotype and phenotype is becoming ever more important for many areas of genomic diagnostics and translational research. The overwhelming majority of clinical descriptions in the medical literature are available only as natural language text, meaning that searching, analysis, and integration of medically relevant information in databases such as PubMed is challenging. The new journal Cold Spring Harbor Molecular Case Studies will require authors to select Human Phenotype Ontology terms for research papers that will be displayed alongside the manuscript, thereby providing a foundation for ontology-based indexing and searching of articles that contain descriptions of phenotypic abnormalities-an important step toward improving the ability of researchers and clinicians to get biomedical information that is critical for clinical care or translational research. PMID:27148566

  16. Finding our way through phenotypes.

    Directory of Open Access Journals (Sweden)

    Andrew R Deans

    2015-01-01

    Full Text Available Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility.

  17. Next-generation phenotypic screening.

    Science.gov (United States)

    Warchal, Scott J; Unciti-Broceta, Asier; Carragher, Neil O

    2016-07-01

    Phenotypic drug discovery (PDD) strategies are defined by screening and selection of hit or lead compounds based on quantifiable phenotypic endpoints without prior knowledge of the drug target. We outline the challenges associated with traditional phenotypic screening strategies and propose solutions and new opportunities to be gained by adopting modern PDD technologies. We highlight both historical and recent examples of approved drugs and new drug candidates discovered by modern phenotypic screening. Finally, we offer a prospective view of a new era of PDD underpinned by a wealth of technology advances in the areas of in vitro model development, high-content imaging and image informatics, mechanism-of-action profiling and target deconvolution. PMID:27357617

  18. Finding our way through phenotypes.

    Science.gov (United States)

    Deans, Andrew R; Lewis, Suzanna E; Huala, Eva; Anzaldo, Salvatore S; Ashburner, Michael; Balhoff, James P; Blackburn, David C; Blake, Judith A; Burleigh, J Gordon; Chanet, Bruno; Cooper, Laurel D; Courtot, Mélanie; Csösz, Sándor; Cui, Hong; Dahdul, Wasila; Das, Sandip; Dececchi, T Alexander; Dettai, Agnes; Diogo, Rui; Druzinsky, Robert E; Dumontier, Michel; Franz, Nico M; Friedrich, Frank; Gkoutos, George V; Haendel, Melissa; Harmon, Luke J; Hayamizu, Terry F; He, Yongqun; Hines, Heather M; Ibrahim, Nizar; Jackson, Laura M; Jaiswal, Pankaj; James-Zorn, Christina; Köhler, Sebastian; Lecointre, Guillaume; Lapp, Hilmar; Lawrence, Carolyn J; Le Novère, Nicolas; Lundberg, John G; Macklin, James; Mast, Austin R; Midford, Peter E; Mikó, István; Mungall, Christopher J; Oellrich, Anika; Osumi-Sutherland, David; Parkinson, Helen; Ramírez, Martín J; Richter, Stefan; Robinson, Peter N; Ruttenberg, Alan; Schulz, Katja S; Segerdell, Erik; Seltmann, Katja C; Sharkey, Michael J; Smith, Aaron D; Smith, Barry; Specht, Chelsea D; Squires, R Burke; Thacker, Robert W; Thessen, Anne; Fernandez-Triana, Jose; Vihinen, Mauno; Vize, Peter D; Vogt, Lars; Wall, Christine E; Walls, Ramona L; Westerfeld, Monte; Wharton, Robert A; Wirkner, Christian S; Woolley, James B; Yoder, Matthew J; Zorn, Aaron M; Mabee, Paula

    2015-01-01

    Despite a large and multifaceted effort to understand the vast landscape of phenotypic data, their current form inhibits productive data analysis. The lack of a community-wide, consensus-based, human- and machine-interpretable language for describing phenotypes and their genomic and environmental contexts is perhaps the most pressing scientific bottleneck to integration across many key fields in biology, including genomics, systems biology, development, medicine, evolution, ecology, and systematics. Here we survey the current phenomics landscape, including data resources and handling, and the progress that has been made to accurately capture relevant data descriptions for phenotypes. We present an example of the kind of integration across domains that computable phenotypes would enable, and we call upon the broader biology community, publishers, and relevant funding agencies to support efforts to surmount today's data barriers and facilitate analytical reproducibility. PMID:25562316

  19. Perinatal risk factors for wheezing phenotypes in the first 8 years of life

    NARCIS (Netherlands)

    Caudri, D.; Savenije, O. E. M.; Smit, H. A.; Postma, D. S.; Koppelman, G. H.; Wijga, A. H.; Kerkhof, M.; Gehring, U.; Hoekstra, M. O.; Brunekreef, B.; de Jongste, J. C.

    2013-01-01

    Background A novel data-driven approach was used to identify wheezing phenotypes in pre-schoolchildren aged 0-8 years, in the Prevention and Incidence of Asthma and Mite Allergy (PIAMA) birth cohort. Five phenotypes were identified: never/infrequent wheeze, transient early wheeze, intermediate onset

  20. Identification of campylobacteria isolated from Danish broilers by phenotypic tests and species-specific PCR assays

    DEFF Research Database (Denmark)

    Wainø, M; Bang, Dan; Lund, Marianne;

    2003-01-01

    To validate a phenotypic Campylobacter species identification method employed to identify campylobacters in broilers by comparison with campylobacterial species identification using various species-specific PCR analyses.......To validate a phenotypic Campylobacter species identification method employed to identify campylobacters in broilers by comparison with campylobacterial species identification using various species-specific PCR analyses....

  1. Network motifs that stabilize the hybrid epithelial/mesenchymal phenotype

    Science.gov (United States)

    Jolly, Mohit Kumar; Jia, Dongya; Tripathi, Satyendra; Hanash, Samir; Mani, Sendurai; Ben-Jacob, Eshel; Levine, Herbert

    Epithelial to Mesenchymal Transition (EMT) and its reverse - MET - are hallmarks of cancer metastasis. While transitioning between E and M phenotypes, cells can also attain a hybrid epithelial/mesenchymal (E/M) phenotype that enables collective cell migration as a cluster of Circulating Tumor Cells (CTCs). These clusters can form 50-times more tumors than individually migrating CTCs, underlining their importance in metastasis. However, this hybrid E/M phenotype has been hypothesized to be only a transient one that is attained en route EMT. Here, via mathematically modeling, we identify certain `phenotypic stability factors' that couple with the core three-way decision-making circuit (miR-200/ZEB) and can maintain or stabilize the hybrid E/M phenotype. Further, we show experimentally that this phenotype can be maintained stably at a single-cell level, and knockdown of these factors impairs collective cell migration. We also show that these factors enable the association of hybrid E/M with high stemness or tumor-initiating potential. Finally, based on these factors, we deduce specific network motifs that can maintain the E/M phenotype. Our framework can be used to elucidate the effect of other players in regulating cellular plasticity during metastasis. This work was supported by NSF PHY-1427654 (Center for Theoretical Biological Physics) and the CPRIT Scholar in Cancer Research of the State of Texas at Rice University.

  2. Advanced phenotyping and phenotype data analysis for the study of plant growth and development

    OpenAIRE

    Rahaman, Md. Matiur; Chen, Dijun; Gillani, Zeeshan; Klukas, Christian; Chen, Ming

    2015-01-01

    Due to an increase in the consumption of food, feed, fuel and to meet global food security needs for the rapidly growing human population, there is a necessity to breed high yielding crops that can adapt to the future climate changes, particularly in developing countries. To solve these global challenges, novel approaches are required to identify quantitative phenotypes and to explain the genetic basis of agriculturally important traits. These advances will facilitate the screening of germpla...

  3. Spice: discovery of phenotype-determining component interplays

    Directory of Open Access Journals (Sweden)

    Chen Zhengzhang

    2012-05-01

    Full Text Available Abstract Background A latent behavior of a biological cell is complex. Deriving the underlying simplicity, or the fundamental rules governing this behavior has been the Holy Grail of systems biology. Data-driven prediction of the system components and their component interplays that are responsible for the target system’s phenotype is a key and challenging step in this endeavor. Results The proposed approach, which we call System Phenotype-related Interplaying Components Enumerator (Spice, iteratively enumerates statistically significant system components that are hypothesized (1 to play an important role in defining the specificity of the target system’s phenotype(s; (2 to exhibit a functionally coherent behavior, namely, act in a coordinated manner to perform the phenotype-specific function; and (3 to improve the predictive skill of the system’s phenotype(s when used collectively in the ensemble of predictive models. Spice can be applied to both instance-based data and network-based data. When validated, Spice effectively identified system components related to three target phenotypes: biohydrogen production, motility, and cancer. Manual results curation agreed with the known phenotype-related system components reported in literature. Additionally, using the identified system components as discriminatory features improved the prediction accuracy by 10% on the phenotype-classification task when compared to a number of state-of-the-art methods applied to eight benchmark microarray data sets. Conclusion We formulate a problem—enumeration of phenotype-determining system component interplays—and propose an effective methodology (Spice to address this problem. Spice improved identification of cancer-related groups of genes from various microarray data sets and detected groups of genes associated with microbial biohydrogen production and motility, many of which were reported in literature. Spice also improved the predictive skill of the

  4. Chronic obstructive pulmonary disease phenotypes: the future of COPD

    DEFF Research Database (Denmark)

    Han, MeiLan K; Agusti, Alvar; Calverley, Peter M; Celli, Bartolome R; Criner, Gerard; Curtis, Jeffrey L; Fabbri, Leonardo M; Goldin, Jonathan G; Jones, Paul W; Macnee, William; Make, Barry J; Rabe, Klaus F; Rennard, Stephen I; Sciurba, Frank C; Silverman, Edwin K; Vestbo, Jørgen; Washko, George R; Wouters, Emiel F M; Martinez, Fernando J

    2010-01-01

    Significant heterogeneity of clinical presentation and disease progression exists within chronic obstructive pulmonary disease (COPD). Although FEV(1) inadequately describes this heterogeneity, a clear alternative has not emerged. The goal of phenotyping is to identify patient groups with unique...... prognostic or therapeutic characteristics, but significant variation and confusion surrounds use of the term "phenotype" in COPD. Phenotype classically refers to any observable characteristic of an organism, and up until now, multiple disease characteristics have been termed COPD phenotypes. We, however......, propose the following variation on this definition: "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes (symptoms, exacerbations, response to therapy, rate of disease progression, or death)." This more...

  5. On identified predictive control

    Science.gov (United States)

    Bialasiewicz, Jan T.

    1993-01-01

    Self-tuning control algorithms are potential successors to manually tuned PID controllers traditionally used in process control applications. A very attractive design method for self-tuning controllers, which has been developed over recent years, is the long-range predictive control (LRPC). The success of LRPC is due to its effectiveness with plants of unknown order and dead-time which may be simultaneously nonminimum phase and unstable or have multiple lightly damped poles (as in the case of flexible structures or flexible robot arms). LRPC is a receding horizon strategy and can be, in general terms, summarized as follows. Using assumed long-range (or multi-step) cost function the optimal control law is found in terms of unknown parameters of the predictor model of the process, current input-output sequence, and future reference signal sequence. The common approach is to assume that the input-output process model is known or separately identified and then to find the parameters of the predictor model. Once these are known, the optimal control law determines control signal at the current time t which is applied at the process input and the whole procedure is repeated at the next time instant. Most of the recent research in this field is apparently centered around the LRPC formulation developed by Clarke et al., known as generalized predictive control (GPC). GPC uses ARIMAX/CARIMA model of the process in its input-output formulation. In this paper, the GPC formulation is used but the process predictor model is derived from the state space formulation of the ARIMAX model and is directly identified over the receding horizon, i.e., using current input-output sequence. The underlying technique in the design of identified predictive control (IPC) algorithm is the identification algorithm of observer/Kalman filter Markov parameters developed by Juang et al. at NASA Langley Research Center and successfully applied to identification of flexible structures.

  6. PhenoMiner: from text to a database of phenotypes associated with OMIM diseases.

    Science.gov (United States)

    Collier, Nigel; Groza, Tudor; Smedley, Damian; Robinson, Peter N; Oellrich, Anika; Rebholz-Schuhmann, Dietrich

    2015-10-01

    Analysis of scientific and clinical phenotypes reported in the experimental literature has been curated manually to build high-quality databases such as the Online Mendelian Inheritance in Man (OMIM). However, the identification and harmonization of phenotype descriptions struggles with the diversity of human expressivity. We introduce a novel automated extraction approach called PhenoMiner that exploits full parsing and conceptual analysis. Apriori association mining is then used to identify relationships to human diseases. We applied PhenoMiner to the BMC open access collection and identified 13,636 phenotype candidates. We identified 28,155 phenotype-disorder hypotheses covering 4898 phenotypes and 1659 Mendelian disorders. Analysis showed: (i) the semantic distribution of the extracted terms against linked ontologies; (ii) a comparison of term overlap with the Human Phenotype Ontology (HP); (iii) moderate support for phenotype-disorder pairs in both OMIM and the literature; (iv) strong associations of phenotype-disorder pairs to known disease-genes pairs using PhenoDigm. The full list of PhenoMiner phenotypes (S1), phenotype-disorder associations (S2), association-filtered linked data (S3) and user database documentation (S5) is available as supplementary data and can be downloaded at http://github.com/nhcollier/PhenoMiner under a Creative Commons Attribution 4.0 license. Database URL: phenominer.mml.cam.ac.uk. PMID:26507285

  7. Linking human diseases to animal models using ontology-based phenotype annotation.

    Directory of Open Access Journals (Sweden)

    Nicole L Washington

    2009-11-01

    Full Text Available Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. The considerable variation in these free-text descriptions has posed a hindrance to the important task of identifying candidate genes and models for human diseases and indicates the need for a computationally tractable method to mine data resources for mutant phenotypes. In this study, we tested the hypothesis that ontological annotation of disease phenotypes will facilitate the discovery of new genotype-phenotype relationships within and across species. To describe phenotypes using ontologies, we used an Entity-Quality (EQ methodology, wherein the affected entity (E and how it is affected (Q are recorded using terms from a variety of ontologies. Using this EQ method, we annotated the phenotypes of 11 gene-linked human diseases described in Online Mendelian Inheritance in Man (OMIM. These human annotations were loaded into our Ontology-Based Database (OBD along with other ontology-based phenotype descriptions of mutants from various model organism databases. Phenotypes recorded with this EQ method can be computationally compared based on the hierarchy of terms in the ontologies and the frequency of annotation. We utilized four similarity metrics to compare phenotypes and developed an ontology of homologous and analogous anatomical structures to compare phenotypes between species. Using these tools, we demonstrate that we can identify, through the similarity of the recorded phenotypes, other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species. We conclude that EQ-based annotation of phenotypes, in conjunction with a cross-species ontology, and a variety of similarity metrics can identify biologically meaningful similarities between genes by comparing phenotypes alone. This annotation and search method provides a novel and efficient means to identify

  8. A case study to identify urban diffuse pollution in the Light Burn Catchment, Glasgow, UK. Stage 3 contribution to: Wade, R et al. (2013) A critical review Of urban diffuse pollution control: methodologies to identify sources, pathways and mitigation measures with multiple benefits. CRW2012/1.

    OpenAIRE

    Fordyce, Fiona M.; Lass-Evans, Solveigh; O Dochartaigh, Brighid E.

    2013-01-01

    This report is the BGS contribution to Stage 3 of the CRW2012/1 Project ‘A critical review of urban diffuse pollution control: Methodologies to identify sources, pathways and mitigation measures with multiple benefits’. A case study of a typical Scottish urban environment is presented. The report documents work to identify and characterise urban diffuse pollution sources and pathways in a case study stream catchment in Glasgow based on existing information. The findings of this report have be...

  9. A genetic screen identifies Tor as an interactor of VAPB in a Drosophila model of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Senthilkumar Deivasigamani

    2014-10-01

    Full Text Available Amyotrophic Lateral Sclerosis (ALS is a progressive neurodegenerative disorder characterized by selective death of motor neurons. In 5–10% of the familial cases, the disease is inherited because of mutations. One such mutation, P56S, was identified in human VAPB that behaves in a dominant negative manner, sequestering wild type protein into cytoplasmic inclusions. We have conducted a reverse genetic screen to identify interactors of Drosophila VAPB. We screened 2635 genes and identified 103 interactors, of which 45 were enhancers and 58 were suppressors of VAPB function. Interestingly, the screen identified known ALS loci – TBPH, alsin2 and SOD1. Also identified were genes involved in cellular energetics and homeostasis which were used to build a gene regulatory network of VAPB modifiers. One key modifier identified was Tor, whose knockdown reversed the large bouton phenotype associated with VAP(P58S expression in neurons. A similar reversal was seen by over-expressing Tuberous Sclerosis Complex (Tsc1,2 that negatively regulates TOR signaling as also by reduction of S6K activity. In comparison, the small bouton phenotype associated with VAP(wt expression was reversed with Tsc1 knock down as well as S6K-CA expression. Tor therefore interacts with both VAP(wt and VAP(P58S, but in a contrasting manner. Reversal of VAP(P58S bouton phenotypes in larvae fed with the TOR inhibitor Rapamycin suggests upregulation of TOR signaling in response to VAP(P58S expression. The VAPB network and further mechanistic understanding of interactions with key pathways, such as the TOR cassette, will pave the way for a better understanding of the mechanisms of onset and progression of motor neuron disease.

  10. Phenotypic MicroRNA Microarrays

    Directory of Open Access Journals (Sweden)

    Veronica Soloveva

    2013-04-01

    Full Text Available Microarray technology has become a very popular approach in cases where multiple experiments need to be conducted repeatedly or done with a variety of samples. In our lab, we are applying our high density spots microarray approach to microscopy visualization of the effects of transiently introduced siRNA or cDNA on cellular morphology or phenotype. In this publication, we are discussing the possibility of using this micro-scale high throughput process to study the role of microRNAs in the biology of selected cellular models. After reverse-transfection of microRNAs and siRNA, the cellular phenotype generated by microRNAs regulated NF-κB expression comparably to the siRNA. The ability to print microRNA molecules for reverse transfection into cells is opening up the wide horizon for the phenotypic high content screening of microRNA libraries using cellular disease models.

  11. RIN2 syndrome: Expanding the clinical phenotype.

    Science.gov (United States)

    Rosato, Simonetta; Syx, Delfien; Ivanovski, Ivan; Pollazzon, Marzia; Santodirocco, Daniela; De Marco, Loredana; Beltrami, Marina; Callewaert, Bert; Garavelli, Livia; Malfait, Fransiska

    2016-09-01

    Biallelic defects in the RIN2 gene, encoding the Ras and Rab interactor 2 protein, are associated with a rare autosomal recessive connective tissue disorder, with only nine patients from four independent families reported to date. The condition was initially termed MACS syndrome (macrocephaly, alopecia, cutis laxa, and scoliosis), based on the clinical features of the first identified family; however, with the expansion of the clinical phenotype in additional families, it was subsequently coined RIN2 syndrome. Hallmark features of this condition include dysmorphic facial features with striking, progressive facial coarsening, sparse hair, normal to enlarged occipitofrontal circumference, soft redundant and/or hyperextensible skin, and scoliosis. Patients with RIN2 syndrome present phenotypic overlap with other conditions, including EDS (especially the dermatosparaxis and kyphoscoliosis subtypes). Here, we describe a 10th patient, the first patient of Caucasian origin and the oldest reported patient so far, who harbors the previously identified homozygous RIN2 mutation c.1878dupC (p. (Ile627Hisfs*7)). Besides the hallmark features, this patient also presents problems not previously associated with RIN2 syndrome, including cervical vertebral fusion, mild hearing loss, and colonic fibrosis. We provide an overview of the clinical findings in all reported patients with RIN2 mutations and summarize some of the possible pathogenic mechanisms that may underlie this condition. © 2016 Wiley Periodicals, Inc. PMID:27277385

  12. Molecular basis of D-negative phenotype (literature review and case reports

    Directory of Open Access Journals (Sweden)

    L. L. Golovkina

    2015-10-01

    Full Text Available The molecular basis of the D-negative phenotype formation in humans is presented in this article. Causes of true and false D-negative phenotype appearance are described. The basis of true D-negative phenotype are changes in the genome, that lead to complete lack of RhD antigen expression on the red blood cells surface, or defective expression of RhD antigen, not detectable by serological methods. The reason for the false D-negative phenotype is the insufficient sensitivity of routine serological methods. Cases of true and false D-negative phenotype identified during the examination of the Russia residents are described. We were able to identify one case of true (RHDψ and five cases of false D-negative phenotype (RHD weak type 2 – two cases, RHD weak type 15 – one case and RHD weak type 20 – two cases by molecular method.

  13. Clinical phenotypes of COPD: identification, definition and implications for guidelines.

    Science.gov (United States)

    Miravitlles, Marc; Calle, Myriam; Soler-Cataluña, Juan José

    2012-03-01

    The term phenotype in the field of COPD is defined as "a single or combination of disease attributes that describe differences between individuals with COPD as they relate to clinically meaningful outcomes". Among all phenotypes described, there are three that are associated with prognosis and especially are associated with a different response to currently available therapies. There phenotypes are: the exacerbator, the overlap COPD-asthma and the emphysema-hyperinflation. The exacerbator is characterised by the presence of, at least, two exacerbations the previous year, and on top of long-acting bronchodilators, may require the use of antiinflammatory drugs. The overlap phenotype presents symptoms of increased variability of airflow and incompletely reversible airflow obstruction. Due to the underlying inflammatory profile, it uses to have a good therapeutic response to inhaled corticosteroids in addition to bronchodilators. Lastly, the emphysema phenotype presents a poor therapeutic response to the existing antiinflammatory drugs and long-acting bronchodilators together with rehabilitation are the treatments of choice. Identifying the peculiarities of the different phenotypes of COPD will allow us to implement a more personalised treatment, in which the characteristics of the patients, together with their severity will be key to choose the best treatment option. PMID:22196477

  14. Automatic and controlled processing and the Broad Autism Phenotype.

    Science.gov (United States)

    Camodeca, Amy; Voelker, Sylvia

    2016-01-30

    Research related to verbal fluency in the Broad Autism Phenotype (BAP) is limited and dated, but generally suggests intact abilities in the context of weaknesses in other areas of executive function (Hughes et al., 1999; Wong et al., 2006; Delorme et al., 2007). Controlled processing, the generation of search strategies after initial, automated responses are exhausted (Spat, 2013), has yet to be investigated in the BAP, and may be evidenced in verbal fluency tasks. One hundred twenty-nine participants completed the Delis-Kaplan Executive Function System Verbal Fluency test (D-KEFS; Delis et al., 2001) and the Broad Autism Phenotype Questionnaire (BAPQ; Hurley et al., 2007). The BAP group (n=53) produced significantly fewer total words during the 2nd 15" interval compared to the Non-BAP (n=76) group. Partial correlations indicated similar relations between verbal fluency variables for each group. Regression analyses predicting 2nd 15" interval scores suggested differentiation between controlled and automatic processing skills in both groups. Results suggest adequate automatic processing, but slowed development of controlled processing strategies in the BAP, and provide evidence for similar underlying cognitive constructs for both groups. Controlled processing was predictive of Block Design score for Non-BAP participants, and was predictive of Pragmatic Language score on the BAPQ for BAP participants. These results are similar to past research related to strengths and weaknesses in the BAP, respectively, and suggest that controlled processing strategy use may be required in instances of weak lower-level skills. PMID:26652842

  15. Ethanol Consumption: How Should We Measure It? Achieving Consilience between Human and Animal Phenotypes

    OpenAIRE

    Leeman, Robert F; Heilig, Markus; Cunningham, Christopher L.; Stephens, David N.; Duka, Taheodora; O’Malley, Stephanie S.

    2010-01-01

    There is only modest overlap in the most common alcohol consumption phenotypes measured in animal studies and those typically studied in humans. To address this issue, we identified a number of alcohol consumption phenotypes of importance to the field that have potential for consilience between human and animal models. These phenotypes can be broken down into three categories: 1) abstinence/the decision to drink or abstain; 2) the actual amount of alcohol consumed and 3) heavy drinking. A num...

  16. Combining Human Disease Genetics and Mouse Model Phenotypes towards Drug Repositioning for Parkinson’s disease

    OpenAIRE

    Chen, Yang; Cai, Xiaoshu; Xu, Rong

    2015-01-01

    Parkinson’s disease (PD) is a severe neurodegenerative disorder without effective treatments. Here, we present a novel drug repositioning approach to predict new drugs for PD leveraging both disease genetics and large amounts of mouse model phenotypes. First, we identified PD-specific mouse phenotypes using well-studied human disease genes. Then we searched all FDA-approved drugs for candidates that share similar mouse phenotype profiles with PD. We demonstrated the validity of our approach u...

  17. Bayesian Genetic Association Test when Secondary Phenotypes Are Available Only in the Case Group

    OpenAIRE

    Yongku Kim; Minjung Kwak

    2016-01-01

    In many case-control genetic association studies, a secondary phenotype that may have common genetic factors with disease status can be identified. When information on the secondary phenotype is available only for the case group due to cost and different data sources, a fitting linear regression model ignoring supplementary phenotype data may provide limited knowledge regarding genetic association. We set up a joint model and use a Bayesian framework to estimate and test the effect of genetic...

  18. Bayesian Inference of the Evolution of a Phenotype Distribution on a Phylogenetic Tree

    Science.gov (United States)

    Ansari, M. Azim; Didelot, Xavier

    2016-01-01

    The distribution of a phenotype on a phylogenetic tree is often a quantity of interest. Many phenotypes have imperfect heritability, so that a measurement of the phenotype for an individual can be thought of as a single realization from the phenotype distribution of that individual. If all individuals in a phylogeny had the same phenotype distribution, measured phenotypes would be randomly distributed on the tree leaves. This is, however, often not the case, implying that the phenotype distribution evolves over time. Here we propose a new model based on this principle of evolving phenotype distribution on the branches of a phylogeny, which is different from ancestral state reconstruction where the phenotype itself is assumed to evolve. We develop an efficient Bayesian inference method to estimate the parameters of our model and to test the evidence for changes in the phenotype distribution. We use multiple simulated data sets to show that our algorithm has good sensitivity and specificity properties. Since our method identifies branches on the tree on which the phenotype distribution has changed, it is able to break down a tree into components for which this distribution is unique and constant. We present two applications of our method, one investigating the association between HIV genetic variation and human leukocyte antigen and the other studying host range distribution in a lineage of Salmonella enterica, and we discuss many other potential applications. PMID:27412711

  19. A residue substitution in the plastid ribosomal protein L12/AL1 produces defective plastid ribosome and causes early seedling lethality in rice.

    Science.gov (United States)

    Zhao, Dong-Sheng; Zhang, Chang-Quan; Li, Qian-Feng; Yang, Qing-Qing; Gu, Ming-Hong; Liu, Qiao-Quan

    2016-05-01

    The plastid ribosome is essential for chloroplast biogenesis as well as seedling formation. As the plastid ribosome closely resembles the prokaryotic 70S ribosome, many plastid ribosomal proteins (PRPs) have been identified in higher plants. However, their assembly in the chloroplast ribosome in rice remains unclear. In the present study, we identified a novel rice mutant, albino lethal 1 (al1), from a chromosome segment substitution line population. The al1 mutant displayed an albino phenotype at the seedling stage and did not survive past the three-leaf stage. No other apparent differences in plant morphology were observed in the al1 mutant. The albino phenotype of the al1 mutant was associated with decreased chlorophyll content and abnormal chloroplast morphology. Using fine mapping, AL1 was shown to encode the PRPL12, a protein localized in the chloroplasts of rice, and a spontaneous single-nucleotide mutation (C/T), resulting in a residue substitution from leucine in AL1 to phenylalanine in al1, was found to be responsible for the early seedling lethality. This point mutation is located at the L10 interface feature of the L12/AL1 protein. Yeast two-hybrid analysis showed that there was no physical interaction between al1 and PRPL10. In addition, the mutation had little effect on the transcript abundance of al1, but had a remarkable effect on the protein abundance of al1 and transcript abundance of chloroplast biogenesis-related and photosynthesis-related genes. These results provide a first glimpse into the molecular details of L12's function in rice. PMID:26873698

  20. Retrospective analysis of cohort database: Phenotypic variability in a large dataset of patients confirmed to have homozygous familial hypercholesterolemia.

    Science.gov (United States)

    Raal, Frederick J; Sjouke, Barbara; Hovingh, G Kees; Isaac, Barton F

    2016-06-01

    These data describe the phenotypic variability in a large cohort of patients confirmed to have homozygous familial hypercholesterolemia. Herein, we describe the observed relationship of treated low-density lipoprotein cholesterol with age. We also overlay the low-density lipoprotein receptor gene (LDLR) functional status with these phenotypic data. A full description of these data is available in our recent study published in Atherosclerosis, "Phenotype Diversity Among Patients With Homozygous Familial Hypercholesterolemia: A Cohort Study" (Raal et al., 2016) [1]. PMID:27182539

  1. Leaf segmentation in plant phenotyping

    NARCIS (Netherlands)

    Scharr, Hanno; Minervini, Massimo; French, Andrew P.; Klukas, Christian; Kramer, David M.; Liu, Xiaoming; Luengo, Imanol; Pape, Jean Michel; Polder, Gerrit; Vukadinovic, Danijela; Yin, Xi; Tsaftaris, Sotirios A.

    2016-01-01

    Image-based plant phenotyping is a growing application area of computer vision in agriculture. A key task is the segmentation of all individual leaves in images. Here we focus on the most common rosette model plants, Arabidopsis and young tobacco. Although leaves do share appearance and shape cha

  2. Global genotype-phenotype correlations in Pseudomonas aeruginosa.

    Directory of Open Access Journals (Sweden)

    Claudia Pommerenke

    Full Text Available Once the genome sequence of an organism is obtained, attention turns from identifying genes to understanding their function, their organization and control of metabolic pathways and networks that determine its physiology. Recent technical advances in acquiring genome-wide data have led to substantial progress in identifying gene functions. However, we still do not know the function of a large number of genes and, even when a gene product has been assigned to a functional class, we cannot normally predict its contribution to the phenotypic behaviour of the cell or organism--the phenome. In this study, we assessed bacterial growth parameters of 4030 non-redundant PA14 transposon mutants in the pathogenic bacterium Pseudomonas aeruginosa. The genome-wide simultaneous analysis of 119 distinct growth-related phenotypes uncovered a comprehensive phenome and provided evidence that most genotypes are not phenotypically isolated but rather define specific complex phenotypic clusters of genotypes. Since phenotypic overlap was demonstrated to reflect the relatedness of genotypes on a global scale, knowledge of an organism's phenome might significantly contribute to the advancement of functional genomics.

  3. 1H NMR spectroscopy-based interventional metabolic phenotyping

    DEFF Research Database (Denmark)

    Lauridsen, Michael B; Bliddal, Henning; Christensen, Robin;

    2010-01-01

    1H NMR spectroscopy-based metabolic phenotyping was used to identify biomarkers in the plasma of patients with rheumatoid arthritis (RA). Forty-seven patients with RA (23 with active disease at baseline and 24 in remission) and 51 healthy subjects were evaluated during a one-year follow-up with...

  4. [Environmental factors in ALS].

    Science.gov (United States)

    Juntas-Morales, Raul; Pageot, Nicolas; Corcia, Philippe; Camu, William

    2014-05-01

    ALS is likely to be a disorder of multifactorial origin. Among all the factors that may increase the risk of ALS, environmental ones are being studied for many years, but in the recent years, several advances have pointed to a new interest in their potential involvement in the disease process, especially for the cyanotoxin BMAA. Food containing BMAA has been found on Guam, a well-known focus of ALS/parkinsonism/dementia and high levels of BMAA have been identified into the brain of these patients. The BMAA cyanotoxin is potentially ubiquitous and have also been found into the food of patients who died from ALS both in Europe and USA. BMAA can be wrongly integrated into the protein structure during mRNA traduction, competing with serine. This may induce abnormal protein folding and a subsequent cell death. Heavy metals, such as lead or mercury may be directly toxic for neuronal cells. Several works have suggested an increased risk of ALS in individuals chronically exposed to these metals. Exposure to pesticides has been suggested to be linked to an increased risk of developing ALS. The mechanism of their toxicity is likely to be mediated by paraoxonases. These proteins are in charge of detoxifying the organism from toxins, and particularly organophosphates. To date, there are insufficient scientific data to suggest that exposure to electromagnetic fields may increase the risk of having ALS. We are particularly missing longitudinal cohorts to demonstrate that risk. PMID:24703731

  5. Phenotypic constraints and phenotypic hitchhiking in a promiscuous enzyme

    OpenAIRE

    Wagner, Andreas; Weikert, Christian

    2012-01-01

    Covarying phenotypic traits can limit natural selection’s ability to modify these traits. Most evolutionary studies on trait covariation use the comparative method to study complex traits of multicellular organisms. Simpler traits have the advantage of being amenable to experimental evolution. Here we study such a simple molecular system, the TEM-1 beta-lactamase protein, a promiscuous enzyme that hydrolyses antibiotics, and thus confers antibiotic resistance to bacteria. We mutagenized large...

  6. High-throughput phenotyping to detect drought tolerance QTL in wild barley introgression lines

    KAUST Repository

    Honsdorf, Nora

    2014-05-13

    Drought is one of the most severe stresses, endangering crop yields worldwide. In order to select drought tolerant genotypes, access to exotic germplasm and efficient phenotyping protocols are needed. In this study the high-throughput phenotyping platform "The Plant Accelerator", Adelaide, Australia, was used to screen a set of 47 juvenile (six week old) wild barley introgression lines (S42ILs) for drought stress responses. The kinetics of growth development was evaluated under early drought stress and well watered treatments. High correlation (r = 0.98) between image based biomass estimates and actual biomass was demonstrated, and the suitability of the system to accurately and non-destructively estimate biomass was validated. Subsequently, quantitative trait loci (QTL) were located, which contributed to the genetic control of growth under drought stress. In total, 44 QTL for eleven out of 14 investigated traits were mapped, which for example controlled growth rate and water use efficiency. The correspondence of those QTL with QTL previously identified in field trials is shown. For instance, six out of eight QTL controlling plant height were also found in previous field and glasshouse studies with the same introgression lines. This indicates that phenotyping juvenile plants may assist in predicting adult plant performance. In addition, favorable wild barley alleles for growth and biomass parameters were detected, for instance, a QTL that increased biomass by approximately 36%. In particular, introgression line S42IL-121 revealed improved growth under drought stress compared to the control Scarlett. The introgression line showed a similar behavior in previous field experiments, indicating that S42IL-121 may be an attractive donor for breeding of drought tolerant barley cultivars. © 2014 Honsdorf et al.

  7. Identification of an Alu-repeat-mediated deletion of OPTN upstream region in a patient with a complex ocular phenotype.

    Science.gov (United States)

    Schilter, Kala F; Reis, Linda M; Sorokina, Elena A; Semina, Elena V

    2015-11-01

    Genetic causes of ocular conditions remain largely unknown. To reveal the molecular basis for a congenital ocular phenotype associated with glaucoma we performed whole-exome sequencing (WES) and whole-genome copy number analyses of patient DNA. WES did not identify a causative variant. Copy number variation analysis identified a deletion of 10p13 in the patient and his unaffected father; the deletion breakpoint contained a single 37-bp sequence that is normally present in two distinct Alu repeats separated by ~181 kb. The deletion removed part of the upstream region of optineurin (OPTN) as well as the upstream sequence and two coding exons of coiled-coil domain containing 3 (CCDC3); analysis of the patient's second allele showed normal OPTN and CCDC3 sequences. Studies of zebrafish orthologs identified expression in the developing eye for both genes. OPTN is a known factor in dominant adult-onset glaucoma and Amyotrophic Lateral Sclerosis (ALS). The deletion eliminates 98 kb of the OPTN upstream sequence leaving only ~1 kb of the proximal promoter region. Comparison of transcriptional activation capability of the 3 kb normal and the rearranged del(10)(p13) OPTN promoter sequences demonstrated a statistically significant decrease for the deleted allele; sequence analysis of the entire deleted region identified multiple conserved elements with possible cis-regulatory activity. Additional screening of CCDC3 indicated that heterozygous loss-of-function alleles are unlikely to cause congenital ocular disease. In summary, we report the first regulatory region deletion involving OPTN, caused by Alu-mediated nonallelic homologous recombination and possibly contributing to the patient's ocular phenotype. In addition, our data indicate that Alu-mediated rearrangements of the OPTN upstream region may represent a new source of affected alleles in human conditions. Evaluation of the upstream OPTN sequences in additional ocular and ALS patients may help to determine the role

  8. Investigation of GRIN2A in common epilepsy phenotypes

    DEFF Research Database (Denmark)

    Lal, Dennis; Steinbrücker, Sandra; Schubert, Julian;

    2015-01-01

    Recently, mutations and deletions in the GRIN2A gene have been identified to predispose to benign and severe idiopathic focal epilepsies (IFE), revealing a higher incidence of GRIN2A alterations among the more severe phenotypes. This study aimed to explore the phenotypic boundaries of GRIN2A muta...

  9. Racial Identity, Phenotype, and Self-Esteem among Biracial Polynesian/White Individuals

    Science.gov (United States)

    Allen, G. E. Kawika; Garriott, Patton O.; Reyes, Carla J.; Hsieh, Catherine

    2013-01-01

    This study examined racial identity, self-esteem, and phenotype among biracial Polynesian/White adults. Eighty-four Polynesian/White persons completed the Biracial Identity Attitude Scale, the Rosenberg Self-Esteem Inventory, and a Polynesian phenotype scale. Profile analyses showed participants identified more with their Polynesian parent. A…

  10. Phenotypes and Emerging Endotypes of Chronic Rhinosinusitis.

    Science.gov (United States)

    Bachert, Claus; Akdis, Cezmi A

    2016-01-01

    Chronic rhinosinusitis can be differentiated into several phenotypes based on clinical criteria; however, these phenotypes do not teach us much about the underlying inflammatory mechanisms. Thus, the use of nasal endoscopy and CT scanning, and eventually taking a swab or a biopsy, may not be sufficient to fully appreciate the individual patient's pathology. Endotyping of chronic rhinosinusitis on the basis of pathomechanisms, functionally and pathologically different from others by the involvement of specific molecules or cells, may in contrast provide us with information on the risk of disease progression or recurrence and on the best available treatment, and also helps us identifying innovative therapeutic targets for treatment. Endotyping may best be structured around T helper cells and their downstream events, such as tissue eosinophilia or neutrophilia; this approach involves the cytokines and chemokines related to specific T helper cell populations, and related markers such as IgE. Endotyping is of specific interest at the time of the arrival of new biologicals, confronting us with the challenge of the selection of eligible patients for treatment and predicting their therapeutic response; defining suitable biomarkers is therefore an urgent task. Failure to appreciate the underlying mechanisms and endotypes of chronic rhinosinusitis may limit progress in the management of the disease at present. PMID:27393777

  11. The hydrogen concentration as parameter to identify natural attenuation processes of volatile chlorinated hydrocarbons in ground water; Die Wasserstoffkonzentration als Parameter zur Identifizierung des natuerlichen Abbaus von leichtfluechtigen Chlorkohlenwasserstoffen (LCKW) im Grundwasser

    Energy Technology Data Exchange (ETDEWEB)

    Alter, M.D.

    2006-06-15

    In this study, the hydrogen concentration as parameter to identify natural attenuation processes of volatile chlorinated hydrocarbons was investigated. The currently accepted and recommended bubble strip method for hydrogen sampling was optimized, and a storage method for hydrogen samples was developed. Furthermore batch experiments with a dechlorinating mixed culture and pure cultures were carried out to study H{sub 2}-concentrations of competing redox processes. The extraction of hydrogen from ground water was optimized by a reduced inlet diameter of the usually applied gas sampling bulbs, allowing a maximal turbulent ow and gas transfer. With a gas volume of 10 ml and flow rates of 50 to 140 ml/min, the course of extraction almost followed the theoretical course of equilibration. At flow rates > 100 ml/min a equilibrium of 98% was achieved within 20 min. Until recently it was generally accepted that hydrogen samples can be stored only for 2 hours and therefore have to be analyzed immediately in the eld. Here, it was shown that eld samples can be stored for 1-3 days until analysis. For the dechlorination of tetrachloroethene (PCE), a hydrogen threshold concentration of 1-2 nM was found with the dechlorinating mixed culture as well as with a pure culture of Sulfurospirillum multivorans in combination with another pure culture Methanosarcina mazei. No dechlorination was detectable below this concentration. With the dechlorinating mixed culture, this finding is valid for all successive dechlorination steps until ethene. The hydrogen threshold concentration for denitrification were below the detection limit of 0,2 nM with the dechlorinating mixed culture. A threshold concentration of 3,1-3,5 nM was found for sulphate reduction and a threshold of 7-9 nM H{sub 2} for hydrogenotrophic methanogenesis. This implies that the natural dechlorination at contaminated sites is preferred to competing processes like sulphate reduction and methanogenesis. The threshold

  12. Identification of Candida spp. by phenotypic tests and PCR

    Directory of Open Access Journals (Sweden)

    Sandra Aparecida Marinho

    2010-06-01

    Full Text Available The correct identification of Candida species is of great importance, as it presents prognostic and therapeutical significance, allowing an early and appropriate antifungical therapy. The purpose of this study was to identify isolates of Candida spp. from oral mucosa of 38 patients with oral candidosis evaluated in 2004 by phenotypic methods and PCR, discriminating C. albicans from the other Candida species. The tests used for phenotypic analysis were germ-tube and chlamydoconidia production, culture in CHROMAgarTM Candida, carbohydrate assimilation test, growth at 45ºC and culture in Tween 80 agar. Genotypic confirmation was performed by PCR. Phenotypic tests showed that 63.2% strains formed germ-tubes, 73.7% produced chlamydoconidia, and 63.2% showed green colonies in chromogenic medium, presumptively indicating C. albicans or C. dubliniensis. The carbohydrate assimilation test confirmed these results. A total of 21% strains were identified as C. krusei and 13.2% were indicative of C. tropicalis. Of these later strains, three produced chlamydoconidia. The association of other phenotypic tests with culture in Tween 80 agar identified 95.8% of strains as C. albicans and 4.2% as C. dubliniensis. All 24 strains indicative of C. albicans and C. dubliniensis were confirmed by PCR as C. albicans.

  13. Phenotypic variability in Meesmann's dystrophy

    DEFF Research Database (Denmark)

    Ehlers, Niels; Hjortdal, Jesper; Nielsen, Kim;

    2008-01-01

    symptoms often include blurred vision and ocular irritation. Typical cases may be entirely free of complaints. Intermittent pain episodes, such as occur in recurrent erosion syndrome, are not the rule. Genetic sequencing indicated a familial relationship with the originally described Meesmann family......'s dystrophy occurs worldwide. The largest family described is the original German one, now supplemented with a Danish branch. Despite the presence of an identical genetic defect, the clinical phenotype varies. This suggests that non-KRT12-related mechanisms are responsible for the variation.......PURPOSE: To describe the phenotypic variability in Meesmann's microcystic dystrophy of the corneal epithelium based on a review of the literature and the presentation of a Danish family. METHODS: We carried out a clinical examination of the family and genetic sequencing of DNA. RESULTS: Subjective...

  14. Identifying Mutations of the Tetratricopeptide Repeat Domain 37 (TTC37) Gene in Infants With Intractable Diarrhea and a Comparison of Asian and Non-Asian Phenotype and Genotype: A Global Case-report Study of a Well-Defined Syndrome With Immunodeficiency.

    Science.gov (United States)

    Lee, Wen-I; Huang, Jing-Long; Chen, Chien-Chang; Lin, Ju-Li; Wu, Ren-Chin; Jaing, Tang-Her; Ou, Liang-Shiou

    2016-03-01

    Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare, autosomal recessive and severe bowel disorder mainly caused by mutations in the tetratricopeptide repeat domain 37 (TTC37) gene which act as heterotetrameric cofactors to enhance aberrant mRNAs decay. The phenotype and immune profiles of SD/THE overlap those of primary immunodeficiency diseases (PIDs). Neonates with intractable diarrhea underwent immunologic assessments including immunoglobulin levels, lymphocyte subsets, lymphocyte proliferation, superoxide production, and IL-10 signaling function. Candidate genes for PIDs predisposing to inflammatory bowel disease were sequencing in this study. Two neonates, born to nonconsanguineous parents, suffered from intractable diarrhea, recurrent infections, and massive hematemesis from esopharyngeal varices due to liver cirrhosis or accompanying Trichorrhexis nodosa that developed with age and thus guided the diagnosis of SD/THE compatible to TTC37 mutations (homozygous DelK1155H, Fs*2; heterozygous Y1169Ter and InsA1143, Fs*3). Their immunologic evaluation showed normal mitogen-stimulated lymphocyte proliferation, superoxide production, and IL-10 signaling, but low IgG levels, undetectable antibody to hepatitis B surface antigen and decreased antigen-stimulated lymphocyte proliferation. A PubMed search for bi-allelic TTC37 mutations and phenotypes were recorded in 14 Asian and 12 non-Asian cases. They had similar presentations of infantile onset refractory diarrhea, facial dysmorphism, hair anomalies, low IgG, low birth weight, and consanguinity. A higher incidence of heart anomalies (8/14 vs 2/12; P = 0.0344, Chi-square), nonsense mutations (19 in 28 alleles), and hot-spot mutations (W936Ter, 2779-2G>A, and Y1169Ter) were found in the Asian compared with the non-Asian patients. Despite immunoglobulin therapy in 20 of the patients, 4 died from liver cirrhosis and 1 died from sepsis. Patients of all ethnicities with SD/THE with the characteristic

  15. Use of a Machine Learning-Based High Content Analysis Approach to Identify Photoreceptor Neurite Promoting Molecules.

    Science.gov (United States)

    Fuller, John A; Berlinicke, Cynthia A; Inglese, James; Zack, Donald J

    2016-01-01

    High content analysis (HCA) has become a leading methodology in phenotypic drug discovery efforts. Typical HCA workflows include imaging cells using an automated microscope and analyzing the data using algorithms designed to quantify one or more specific phenotypes of interest. Due to the richness of high content data, unappreciated phenotypic changes may be discovered in existing image sets using interactive machine-learning based software systems. Primary postnatal day four retinal cells from the photoreceptor (PR) labeled QRX-EGFP reporter mice were isolated, seeded, treated with a set of 234 profiled kinase inhibitors and then cultured for 1 week. The cells were imaged with an Acumen plate-based laser cytometer to determine the number and intensity of GFP-expressing, i.e. PR, cells. Wells displaying intensities and counts above threshold values of interest were re-imaged at a higher resolution with an INCell2000 automated microscope. The images were analyzed with an open source HCA analysis tool, PhenoRipper (Rajaram et al., Nat Methods 9:635-637, 2012), to identify the high GFP-inducing treatments that additionally resulted in diverse phenotypes compared to the vehicle control samples. The pyrimidinopyrimidone kinase inhibitor CHEMBL-1766490, a pan kinase inhibitor whose major known targets are p38α and the Src family member lck, was identified as an inducer of photoreceptor neuritogenesis by using the open-source HCA program PhenoRipper. This finding was corroborated using a cell-based method of image analysis that measures quantitative differences in the mean neurite length in GFP expressing cells. Interacting with data using machine learning algorithms may complement traditional HCA approaches by leading to the discovery of small molecule-induced cellular phenotypes in addition to those upon which the investigator is initially focusing. PMID:26427464

  16. Phenotypic expression in mucopolysaccharidosis VII.

    OpenAIRE

    Bernsen, P L; Wevers, R. A.; Gabreëls, F J; Lamers, K J; Sonnen, A E; Stekhoven, J H

    1987-01-01

    beta-glucuronidase deficiency is an extremely rare disorder which is known to have a considerable phenotypic variation. A survey of the clinical findings in 19 previously reported patients with mucopolysaccharidosis VII is presented together with the results of clinical and biochemical studies in two further patients. Because a similar clinical picture is present in a heterozygotic sister it is doubted whether all signs and symptoms can be attributed to the beta-glucuronidase deficiency. The ...

  17. [Plasticity of the cellular phenotype].

    Science.gov (United States)

    Chneiweiss, Hervé

    2011-01-01

    The tragical consequences of the Hiroshima and Nagasaki atomic bombs in 1945 were to lead to the discovery of hematopoietic stem cells and their phenotypic plasticity, in response to environmental factors. These concepts were much later extended to the founding cells of other tissues. In the following collection of articles, the mechanisms underlying this plasticity, at the frontiers of developmental biology and oncology, are illustrated in the case of various cell types of neural origin and of some tumours. PMID:21501574

  18. Wine Expertise Predicts Taste Phenotype

    OpenAIRE

    Hayes, John E.; Pickering, Gary J

    2012-01-01

    Taste phenotypes have long been studied in relation to alcohol intake, dependence, and family history, with contradictory findings. However, on balance – with appropriate caveats about populations tested, outcomes measured and psychophysical methods used – an association between variation in taste responsiveness and some alcohol behaviors is supported. Recent work suggests super-tasting (operationalized via propylthiouracil (PROP) bitterness) not only associates with heightened response but a...

  19. Genetic background of phenotypic variation

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    A noteworthy feature of the living world is its bewildering variability. A key issue in several biological disciplines is the achievement of an understanding of the hereditary basis of this variability. Two opposing, but not necessarily irreconcilable conceptions attempt to explain the underlying mechanism. The gene function paradigm postulates that phenotypic variance is generated by the polymorphism in the coding sequences of genes. However, comparisons of a great number of homologous gene and protein sequences have revealed that they predominantly remained functionally conserved even across distantly related phylogenic taxa. Alternatively, the gene regulation paradigm assumes that differences in the cis-regulatory region of genes do account for phenotype variation within species. An extension of this latter concept is that phenotypic variability is generated by the polyrnorphism in the overall gene expression profiles of gene networks.In other words, the activity of a particular gene is a system property determined both by the cis-regulatory sequences of the given genes and by the other genes of a gene network, whose expressions vary among individuals, too. Novel proponents of gene function paradigm claim that functional genetic variance within the coding sequences of regulatory genes is critical for the generation of morphological polymorphism. Note, however, that these developmental genes play direct regulatory roles in the control of gene expression.

  20. Similarity-based search of model organism, disease and drug effect phenotypes

    KAUST Repository

    Hoehndorf, Robert

    2015-02-19

    Background: Semantic similarity measures over phenotype ontologies have been demonstrated to provide a powerful approach for the analysis of model organism phenotypes, the discovery of animal models of human disease, novel pathways, gene functions, druggable therapeutic targets, and determination of pathogenicity. Results: We have developed PhenomeNET 2, a system that enables similarity-based searches over a large repository of phenotypes in real-time. It can be used to identify strains of model organisms that are phenotypically similar to human patients, diseases that are phenotypically similar to model organism phenotypes, or drug effect profiles that are similar to the phenotypes observed in a patient or model organism. PhenomeNET 2 is available at http://aber-owl.net/phenomenet. Conclusions: Phenotype-similarity searches can provide a powerful tool for the discovery and investigation of molecular mechanisms underlying an observed phenotypic manifestation. PhenomeNET 2 facilitates user-defined similarity searches and allows researchers to analyze their data within a large repository of human, mouse and rat phenotypes.

  1. Missing heritability of complex diseases: Enlightenment by genetic variants from intermediate phenotypes.

    Science.gov (United States)

    Blanco-Gómez, Adrián; Castillo-Lluva, Sonia; Del Mar Sáez-Freire, María; Hontecillas-Prieto, Lourdes; Mao, Jian Hua; Castellanos-Martín, Andrés; Pérez-Losada, Jesus

    2016-07-01

    Diseases of complex origin have a component of quantitative genetics that contributes to their susceptibility and phenotypic variability. However, after several studies, a major part of the genetic component of complex phenotypes has still not been found, a situation known as "missing heritability." Although there have been many hypotheses put forward to explain the reasons for the missing heritability, its definitive causes remain unknown. Complex diseases are caused by multiple intermediate phenotypes involved in their pathogenesis and, very often, each one of these intermediate phenotypes also has a component of quantitative inheritance. Here we propose that at least part of the missing heritability can be explained by the genetic component of intermediate phenotypes that is not detectable at the level of the main complex trait. At the same time, the identification of the genetic component of intermediate phenotypes provides an opportunity to identify part of the missing heritability of complex diseases. PMID:27241833

  2. Strategy revealing phenotypic differences among synthetic oscillator designs.

    Science.gov (United States)

    Lomnitz, Jason G; Savageau, Michael A

    2014-09-19

    Considerable progress has been made in identifying and characterizing the component parts of genetic oscillators, which play central roles in all organisms. Nonlinear interaction among components is sufficiently complex that mathematical models are required to elucidate their elusive integrated behavior. Although natural and synthetic oscillators exhibit common architectures, there are numerous differences that are poorly understood. Utilizing synthetic biology to uncover basic principles of simpler circuits is a way to advance understanding of natural circadian clocks and rhythms. Following this strategy, we address the following questions: What are the implications of different architectures and molecular modes of transcriptional control for the phenotypic repertoire of genetic oscillators? Are there designs that are more realizable or robust? We compare synthetic oscillators involving one of three architectures and various combinations of the two modes of transcriptional control using a methodology that provides three innovations: a rigorous definition of phenotype, a procedure for deconstructing complex systems into qualitatively distinct phenotypes, and a graphical representation for illuminating the relationship between genotype, environment, and the qualitatively distinct phenotypes of a system. These methods provide a global perspective on the behavioral repertoire, facilitate comparisons of alternatives, and assist the rational design of synthetic gene circuitry. In particular, the results of their application here reveal distinctive phenotypes for several designs that have been studied experimentally as well as a best design among the alternatives that has yet to be constructed and tested. PMID:25019938

  3. Natural variation of model mutant phenotypes in Ciona intestinalis.

    Directory of Open Access Journals (Sweden)

    Paolo Sordino

    Full Text Available BACKGROUND: The study of ascidians (Chordata, Tunicata has made a considerable contribution to our understanding of the origin and evolution of basal chordates. To provide further information to support forward genetics in Ciona intestinalis, we used a combination of natural variation and neutral population genetics as an approach for the systematic identification of new mutations. In addition to the significance of developmental variation for phenotype-driven studies, this approach can encompass important implications in evolutionary and population biology. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report a preliminary survey for naturally occurring mutations in three geographically interconnected populations of C. intestinalis. The influence of historical, geographical and environmental factors on the distribution of abnormal phenotypes was assessed by means of 12 microsatellites. We identified 37 possible mutant loci with stereotyped defects in embryonic development that segregate in a way typical of recessive alleles. Local populations were found to differ in genetic organization and frequency distribution of phenotypic classes. CONCLUSIONS/SIGNIFICANCE: Natural genetic polymorphism of C. intestinalis constitutes a valuable source of phenotypes for studying embryonic development in ascidians. Correlating genetic structure and the occurrence of abnormal phenotypes is a crucial focus for understanding the selective forces that shape natural finite populations, and may provide insights of great importance into the evolutionary mechanisms that generate animal diversity.

  4. Phenotype standardization for drug-induced kidney disease.

    Science.gov (United States)

    Mehta, Ravindra L; Awdishu, Linda; Davenport, Andrew; Murray, Patrick T; Macedo, Etienne; Cerda, Jorge; Chakaravarthi, Raj; Holden, Arthur L; Goldstein, Stuart L

    2015-08-01

    Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition. PMID:25853333

  5. Phenotypic Screening of Primary Human Cell Culture Systems to Identify Potential for Compound Toxicity (CHI Phenotypic Screening)

    Science.gov (United States)

    Addressing safety aspects of drugs and environmental chemicals has historically been undertaken through animal testing. However, the quantity of chemicals needing assessment and the challenge of species extrapolation require development of alternative approaches. Assessing phenot...

  6. Phenotypic and immunohistochemical characterization of sarcoglycanopathies

    Directory of Open Access Journals (Sweden)

    Ana F. B. Ferreira

    2011-01-01

    Full Text Available INTRODUCTION: Limb-girdle muscular dystrophy presents with heterogeneous clinical and molecular features. The primary characteristic of this disorder is proximal muscular weakness with variable age of onset, speed of progression, and intensity of symptoms. Sarcoglycanopathies, which are a subgroup of the limb-girdle muscular dystrophies, are caused by mutations in sarcoglycan genes. Mutations in these genes cause secondary deficiencies in other proteins, due to the instability of the dystrophin-glycoprotein complex. Therefore, determining the etiology of a given sarcoglycanopathy requires costly and occasionally inaccessible molecular methods. OBJECTIVE: The aim of this study was to identify phenotypic differences among limb-girdle muscular dystrophy patients who were grouped according to the immunohistochemical phenotypes for the four sarcoglycans. METHODS: To identify phenotypic differences among patients with different types of sarcoglycanopathies, a questionnaire was used and the muscle strength and range of motion of nine joints in 45 patients recruited from the Department of Neurology - HC-FMUSP (Clinics Hospital of the Faculty of Medicine of the University of São Paulo were evaluated. The findings obtained from these analyses were compared with the results of the immunohistochemical findings. RESULTS: The patients were divided into the following groups based on the immunohistochemical findings: a-sarcoglycanopathies (16 patients, b-sarcoglycanopathies (1 patient, y-sarcoglycanopathies (5 patients, and nonsarcoglycanopathies (23 patients. The muscle strength analysis revealed significant differences for both upper and lower limb muscles, particularly the shoulder and hip muscles, as expected. No pattern of joint contractures was found among the four groups analyzed, even within the same family. However, a high frequency of tiptoe gait was observed in patients with a-sarcoglycanopathies, while calf pseudo-hypertrophy was most common in

  7. Manual Evaluation of Robot Performance in Identifying Open Access Articles

    OpenAIRE

    Hajjem, Chawki; Harnad, Stevan

    2006-01-01

    Antelman et al. (2005) hand-tested the accuracy of the algorithm that Hajjem et al.'s (2005) software robot used to to trawl the web and automatically identify Open Access (OA) and Non-Open-Access (NOA) articles (references derived from the ISI database). Antelman et al. found much lower accuracy than Hajjem et al. Had reported. Hajjem et al. have now re-done the hand-testing on a larger sample (1000) in Biology, and demonstrated that Hajjem et al.'s original estimate of the robot's accuracy ...

  8. Accuracy of phenotyping children with autism based on parent report: what specifically do we gain phenotyping "rapidly"?

    Science.gov (United States)

    Warren, Zachary; Vehorn, Alison; Dohrmann, Elizabeth; Nicholson, Amy; Sutcliffe, James S; Veenstra-Vanderweele, Jeremy

    2012-02-01

    Autism spectrum disorder (ASD) is considered among the most heritable of all neurodevelopmental and psychiatric disorders, but identification of etiologically significant genetic markers and risk variants has been hampered by a lack of sufficiently large samples. Rapid phenotyping procedures, where self-report measures are used instead of extensive clinical assessment, have been proposed as methods for amassing large genetic databases due to their hypothesized time-efficiency and affordability. We assessed the diagnostic accuracy of potential rapid phenotyping procedures using the Social Communication Questionnaire and the Social Responsiveness Scale in a sample of 333 children who also received extensive phenotypic assessments. While the rapid phenotyping measures were able to accurately identify a large number of children with ASD, they also frequently failed to differentiate children with ASD from children with other complex neurobehavioral profiles. These data support the continued need of expert clinical validation in combination with rapid phenotyping procedures in order to accurately amass large-scale genetic collections of children with ASD. PMID:21972233

  9. Knowledge-based analysis of phenotypes

    KAUST Repository

    Hoendorf, Robert

    2016-01-27

    Phenotypes are the observable characteristics of an organism, and they are widely recorded in biology and medicine. To facilitate data integration, ontologies that formally describe phenotypes are being developed in several domains. I will describe a formal framework to describe phenotypes. A formalized theory of phenotypes is not only useful for domain analysis, but can also be applied to assist in the diagnosis of rare genetic diseases, and I will show how our results on the ontology of phenotypes is now applied in biomedical research.

  10. Searching for RFLP markers to identify genes for aluminum tolerance in maize

    International Nuclear Information System (INIS)

    The objective of this study was to identify restriction fragment length polymorphism (RFLP) markers linked to Quantitative Trait Loci (QTL) that control aluminum (Al) tolerance in maize. The strategy used was bulked segregant analysis (BSA) and the genetic materials utilized were the F2, F3 and F4 populations derived from a cross between the Al-susceptible inbred line L53 and Al-tolerant inbred line L1327. The populations were evaluated in a nutrient solution containing a toxic concentration of Al (6 ppm) and relative seminal root length (RSRL) was used as a phenotypic measure of tolerance. Seedlings of the F2 population with the highest and lowest RSRL values were transplanted to the field and subsequently selfed to obtain F3 and F4 families. The efficiency of the phenotypic index for selection was found to be greater when mean values were used instead of individual RSRL values. F3 and F4 families were then evaluated in nutrient solution to identify those that were not segregating. One hundred and thirteen probes, with an average interval of 30 cM, covering the 10 maize chromosomes were tested for their ability to discriminate the parental lines. Fifty four of these probes were polymorphic with 46 showing codominance. These probes were hybridized with DNA from two F3 contrasting, bulks and three probes on chromosome 8 were found to be able distinguish the F3 contrasting bulks on the basis of band position and intensity. DNA of families from the F3 bulks hybridized with these probes showed the presence of heterozygous individuals. These three selected probes were also hybridized with DNA from F2 individuals. Two of them showed a significant regression coefficient with the character. However, each of these probes explained only about 10% of the phenotypic variance observed in 70 F2 individuals. One of the probes UMC 103 was hybridized with DNA from 168 F4 families and the regression analysis of RFLP data showed a significant regression coefficient with a

  11. Multiparametric classification links tumor microenvironments with tumor cell phenotype.

    Directory of Open Access Journals (Sweden)

    Bojana Gligorijevic

    2014-11-01

    Full Text Available While it has been established that a number of microenvironment components can affect the likelihood of metastasis, the link between microenvironment and tumor cell phenotypes is poorly understood. Here we have examined microenvironment control over two different tumor cell motility phenotypes required for metastasis. By high-resolution multiphoton microscopy of mammary carcinoma in mice, we detected two phenotypes of motile tumor cells, different in locomotion speed. Only slower tumor cells exhibited protrusions with molecular, morphological, and functional characteristics associated with invadopodia. Each region in the primary tumor exhibited either fast- or slow-locomotion. To understand how the tumor microenvironment controls invadopodium formation and tumor cell locomotion, we systematically analyzed components of the microenvironment previously associated with cell invasion and migration. No single microenvironmental property was able to predict the locations of tumor cell phenotypes in the tumor if used in isolation or combined linearly. To solve this, we utilized the support vector machine (SVM algorithm to classify phenotypes in a nonlinear fashion. This approach identified conditions that promoted either motility phenotype. We then demonstrated that varying one of the conditions may change tumor cell behavior only in a context-dependent manner. In addition, to establish the link between phenotypes and cell fates, we photoconverted and monitored the fate of tumor cells in different microenvironments, finding that only tumor cells in the invadopodium-rich microenvironments degraded extracellular matrix (ECM and disseminated. The number of invadopodia positively correlated with degradation, while the inhibiting metalloproteases eliminated degradation and lung metastasis, consistent with a direct link among invadopodia, ECM degradation, and metastasis. We have detected and characterized two phenotypes of motile tumor cells in vivo, which

  12. Phenotyping bananas for drought resistance

    OpenAIRE

    IyyakuttyRavi

    2013-01-01

    Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with ‘B’ genome are more tolerant to abiotic stresses than those solely based on ‘A’ genome. In particular, bananas with ‘ABB’ genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite f...

  13. Phenotyping bananas for drought resistance

    OpenAIRE

    Ravi, Iyyakkutty; Uma, Subbaraya; Vaganan, Muthu Mayil; Mustaffa, Mohamed M.

    2013-01-01

    Drought has emerged as one of the major constraints in banana production. Its effects are pronounced substantially in the tropics and sub-tropics of the world due to climate change. Bananas are quite sensitive to drought; however, genotypes with “B” genome are more tolerant to abiotic stresses than those solely based on “A” genome. In particular, bananas with “ABB” genomes are more tolerant to drought and other abiotic stresses than other genotypes. A good phenotyping plan is a prerequisite f...

  14. Phenotypic MicroRNA Microarrays

    OpenAIRE

    Veronica Soloveva; Michel Liuzzi; Jin Yeop Kim; Hi Chul Kim; Jin Yeong Heo; Yong-Jun Kwon

    2013-01-01

    Microarray technology has become a very popular approach in cases where multiple experiments need to be conducted repeatedly or done with a variety of samples. In our lab, we are applying our high density spots microarray approach to microscopy visualization of the effects of transiently introduced siRNA or cDNA on cellular morphology or phenotype. In this publication, we are discussing the possibility of using this micro-scale high throughput process to study the role of microRNAs in the bio...

  15. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    Science.gov (United States)

    Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

    2015-06-01

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  16. Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

    KAUST Repository

    Hoehndorf, Robert

    2015-06-08

    Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

  17. Color change, phenotypic plasticity, and camouflage

    Directory of Open Access Journals (Sweden)

    Martin eStevens

    2016-05-01

    Full Text Available The ability to change appearance over a range of timescales is widespread in nature, existing in many invertebrate and vertebrate groups. This can include color change occurring in seconds, minutes, and hours, to longer term changes associated with phenotypic plasticity and development. A major function is for camouflage against predators because color change and plasticity enables animals to match their surroundings and potentially reduce the risk of predation. Recently, we published findings (Stevens et al. 2014a showing how shore crabs can change their appearance and better match the background to predator vision in the short term. This, coupled with a number of past studies, emphasizes the potential that animals have to modify their appearance for camouflage. However, the majority of studies on camouflage and color plasticity have focused on a small number of species capable of unusually rapid changes. There are many broad questions that remain about the nature, mechanisms, evolution, and adaptive value of color change and plasticity for concealment. Here, I discuss past work and outline six questions relating to color change and plasticity, as well as major avenues for future work.

  18. Phenotype heterogeneity in cancer cell populations

    Science.gov (United States)

    Almeida, Luis; Chisholm, Rebecca; Clairambault, Jean; Escargueil, Alexandre; Lorenzi, Tommaso; Lorz, Alexander; Trélat, Emmanuel

    2016-06-01

    Phenotype heterogeneity in cancer cell populations, be it of genetic, epigenetic or stochastic origin, has been identified as a main source of resistance to drug treatments and a major source of therapeutic failures in cancers. The molecular mechanisms of drug resistance are partly understood at the single cell level (e.g., overexpression of ABC transporters or of detoxication enzymes), but poorly predictable in tumours, where they are hypothesised to rely on heterogeneity at the cell population scale, which is thus the right level to describe cancer growth and optimise its control by therapeutic strategies in the clinic. We review a few results from the biological literature on the subject, and from mathematical models that have been published to predict and control evolution towards drug resistance in cancer cell populations. We propose, based on the latter, optimisation strategies of combined treatments to limit emergence of drug resistance to cytotoxic drugs in cancer cell populations, in the monoclonal situation, which limited as it is still retains consistent features of cell population heterogeneity. The polyclonal situation, that may be understood as "bet hedging" of the tumour, thus protecting itself from different sources of drug insults, may lie beyond such strategies and will need further developments. In the monoclonal situation, we have designed an optimised therapeutic strategy relying on a scheduled combination of cytotoxic and cytostatic treatments that can be adapted to different situations of cancer treatments. Finally, we review arguments for biological theoretical frameworks proposed at different time and development scales, the so-called atavistic model (diachronic view relying on Darwinian genotype selection in the coursof billions of years) and the Waddington-like epigenetic landscape endowed with evolutionary quasi-potential (synchronic view relying on Lamarckian phenotype instruction of a given genome by reversible mechanisms), to

  19. Iron Metabolism Disturbance in a French Cohort of ALS Patients

    OpenAIRE

    Charlotte Veyrat-Durebex; Philippe Corcia; Aleksandra Mucha; Simon Benzimra; Cindy Mallet; Chantal Gendrot; Caroline Moreau; David Devos; Eric Piver; Jean-Christophe Pagès; François Maillot; Andres, Christian R.; Patrick Vourc’h; Hélène Blasco

    2014-01-01

    Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS) patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC) from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as...

  20. The neurobehavioral phenotype in mucopolysaccharidosis Type IIIB: An exploratory study

    OpenAIRE

    Shapiro, E; King, K; Ahmed, A.; Rudser, K.; R. Rumsey; Yund, B.; Delaney, K; I. Nestrasil; Whitley, C.; M. Potegal

    2016-01-01

    Objectives: Our goal was to describe the neurobehavioral phenotype in mucopolysaccharidosis Type IIIB (MPS IIIB). Parents report that behavioral abnormalities are a major problem in MPS III posing serious challenges to parenting and quality-of-life for both patient and parent. Our previous research on MPS IIIA identified autistic symptoms, and a Klüver-Bucy-type syndrome as indicated by reduced startle and loss of fear associated with amygdala atrophy. We hypothesized that MPS IIIB would mani...

  1. Rumen microbial communities influence metabolic phenotypes in lambs

    OpenAIRE

    Morgavi, Diego P.; Rathahao-Paris, Estelle; Popova, Milka; Boccard, Julien; Nielsen, Kristian F; Boudra, Hamid

    2015-01-01

    The rumen microbiota is an essential part of ruminants forging their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to pract...

  2. Clinical Asthma Phenotypes and Therapeutic Responses

    OpenAIRE

    Zedan, M.; Attia, G.; Zedan, M. M.; Osman, A; Abo-Elkheir, N.; Maysara, N.; Barakat, T.; Gamil, N.

    2013-01-01

    Asthma is a heterogeneous disease that means not all asthmatics respond to the same treatment. We hypothesize an approach to characterize asthma phenotypes based on symptomatology (shortness of breath (SOB), cough, and wheezy phenotypes) in correlation with airway inflammatory biomarkers and FEV1. We aimed to detect whether those clinical phenotypes have an impact on the response to asthma medications. Two hundred three asthmatic children were allocated randomly to receive either montelukast ...

  3. Latent phenotypes pervade gene regulatory circuits.

    OpenAIRE

    Payne, Joshua L.; Wagner, Andreas

    2014-01-01

    BACKGROUND Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. RESULTS Here, we study a space of more than sixteen million three-gene model regulatory circ...

  4. Latent phenotypes pervade gene regulatory circuits

    OpenAIRE

    Payne, Joshua L.; Wagner, Andreas

    2014-01-01

    Background Latent phenotypes are non-adaptive byproducts of adaptive phenotypes. They exist in biological systems as different as promiscuous enzymes and genome-scale metabolic reaction networks, and can give rise to evolutionary adaptations and innovations. We know little about their prevalence in the gene expression phenotypes of regulatory circuits, important sources of evolutionary innovations. Results Here, we study a space of more than sixteen million three-gene model regulatory circuit...

  5. Phenotype Information Retrieval for Existing GWAS Studies

    OpenAIRE

    Alipanah, Neda; Lin, Ko-Wei; Venkatesh, Vinay; Farzaneh, Seena; Kim, Hyeon-eui

    2013-01-01

    The database of Genotypes and Phenotypes (dbGaP) is archiving the results of different Genome Wide Association Studies (GWAS). dbGaP has a multitude of phenotype variables, but they are not harmonized across studies. We proposed a method to standardize phenotype variables by classifying similar variables based on semantic distances. We first extracted variables description, enriched them using domain knowledge, and computed the distances among them. We used clustering techniques to classify t...

  6. Phenotypes and Survival of Hatchling Lizards

    OpenAIRE

    Warner, Daniel Augustus

    2001-01-01

    The phenotypes of hatchling reptiles are influenced by the environmental conditions that embryos experience during incubation, by yolk invested into the egg, and by the genetic contributions of the parents. Phenotypic traits are influenced by these factors in ways that potentially affect the fitness of hatchlings. The physical conditions that embryos experience within the nest affects development, hatching success, and hatchling phenotypes. Thus, the nest site that a female selects can inf...

  7. Immunogenetic phenotypes in inflammatory bowel disease

    Institute of Scientific and Technical Information of China (English)

    Marla C Dubinsky; Kent Taylor; Stephan R Targan; Jerome I Rotter

    2006-01-01

    The currently accepted etiopathogenic hypothesis suggests that the chronic intestinal inflammation and related systemic manifestations characteristic of inflammatory bowel disease (IBD) are due to an overly aggressive or pathologic immune response to resident luminal bacterial constituents. Predisposing factors are genetic dysregulation of mucosal immune responses and/or barrier function, with onset triggered by environmental stimuli. These factors and their interactions may also be important determinants of disease phenotype and disease progression. The emergence of immunogenetic phenotypes lends support to the proposed hypothesis that susceptibility genes regulate distinct immune processes, driven by luminal antigens, expressed as specific immune phenotypes which in turn influence clinical phenotypes in IBD patient

  8. Discrimination of meniscal cell phenotypes using gene expression profiles

    Directory of Open Access Journals (Sweden)

    M Son

    2012-03-01

    Full Text Available The lack of quantitative and objective metrics to assess cartilage and meniscus cell phenotypes contributes to the challenges in fibrocartilage tissue engineering. Although functional assessment of the final resulting tissue is essential, initial characterization of cell sources and quantitative description of their progression towards the natural, desired cell phenotype would provide an effective tool in optimizing cell-based tissue engineering strategies. The purpose of this study was to identify quantifiable characteristics of meniscal cells and thereby find phenotypical markers that could effectively categorize cells based on their tissue of origin (cartilage, inner, middle, and outer meniscus. The combination of gene expression ratios collagen VI/collagen II, ADAMTS-5/collagen II, and collagen I/collagen II was the most effective indicator of variation among different tissue regions. We additionally demonstrate a possible application of these quantifiable metrics in evaluating the use of serially passaged chondrocytes as a possible cell source in fibrocartilage engineering. Comparing the ratios of the passaged chondrocytes and the native meniscal cells may provide direction to optimize towards the desired cell phenotype. We have thus shown that measurable markers defining the characteristics of the native meniscus can establish a standard by which different tissue engineering strategies can be objectively assessed. Such metrics could additionally be useful in exploring the different stages of meniscal degradation in osteoarthritis and provide some insight in the disease progression.

  9. Establishment and genetic characterization of a novel mixed-phenotype acute leukemia cell line with EP300-ZNF384 fusion

    OpenAIRE

    Ping, Nana; Qiu, Huiying; Wang, Qian; Dai, Haiping; Ruan, Changgeng; Ehrentraut, Stefan; Drexler, Hans G.; MacLeod, Roderick A. F.; Chen, Suning

    2015-01-01

    Herein, we describe the establishment and characterization of the first mixed-phenotype acute leukemia cell line (JIH-5). The JIH-5 cell line was established from leukemia cells with B lymphoid/myeloid phenotype from a female mixed-phenotype acute leukemia patient. JIH-5 cells exhibit an immunophenotype comprised of myeloid and B lymphoid antigens. Whole-exome sequencing revealed somatic mutations in nine genes in JIH-5 cells. Transcriptional sequencing of JIH-5 cells identified EP300-ZNF384 ...

  10. Novel strategies to enforce an epithelial phenotype in mesenchymal cells.

    Science.gov (United States)

    Dragoi, Ana-Maria; Swiss, Rachel; Gao, Beile; Agaisse, Hervé

    2014-07-15

    E-cadherin downregulation in cancer cells is associated with epithelial-to-mesenchymal transition (EMT) and metastatic prowess, but the underlying mechanisms are incompletely characterized. In this study, we probed E-cadherin expression at the plasma membrane as a functional assay to identify genes involved in E-cadherin downregulation. The assay was based on the E-cadherin-dependent invasion properties of the intracellular pathogen Listeria monocytogenes. On the basis of a functional readout, automated microscopy and computer-assisted image analysis were used to screen siRNAs targeting 7,000 human genes. The validity of the screen was supported by its definition of several known regulators of E-cadherin expression, including ZEB1, HDAC1, and MMP14. We identified three new regulators (FLASH, CASP7, and PCGF1), the silencing of which was sufficient to restore high levels of E-cadherin transcription. In addition, we identified two new regulators (FBXL5 and CAV2), the silencing of which was sufficient to increase E-cadherin expression at a posttranscriptional level. FLASH silencing regulated the expression of E-cadherin and other ZEB1-dependent genes, through posttranscriptional regulation of ZEB1, but it also regulated the expression of numerous ZEB1-independent genes with functions predicted to contribute to a restoration of the epithelial phenotype. Finally, we also report the identification of siRNA duplexes that potently restored the epithelial phenotype by mimicking the activity of known and putative microRNAs. Our findings suggest new ways to enforce epithelial phenotypes as a general strategy to treat cancer by blocking invasive and metastatic phenotypes associated with EMT. PMID:24845104

  11. Phenotypic robustness can increase phenotypic variability after non-genetic perturbations in gene regulatory circuits

    OpenAIRE

    Espinosa-Soto, C.; Martin, O. C.; Wagner, A

    2010-01-01

    Non-genetic perturbations, such as environmental change or developmental noise, can induce novel phenotypes. If an induced phenotype confers a fitness advantage, selection may promote its genetic stabilization. Non-genetic perturbations can thus initiate evolutionary innovation. Genetic variation that is not usually phenotypically visible may play an important role in this process. Populations under stabilizing selection on a phenotype that is robust to mutations can accumulate such variation...

  12. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    NARCIS (Netherlands)

    Kohler, S.; Doelken, S.C.; Mungall, C.J.; Bauer, S.; Firth, H.V.; Bailleul-Forestier, I.; Black, G.C.M.; Brown, D.L.; Brudno, M.; Campbell, J.; FitzPatrick, D.R.; Eppig, J.T.; Jackson, A.P.; Freson, K.; Girdea, M.; Helbig, I.; Hurst, J.A.; Jahn, J.; Jackson, L.G.; Kelly, A.M.; Ledbetter, D.H.; Mansour, S.; Martin, C.L.; Moss, C.; Mumford, A.; Ouwehand, W.H.; Park, S.M.; Riggs, E.R.; Scott, R.H.; Sisodiya, S.; Vooren, S. van der; Wapner, R.J.; Wilkie, A.O.; Wright, C.F.; Silfhout, A.T. van; Leeuw, N. de; Vries, B. de; Washingthon, N.L.; Smith, C.L.; Westerfield, M.; Schofield, P.; Ruef, B.J.; Gkoutos, G.V.; Haendel, M.; Smedley, D.; Lewis, S.E.; Robinson, P.N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have d

  13. The Cognitive Phenotype of Spina Bifida Meningomyelocele

    Science.gov (United States)

    Dennis, Maureen; Barnes, Marcia A.

    2010-01-01

    A cognitive phenotype is a product of both assets and deficits that specifies what individuals with spina bifida meningomyelocele (SBM) can and cannot do and why they can or cannot do it. In this article, we review the cognitive phenotype of SBM and describe the processing assets and deficits that cut within and across content domains, sensory…

  14. Distribution of phenotypes among Bacillus thuringiensis strains

    Science.gov (United States)

    An extensive collection of Bacillus thuringiensis isolates from around the world were phenotypically profiled using standard biochemical tests. Six phenotypic traits occurred in 20-86% of the isolates and were useful in distinguishing isolates: production of urease (U; 20.5% of isolates), hydrolysis...

  15. The puzzle of immune phenotypes of childhood asthma.

    Science.gov (United States)

    Landgraf-Rauf, Katja; Anselm, Bettina; Schaub, Bianca

    2016-12-01

    Asthma represents the most common chronic childhood disease worldwide. Whereas preschool children present with wheezing triggered by different factors (multitrigger and viral wheeze), clinical asthma manifestation in school children has previously been classified as allergic and non-allergic asthma. For both, the underlying immunological mechanisms are not yet understood in depth in children. Treatment is still prescribed regardless of underlying mechanisms, and children are not always treated successfully. This review summarizes recent key findings on the complex mechanisms of the development and manifestation of childhood asthma. Whereas traditional classification of childhood asthma is primarily based on clinical symptoms like wheezing and atopy, novel approaches to specify asthma phenotypes are under way and face challenges such as including the stability of phenotypes over time and transition into adulthood. Epidemiological studies enclose more information on the patient's disease history and environmental influences. Latest studies define endotypes based on molecular and cellular mechanisms, for example defining risk and protective single nucleotide polymorphisms (SNPs) and new immune phenotypes, showing promising results. Also, regulatory T cells and recently discovered T helper cell subtypes such as Th9 and Th17 cells were shown to be important for the development of asthma. Innate lymphoid cells (ILC) could play a critical role in asthma patients as they produce different cytokines associated with asthma. Epigenetic findings showed different acetylation and methylation patterns for children with allergic and non-allergic asthma. On a posttranscriptional level, miRNAs are regulating factors identified to differ between asthma patients and healthy controls and also indicate differences within asthma phenotypes. Metabolomics is another exciting chapter important for endotyping asthmatic children. Despite the development of new biomarkers and the discovery of

  16. Cytochrome P450 reaction-phenotyping: an industrial perspective.

    Science.gov (United States)

    Zhang, Hongjian; Davis, Carl D; Sinz, Michael W; Rodrigues, A David

    2007-10-01

    It is now widely accepted that the fraction of the dose metabolized by a given drug-metabolizing enzyme is one of the major factors governing the magnitude of a drug interaction and the impact of a polymorphism on (total) drug clearance. Therefore, most pharmaceutical companies determine the enzymes involved in the metabolism of a new chemical entity (NCE) in vitro, in conjunction with human data on absorption, distribution, metabolism and excretion. This so called reaction-phenotyping, or isozyme-mapping, usually involves the use of multiple reagents (e.g., recombinant proteins, liver subcellular fractions, enzyme-selective chemical inhibitors and antibodies). For the human CYPs, reagents are readily available and in vitro reaction-phenotyping data are now routinely included in most regulatory documents. Ideally, the various metabolites have been definitively identified, incubation conditions have afforded robust kinetic analyses, and well characterized (high quality) reagents and human tissues have been employed. It is also important that the various in vitro data are consistent (e.g., scaled turnover with recombinant CYP proteins, CYP inhibition and correlation data with human liver microsomes) and enable an integrated in vitro CYP reaction-phenotype. Results of the in vitro CYP reaction-phenotyping are integrated with clinical data (e.g., human radiolabel and drug interaction studies) and a complete package is then submitted for regulatory review. If the NCE receives market approval, information on key routes of clearance and their associated potential for drug-drug interactions are included in the product label. The present review focuses on in vitro CYP reaction-phenotyping and the integration of data. Relatively simple strategies enabling the design and prioritization of follow up clinical studies are also discussed. PMID:17916054

  17. Metabolomic phenotyping of af cloned pig model

    DEFF Research Database (Denmark)

    Clausen, Morten Rahr; Christensen, Kirstine Lykke; Hedemann, Mette Skou;

    2011-01-01

    Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and...... possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal...... outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5) was for the first time elucidated by nuclear magnetic resonance (NMR)-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n...

  18. Adjusting phenotypes by noise control.

    Directory of Open Access Journals (Sweden)

    Kyung H Kim

    2012-01-01

    Full Text Available Genetically identical cells can show phenotypic variability. This is often caused by stochastic events that originate from randomness in biochemical processes involving in gene expression and other extrinsic cellular processes. From an engineering perspective, there have been efforts focused on theory and experiments to control noise levels by perturbing and replacing gene network components. However, systematic methods for noise control are lacking mainly due to the intractable mathematical structure of noise propagation through reaction networks. Here, we provide a numerical analysis method by quantifying the parametric sensitivity of noise characteristics at the level of the linear noise approximation. Our analysis is readily applicable to various types of noise control and to different types of system; for example, we can orthogonally control the mean and noise levels and can control system dynamics such as noisy oscillations. As an illustration we applied our method to HIV and yeast gene expression systems and metabolic networks. The oscillatory signal control was applied to p53 oscillations from DNA damage. Furthermore, we showed that the efficiency of orthogonal control can be enhanced by applying extrinsic noise and feedback. Our noise control analysis can be applied to any stochastic model belonging to continuous time Markovian systems such as biological and chemical reaction systems, and even computer and social networks. We anticipate the proposed analysis to be a useful tool for designing and controlling synthetic gene networks.

  19. Discovery of rare variants for complex phenotypes.

    Science.gov (United States)

    Kosmicki, Jack A; Churchhouse, Claire L; Rivas, Manuel A; Neale, Benjamin M

    2016-06-01

    With the rise of sequencing technologies, it is now feasible to assess the role rare variants play in the genetic contribution to complex trait variation. While some of the earlier targeted sequencing studies successfully identified rare variants of large effect, unbiased gene discovery using exome sequencing has experienced limited success for complex traits. Nevertheless, rare variant association studies have demonstrated that rare variants do contribute to phenotypic variability, but sample sizes will likely have to be even larger than those of common variant association studies to be powered for the detection of genes and loci. Large-scale sequencing efforts of tens of thousands of individuals, such as the UK10K Project and aggregation efforts such as the Exome Aggregation Consortium, have made great strides in advancing our knowledge of the landscape of rare variation, but there remain many considerations when studying rare variation in the context of complex traits. We discuss these considerations in this review, presenting a broad range of topics at a high level as an introduction to rare variant analysis in complex traits including the issues of power, study design, sample ascertainment, de novo variation, and statistical testing approaches. Ultimately, as sequencing costs continue to decline, larger sequencing studies will yield clearer insights into the biological consequence of rare mutations and may reveal which genes play a role in the etiology of complex traits. PMID:27221085

  20. Factors contributing to the biofilm-deficient phenotype of Staphylococcus aureus sarA mutants.

    Directory of Open Access Journals (Sweden)

    Laura H Tsang

    Full Text Available Mutation of sarA in Staphylococcus aureus results in a reduced capacity to form a biofilm, but the mechanistic basis for this remains unknown. Previous transcriptional profiling experiments identified a number of genes that are differentially expressed both in a biofilm and in a sarA mutant. This included genes involved in acid tolerance and the production of nucleolytic and proteolytic exoenzymes. Based on this we generated mutations in alsSD, nuc and sspA in the S. aureus clinical isolate UAMS-1 and its isogenic sarA mutant and assessed the impact on biofilm formation. Because expression of alsSD was increased in a biofilm but decreased in a sarA mutant, we also generated a plasmid construct that allowed expression of alsSD in a sarA mutant. Mutation of alsSD limited biofilm formation, but not to the degree observed with the corresponding sarA mutant, and restoration of alsSD expression did not restore the ability to form a biofilm. In contrast, concomitant mutation of sarA and nuc significantly enhanced biofilm formation by comparison to the sarA mutant. Although mutation of sspA had no significant impact on the ability of a sarA mutant to form a biofilm, a combination of protease inhibitors (E-64, 1-10-phenanthroline, and dichloroisocoumarin that was shown to inhibit the production of multiple extracellular proteases without inhibiting growth was also shown to enhance the ability of a sarA mutant to form a biofilm. This effect was evident only when all three inhibitors were used concurrently. This suggests that the reduced capacity of a sarA mutant to form a biofilm involves extracellular proteases of all three classes (serine, cysteine and metalloproteases. Inclusion of protease inhibitors also enhanced biofilm formation in a sarA/nuc mutant, with the combined effect of mutating nuc and adding protease inhibitors resulting in a level of biofilm formation with the sarA mutant that approached that of the UAMS-1 parent strain. These results

  1. WDR35 Mutation in Siblings with Sensenbrenner Syndrome: A Ciliopathy With Variable Phenotype

    OpenAIRE

    Bacino, Carlos A.; Dhar, Shweta U.; Brunetti-Pierri, Nicola; Lee, Brendan; Bonnen, Penelope E

    2012-01-01

    Sensenbrenner syndrome and unclassified short rib-polydactyly conditions are ciliopathies with overlapping phenotypes and genetic heterogeneity. Mutations in WDR35 were identified recently in a sub-group of patients with Sensenbrenner syndrome and in a single family that presented with an unclassified form of short-rib polydactyly (SRP) syndrome. We report on siblings with an unusual combination of phenotypes: narrow thorax, short stature, minor anomalies, developmental delay, and severe hepa...

  2. PhenoMiner: from text to a database of phenotypes associated with OMIM diseases

    OpenAIRE

    Collier, Nigel; Groza, Tudor; Smedley, Damian; Robinson, Peter N; Oellrich, Anika; Rebholz-Schuhmann, Dietrich

    2015-01-01

    Analysis of scientific and clinical phenotypes reported in the experimental literature has been curated manually to build high-quality databases such as the Online Mendelian Inheritance in Man (OMIM). However, the identification and harmonization of phenotype descriptions struggles with the diversity of human expressivity. We introduce a novel automated extraction approach called PhenoMiner that exploits full parsing and conceptual analysis. Apriori association mining is then used to identify...

  3. Genome-wide polygenic scoring for a 14-year long-term average depression phenotype

    OpenAIRE

    Chang, Shun-Chiao; Glymour, M. Maria; Walter, Stefan; Liang, Liming; Koenen, Karestan C.; Tchetgen, Eric J; Cornelis, Marilyn C; Kawachi, Ichiro; Rimm, Eric; Kubzansky, Laura D.

    2014-01-01

    Background: Despite moderate heritability estimates for depression-related phenotypes, few robust genetic predictors have been identified. Potential explanations for this discrepancy include the use of phenotypic measures taken from a single time point, rather than integrating information over longer time periods via multiple assessments, and the possibility that genetic risk is shaped by multiple loci with small effects. Methods: We developed a 14-year long-term average depression measure ba...

  4. Genome-wide polygenic scoring for a 14-year long-term average depression phenotype

    OpenAIRE

    Chang, Shun-Chiao; Glymour, M. Maria; Walter, Stefan; Liang, Liming; Koenen, Karestan C.; Tchetgen, Eric J; Cornelis, Marilyn C; Kawachi, Ichiro; Rimm, Eric; Kubzansky, Laura D.

    2014-01-01

    Background Despite moderate heritability estimates for depression-related phenotypes, few robust genetic predictors have been identified. Potential explanations for this discrepancy include the use of phenotypic measures taken from a single time point, rather than integrating information over longer time periods via multiple assessments, and the possibility that genetic risk is shaped by multiple loci with small effects. Methods We developed a 14-year long-term average depression measure base...

  5. Computational models for prediction of yeast strain potential for winemaking from phenotypic profiles

    OpenAIRE

    Mendes, Ines; Franco-Duarte, Ricardo; Umek, Lan; Fonseca, Elza; Drumonde-Neves, Joao; Dequin, Sylvie; Zupan, Blaz; Schuller, Dorit

    2013-01-01

    Saccharomyces cerevisiae strains from diverse natural habitats harbour a vast amount of phenotypic diversity, driven by interactions between yeast and the respective environment. In grape juice fermentations, strains are exposed to a wide array of biotic and abiotic stressors, which may lead to strain selection and generate naturally arising strain diversity. Certain phenotypes are of particular interest for the winemaking industry and could be identified by screening of large number of diffe...

  6. Computational models for prediction of yeast strain potential for winemaking from phenotypic profiles

    OpenAIRE

    Inês Mendes; Ricardo Franco-Duarte; Lan Umek; Elza Fonseca; João Drumonde-Neves; Sylvie Dequin; Blaz Zupan; Dorit Schuller

    2015-01-01

    Saccharomyces cerevisiae strains from diverse natural habitats harbour a vast amount of phenotypic diversity, driven by interactions between yeast and the respective environment. In grape juice fermentations, strains are exposed to a wide array of biotic and abiotic stressors, which may lead to strain selection and generate naturally arising strain diversity. Certain phenotypes are of particular interest for the winemaking industry and could be identified by screening of large number of diffe...

  7. Keratocyte phenotype is enhanced in the absence of attachment to the substratum

    OpenAIRE

    Martha L Funderburgh; Mann, Mary M.; Funderburgh, James L.

    2008-01-01

    Purpose Keratocytes, mesenchymal cells populating the corneal stroma, secrete the unique transparent connective tissue of the cornea as well as opaque scar tissue after injury. Previous studies identified factors mediating keratocyte phenotype in vitro, particularly the expression of the keratan sulfate proteoglycans, which are essential for vision. Whereas earlier work emphasized effects of cytokines, the current study examines the effects of substratum attachment on keratocyte phenotype. Me...

  8. Comparación de dos métodos para identificar los factores asociados al inicio del consumo de cannabis en un estudio de cohortes Comparison of two methods to identify factors associated with the onset of cannabis use in a cohort study

    Directory of Open Access Journals (Sweden)

    Mònica Guxens

    2007-12-01

    Full Text Available Objetivo: Comparar la utilidad de 2 métodos analíticos multivariados, el análisis como casos y controles (CC y como casos y controles anidados (CCa en una cohorte, para identificar los factores asociados al inicio del consumo de cannabis. Métodos: Estudio longitudinal con una muestra de 1.056 alumnos de primer curso de Educación Secundaria Obligatoria (ESO, seguidos anualmente hasta cuarto de ESO. En el análisis como CC se consideraron casos los que declararon, en el cuarto año, haber consumido cannabis y controles los que no habían consumido nunca, estimando modelos de regresión logística (RL. En el análisis como CCa, se compararon los casos de cada año de seguimiento con una muestra aleatoria de controles de riesgo en ese mismo año, estimando modelos de RL condicional. Resultados: En el análisis como CC, se identificaron 6 variables en los chicos y 9 en las chicas en los modelos bivariados, y 3 en los chicos y 4 en las chicas en los multivariados. En el análisis como CCa se obtuvieron 17 variables en los modelos bivariados y 4 en los multivariados, tanto en los chicos como en las chicas. Los estimadores del análisis como CC tenían 1,2 veces más variabilidad. Conclusiones: El análisis como CCa permitió identificar un mayor número de factores asociados al consumo de cannabis y los estimadores fueron más precisos. El CCa puede ser una alternativa más eficiente frente al análisis como CC.Objective: To compare the utility of two multivariate analytic methods, case-control (CC analysis and nested case-control (NCC analysis in a cohort, to identify the factors associated with the onset of cannabis use. Methods: A longitudinal cohort study of a sample of secondary school students (n = 1,056 in the first year of secondary school was carried out. Participating students were followed-up annually until the fourth year of secondary school. In the CC analysis, students in the fourth year who reported having consumed cannabis at some

  9. Transcriptomic Analysis of Phenotypic Changes in Birch (Betula platyphylla Autotetraploids

    Directory of Open Access Journals (Sweden)

    Gui-Feng Liu

    2012-10-01

    Full Text Available Plant breeders have focused much attention on polyploid trees because of their importance to forestry. To evaluate the impact of intraspecies genome duplication on the transcriptome, a series of Betula platyphylla autotetraploids and diploids were generated from four full-sib families. The phenotypes and transcriptomes of these autotetraploid individuals were compared with those of diploid trees. Autotetraploids were generally superior in breast-height diameter, volume, leaf, fruit and stoma and were generally inferior in height compared to diploids. Transcriptome data revealed numerous changes in gene expression attributable to autotetraploidization, which resulted in the upregulation of 7052 unigenes and the downregulation of 3658 unigenes. Pathway analysis revealed that the biosynthesis and signal transduction of indoleacetate (IAA and ethylene were altered after genome duplication, which may have contributed to phenotypic changes. These results shed light on variations in birch autotetraploidization and help identify important genes for the genetic engineering of birch trees.

  10. Mesenchymal stem cell subpopulations: phenotype, property and therapeutic potential.

    Science.gov (United States)

    Mo, Miaohua; Wang, Shan; Zhou, Ying; Li, Hong; Wu, Yaojiong

    2016-09-01

    Mesenchymal stem cells (MSC) are capable of differentiating into cells of multiple cell lineages and have potent paracrine effects. Due to their easy preparation and low immunogenicity, MSC have emerged as an extremely promising therapeutic agent in regenerative medicine for diverse diseases. However, MSC are heterogeneous with respect to phenotype and function in current isolation and cultivation regimes, which often lead to incomparable experimental results. In addition, there may be specific stem cell subpopulations with definite differentiation capacity toward certain lineages in addition to stem cells with multi-differentiation potential. Recent studies have identified several subsets of MSC which exhibit distinct features and biological activities, and enhanced therapeutic potentials for certain diseases. In this review, we give an overview of these subsets for their phenotypic, biological and functional properties. PMID:27141940

  11. Jagged 1 Rescues the Duchenne Muscular Dystrophy Phenotype.

    Science.gov (United States)

    Vieira, Natassia M; Elvers, Ingegerd; Alexander, Matthew S; Moreira, Yuri B; Eran, Alal; Gomes, Juliana P; Marshall, Jamie L; Karlsson, Elinor K; Verjovski-Almeida, Sergio; Lindblad-Toh, Kerstin; Kunkel, Louis M; Zatz, Mayana

    2015-11-19

    Duchenne muscular dystrophy (DMD), caused by mutations at the dystrophin gene, is the most common form of muscular dystrophy. There is no cure for DMD and current therapeutic approaches to restore dystrophin expression are only partially effective. The absence of dystrophin in muscle results in dysregulation of signaling pathways, which could be targets for disease therapy and drug discovery. Previously, we identified two exceptional Golden Retriever muscular dystrophy (GRMD) dogs that are mildly affected, have functional muscle, and normal lifespan despite the complete absence of dystrophin. Now, our data on linkage, whole-genome sequencing, and transcriptome analyses of these dogs compared to severely affected GRMD and control animals reveals that increased expression of Jagged1 gene, a known regulator of the Notch signaling pathway, is a hallmark of the mild phenotype. Functional analyses demonstrate that Jagged1 overexpression ameliorates the dystrophic phenotype, suggesting that Jagged1 may represent a target for DMD therapy in a dystrophin-independent manner. PAPERCLIP. PMID:26582133

  12. Genetic association analysis of complex diseases incorporating intermediate phenotype information.

    Directory of Open Access Journals (Sweden)

    Yafang Li

    Full Text Available Genetic researchers often collect disease related quantitative traits in addition to disease status because they are interested in understanding the pathophysiology of disease processes. In genome-wide association (GWA studies, these quantitative phenotypes may be relevant to disease development and serve as intermediate phenotypes or they could be behavioral or other risk factors that predict disease risk. Statistical tests combining both disease status and quantitative risk factors should be more powerful than case-control studies, as the former incorporates more information about the disease. In this paper, we proposed a modified inverse-variance weighted meta-analysis method to combine disease status and quantitative intermediate phenotype information. The simulation results showed that when an intermediate phenotype was available, the inverse-variance weighted method had more power than did a case-control study of complex diseases, especially in identifying susceptibility loci having minor effects. We further applied this modified meta-analysis to a study of imputed lung cancer genotypes with smoking data in 1154 cases and 1137 matched controls. The most significant SNPs came from the CHRNA3-CHRNA5-CHRNB4 region on chromosome 15q24-25.1, which has been replicated in many other studies. Our results confirm that this CHRNA region is associated with both lung cancer development and smoking behavior. We also detected three significant SNPs--rs1800469, rs1982072, and rs2241714--in the promoter region of the TGFB1 gene on chromosome 19 (p = 1.46×10(-5, 1.18×10(-5, and 6.57×10(-6, respectively. The SNP rs1800469 is reported to be associated with chronic obstructive pulmonary disease and lung cancer in cigarette smokers. The present study is the first GWA study to replicate this result. Signals in the 3q26 region were also identified in the meta-analysis. We demonstrate the intermediate phenotype can potentially enhance the power of complex

  13. Identification of campylobacteria isolated from Danish broilers by phenotypic tests and species-specific PCR assays

    DEFF Research Database (Denmark)

    Wainø, M.; Bang, Dang Duong; Lund, Marianne;

    2003-01-01

    Aims: To validate a phenotypic Campylobacter species identification method employed to identify campylobacters in broilers by comparison with campylobacterial species identification using various species-specific PCR analyses. Methods and Results: From a collection of 2733 phenotypically identified...... campylobacterial cultures, 108 Campylobacter jejuni cultures and 351 campylobacterial cultures other than Camp. jejuni were subjected to various species-specific PCR assays. On the basis of the genotypic tests, it was demonstrated that Camp. jejuni and Camp. coli constituted approx. 99% of all cultures, while...... other species identified were Helicobacter pullorum, Camp. lari and Camp. upsaliensis. However, 29% of the 309 Camp. coli cultures identified by phenotypic tests were hippurate-variable or negative Camp. jejuni cultures, whereas some Camp. lari cultures and unspeciated campylobacter cultures belonged to...

  14. Evolution and diversity of the mechanisms endowing resistance to herbicides inhibiting acetolactate-synthase (ALS) in corn poppy (Papaver rhoeas L.).

    Science.gov (United States)

    Délye, Christophe; Pernin, Fanny; Scarabel, Laura

    2011-02-01

    We investigated the diversity of mechanisms conferring resistance to herbicides inhibiting acetolactate synthase (ALS) in corn poppy (Papaver rhoeas L.) and the processes underlying the selection for resistance. Six mutant ALS alleles, Arg₁₉₇, His₁₉₇, Leu₁₉₇, Ser₁₉₇, Thr₁₉₇ and Leu₅₇₄ were identified in five Italian populations. Different alleles were found in a same population or a same plant. Comparison of individual plant phenotype (herbicide sensitivity) and genotype (amino-acid substitution(s) at codon 197) showed that all mutant ALS alleles conferred dominant resistance to the field rate of the sulfonylurea tribenuron and moderate or no resistance to the field rate of the triazolopyrimidine florasulam. Depending on the allele, dominant or partially dominant resistance to the field rate of the imidazolinone imazamox was observed. Putative non-target-site resistance mechanisms were also likely present in the populations investigated. The derived Cleaved Amplified Polymorphic Sequence assays targeting ALS codons crucial for herbicide sensitivity developed in this work will facilitate the detection of resistance due to mutant ALS alleles. Nucleotide variation around codon 197 indicated that mutant ALS alleles evolved by multiple, independent appearances. Resistance to ALS inhibitors in P. rhoeas clearly evolved by redundant evolution of a set of mutant ALS alleles and likely of non-target-site mechanisms. PMID:21421378

  15. The use of whole-exome sequencing to disentangle complex phenotypes.

    Science.gov (United States)

    Williams, Hywel J; Hurst, John R; Ocaka, Louise; James, Chela; Pao, Caroline; Chanudet, Estelle; Lescai, Francesco; Stanescu, Horia C; Kleta, Robert; Rosser, Elisabeth; Bacchelli, Chiara; Beales, Philip

    2016-02-01

    The success of whole-exome sequencing to identify mutations causing single-gene disorders has been well documented. In contrast whole-exome sequencing has so far had limited success in the identification of variants causing more complex phenotypes that seem unlikely to be due to the disruption of a single gene. We describe a family where two male offspring of healthy first cousin parents present a complex phenotype consisting of peripheral neuropathy and bronchiectasis that has not been described previously in the literature. Due to the fact that both children had the same problems in the context of parental consanguinity we hypothesised illness resulted from either X-linked or autosomal recessive inheritance. Through the use of whole-exome sequencing we were able to simplify this complex phenotype and identified a causative mutation (p.R1070*) in the gene periaxin (PRX), a gene previously shown to cause peripheral neuropathy (Dejerine-Sottas syndrome) when this mutation is present. For the bronchiectasis phenotype we were unable to identify a causal single mutation or compound heterozygote, reflecting the heterogeneous nature of this phenotype. In conclusion, in this study we show that whole-exome sequencing has the power to disentangle complex phenotypes through the identification of causative genetic mutations for distinct clinical disorders that were previously masked. PMID:26059842

  16. Cluster analysis in severe emphysema subjects using phenotype and genotype data: an exploratory investigation

    Directory of Open Access Journals (Sweden)

    Martinez Fernando J

    2010-03-01

    Full Text Available Abstract Background Numerous studies have demonstrated associations between genetic markers and COPD, but results have been inconsistent. One reason may be heterogeneity in disease definition. Unsupervised learning approaches may assist in understanding disease heterogeneity. Methods We selected 31 phenotypic variables and 12 SNPs from five candidate genes in 308 subjects in the National Emphysema Treatment Trial (NETT Genetics Ancillary Study cohort. We used factor analysis to select a subset of phenotypic variables, and then used cluster analysis to identify subtypes of severe emphysema. We examined the phenotypic and genotypic characteristics of each cluster. Results We identified six factors accounting for 75% of the shared variability among our initial phenotypic variables. We selected four phenotypic variables from these factors for cluster analysis: 1 post-bronchodilator FEV1 percent predicted, 2 percent bronchodilator responsiveness, and quantitative CT measurements of 3 apical emphysema and 4 airway wall thickness. K-means cluster analysis revealed four clusters, though separation between clusters was modest: 1 emphysema predominant, 2 bronchodilator responsive, with higher FEV1; 3 discordant, with a lower FEV1 despite less severe emphysema and lower airway wall thickness, and 4 airway predominant. Of the genotypes examined, membership in cluster 1 (emphysema-predominant was associated with TGFB1 SNP rs1800470. Conclusions Cluster analysis may identify meaningful disease subtypes and/or groups of related phenotypic variables even in a highly selected group of severe emphysema subjects, and may be useful for genetic association studies.

  17. PHENOTYPIC TRAITS IN ZAGORJE TURKEY

    Directory of Open Access Journals (Sweden)

    Z. Janječić

    2007-06-01

    Full Text Available Production of turkeys in the region of Hrvatsko zagorje began in second half of 16th century, when there was a little influence of other turkey breeds from other region. Recently, interest for protection and preservation of autochthonous poultry breeds in Croatia is growing and in that sense this investigation was set to determine the phenotypic traits of Zagorje turkey. One hundred 10-month old turkeys (5 males and 20 females of four strains (bronze, black, grey and pale were measured, while egg production data were collected by a poll among the breeders. Average body weight of bronze, black, grey and pale strain males were 7.08, 6.88, 6.10 and 6.09 kg, respectively, while in females the average values were 4.02, 4.07, 3.63, and 3.68 kg. Generally, according to body measures of male birds, other than body weight, of all of the strains of Zagorje turkey, the black one is the biggest, as it had the highest values for body length, length of sternum, length of drumstick, length of shank, depth of chest and head measures. At the same time, the bronze strain had the highest value for carcass width. Body measures mentioned previously were not so different in females. Number of reared chicks was lowest in the pale strain. From the body measures assessed it is possible to conclude that Zagorje turkeys are rather uniform within the strain but differences in most of the breed traits are present between the strains, especially in males of bronze and black strain, when compared to gray and pale strain.

  18. Metabolomic phenotyping of a cloned pig model

    Directory of Open Access Journals (Sweden)

    Callesen Henrik

    2011-08-01

    Full Text Available Abstract Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal outbred pigs. Results The metabolic phenotype of cloned pigs (n = 5 was for the first time elucidated by nuclear magnetic resonance (NMR-based metabolomic analysis of multiple bio-fluids including plasma, bile and urine. The metabolic phenotype of the cloned pigs was compared with normal outbred pigs (n = 6 by multivariate data analysis, which revealed differences in the metabolic phenotypes. Plasma lactate was higher for cloned vs control pigs, while multiple metabolites were altered in the bile. However a lower inter-individual variability for cloned pigs compared with control pigs could not be established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals.

  19. Efficient α, β-motif finder for identification of phenotype-related functional modules

    Directory of Open Access Journals (Sweden)

    Schmidt Matthew C

    2011-11-01

    Full Text Available Abstract Background Microbial communities in their natural environments exhibit phenotypes that can directly cause particular diseases, convert biomass or wastewater to energy, or degrade various environmental contaminants. Understanding how these communities realize specific phenotypic traits (e.g., carbon fixation, hydrogen production is critical for addressing health, bioremediation, or bioenergy problems. Results In this paper, we describe a graph-theoretical method for in silico prediction of the cellular subsystems that are related to the expression of a target phenotype. The proposed (α, β-motif finder approach allows for identification of these phenotype-related subsystems that, in addition to metabolic subsystems, could include their regulators, sensors, transporters, and even uncharacterized proteins. By comparing dozens of genome-scale networks of functionally associated proteins, our method efficiently identifies those statistically significant functional modules that are in at least α networks of phenotype-expressing organisms but appear in no more than β networks of organisms that do not exhibit the target phenotype. It has been shown via various experiments that the enumerated modules are indeed related to phenotype-expression when tested with different target phenotypes like hydrogen production, motility, aerobic respiration, and acid-tolerance. Conclusion Thus, we have proposed a methodology that can identify potential statistically significant phenotype-related functional modules. The functional module is modeled as an (α, β-clique, where α and β are two criteria introduced in this work. We also propose a novel network model, called the two-typed, divided network. The new network model and the criteria make the problem tractable even while very large networks are being compared. The code can be downloaded from http://www.freescience.org/cs/ABClique/

  20. Dimensional Structure of the Autism Phenotype: Relations between Early Development and Current Presentation

    Science.gov (United States)

    Kamp-Becker, Inge; Ghahreman, Mardjan; Smidt, Judith; Remschmidt, Helmut

    2009-01-01

    The dimensional structure of higher functioning autism phenotype was investigated by factor analysis. The goal of this study was to identify the degree to which early symptoms of autism (measured using the ADI-R) could be predictive of the current symptoms of autism as identified using the ADOS, the adaptive behavior scales, IQ scores and theory…

  1. CD4 T-helper cell cytokine phenotypes and antibody response following tetanus toxoid booster immunization

    Science.gov (United States)

    Routine methods for enumerating antigen-specific T-helper cells may not identify low-frequency phenotypes such as Th2 cells. We compared methods of evaluating such responses to identify tetanus toxoid- (TT) specific Th1, Th2, Th17 and IL10+ cells. Eight healthy subjects were given a TT booster vacci...

  2. Increased entropy of signal transduction in the cancer metastasis phenotype

    Directory of Open Access Journals (Sweden)

    Teschendorff Andrew E

    2010-07-01

    Full Text Available Abstract Background The statistical study of biological networks has led to important novel biological insights, such as the presence of hubs and hierarchical modularity. There is also a growing interest in studying the statistical properties of networks in the context of cancer genomics. However, relatively little is known as to what network features differ between the cancer and normal cell physiologies, or between different cancer cell phenotypes. Results Based on the observation that frequent genomic alterations underlie a more aggressive cancer phenotype, we asked if such an effect could be detectable as an increase in the randomness of local gene expression patterns. Using a breast cancer gene expression data set and a model network of protein interactions we derive constrained weighted networks defined by a stochastic information flux matrix reflecting expression correlations between interacting proteins. Based on this stochastic matrix we propose and compute an entropy measure that quantifies the degree of randomness in the local pattern of information flux around single genes. By comparing the local entropies in the non-metastatic versus metastatic breast cancer networks, we here show that breast cancers that metastasize are characterised by a small yet significant increase in the degree of randomness of local expression patterns. We validate this result in three additional breast cancer expression data sets and demonstrate that local entropy better characterises the metastatic phenotype than other non-entropy based measures. We show that increases in entropy can be used to identify genes and signalling pathways implicated in breast cancer metastasis and provide examples of de-novo discoveries of gene modules with known roles in apoptosis, immune-mediated tumour suppression, cell-cycle and tumour invasion. Importantly, we also identify a novel gene module within the insulin growth factor signalling pathway, alteration of which may

  3. Identifiability in stochastic models

    CERN Document Server

    1992-01-01

    The problem of identifiability is basic to all statistical methods and data analysis, occurring in such diverse areas as Reliability Theory, Survival Analysis, and Econometrics, where stochastic modeling is widely used. Mathematics dealing with identifiability per se is closely related to the so-called branch of ""characterization problems"" in Probability Theory. This book brings together relevant material on identifiability as it occurs in these diverse fields.

  4. Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4 phenotype

    Directory of Open Access Journals (Sweden)

    Fernandez Bridget A

    2012-11-01

    Full Text Available Abstract Background Severe congenital neutropenia type 4 (SCN4 is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3. Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4 is caused by autosomal recessive mutations in SLC45A2. Methods We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. Results The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. Conclusions This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

  5. Phenotypic heterogeneity in hidradenitis suppurativa (acne inversa): classification is an essential step toward personalized therapy.

    Science.gov (United States)

    Ingram, John R; Piguet, Vincent

    2013-06-01

    Awareness is increasing that there is phenotypic heterogeneity within the hidradenitis suppurativa (HS) disease spectrum. However, the few randomized HS trials that are available have not distinguished between the subtypes of the disease. In this issue, Canoui-Poitrine et al. used latent class (LC) analysis of the largest HS cohort described to date to generate three phenotypic subtypes. LC 1 correlates with "typical" European HS, mainly involving the axilla, groin, and, in women, the inframammary region. "Atypical" HS, which may be linked to γ-secretase gene mutations, was subdivided further into LC2 and LC3 subtypes. PMID:23673498

  6. Computational models for prediction of yeast strain potential for winemaking from phenotypic profiles.

    Directory of Open Access Journals (Sweden)

    Inês Mendes

    Full Text Available Saccharomyces cerevisiae strains from diverse natural habitats harbour a vast amount of phenotypic diversity, driven by interactions between yeast and the respective environment. In grape juice fermentations, strains are exposed to a wide array of biotic and abiotic stressors, which may lead to strain selection and generate naturally arising strain diversity. Certain phenotypes are of particular interest for the winemaking industry and could be identified by screening of large number of different strains. The objective of the present work was to use data mining approaches to identify those phenotypic tests that are most useful to predict a strain's potential for winemaking. We have constituted a S. cerevisiae collection comprising 172 strains of worldwide geographical origins or technological applications. Their phenotype was screened by considering 30 physiological traits that are important from an oenological point of view. Growth in the presence of potassium bisulphite, growth at 40 °C, and resistance to ethanol were mostly contributing to strain variability, as shown by the principal component analysis. In the hierarchical clustering of phenotypic profiles the strains isolated from the same wines and vineyards were scattered throughout all clusters, whereas commercial winemaking strains tended to co-cluster. Mann-Whitney test revealed significant associations between phenotypic results and strain's technological application or origin. Naïve Bayesian classifier identified 3 of the 30 phenotypic tests of growth in iprodion (0.05 mg/mL, cycloheximide (0.1 µg/mL and potassium bisulphite (150 mg/mL that provided most information for the assignment of a strain to the group of commercial strains. The probability of a strain to be assigned to this group was 27% using the entire phenotypic profile and increased to 95%, when only results from the three tests were considered. Results show the usefulness of computational approaches to simplify strain

  7. Computational models for prediction of yeast strain potential for winemaking from phenotypic profiles.

    Science.gov (United States)

    Mendes, Inês; Franco-Duarte, Ricardo; Umek, Lan; Fonseca, Elza; Drumonde-Neves, João; Dequin, Sylvie; Zupan, Blaz; Schuller, Dorit

    2013-01-01

    Saccharomyces cerevisiae strains from diverse natural habitats harbour a vast amount of phenotypic diversity, driven by interactions between yeast and the respective environment. In grape juice fermentations, strains are exposed to a wide array of biotic and abiotic stressors, which may lead to strain selection and generate naturally arising strain diversity. Certain phenotypes are of particular interest for the winemaking industry and could be identified by screening of large number of different strains. The objective of the present work was to use data mining approaches to identify those phenotypic tests that are most useful to predict a strain's potential for winemaking. We have constituted a S. cerevisiae collection comprising 172 strains of worldwide geographical origins or technological applications. Their phenotype was screened by considering 30 physiological traits that are important from an oenological point of view. Growth in the presence of potassium bisulphite, growth at 40 °C, and resistance to ethanol were mostly contributing to strain variability, as shown by the principal component analysis. In the hierarchical clustering of phenotypic profiles the strains isolated from the same wines and vineyards were scattered throughout all clusters, whereas commercial winemaking strains tended to co-cluster. Mann-Whitney test revealed significant associations between phenotypic results and strain's technological application or origin. Naïve Bayesian classifier identified 3 of the 30 phenotypic tests of growth in iprodion (0.05 mg/mL), cycloheximide (0.1 µg/mL) and potassium bisulphite (150 mg/mL) that provided most information for the assignment of a strain to the group of commercial strains. The probability of a strain to be assigned to this group was 27% using the entire phenotypic profile and increased to 95%, when only results from the three tests were considered. Results show the usefulness of computational approaches to simplify strain selection

  8. Diagnostic tools to identify black Aspergilli

    DEFF Research Database (Denmark)

    Samson, Robert A.; Noonim, P.; Meijer, M.; Houbraken, J.; Frisvad, Jens Christian; Varga, J.

    2007-01-01

    The present taxonomy of the black aspergilli reveals that there are 19 accepted taxa. However the identification of species of Aspergillus section Nigri is often problematic in spite of the existence of numerous methods proposed. An overview is provided of phenotypic and molecular methods to...... identify the accepted species of the black aspergilli. Colony morphology, conidial size and ornamentation of the ex type cultures is presented in a pictorial overview. The temperature range of all species is given and their growth characteristics on creatine agar and boscalid agar, a medium which was...... evaluation of the usefulness of various techniques and genomic loci for species identification of black aspergilli is presented....

  9. The Role of Anti-Müllerian Hormone in the Characterization of the Different Polycystic Ovary Syndrome Phenotypes.

    Science.gov (United States)

    Romualdi, Daniela; Di Florio, C; Tagliaferri, V; De Cicco, S; Gagliano, D; Immediata, V; Lanzone, A; Guido, M

    2016-05-01

    Rotterdam criteria identified 4 polycystic ovary syndrome (PCOS) phenotypes based on the combination of anovulation (ANOV), hyperandrogenism (HA), and polycystic ovaries (PCOs): phenotype 1 (ANOV + HA + PCO), phenotype 2 (ANOV + HA), phenotype 3 (HA + PCO), and phenotype 4 (ANOV + PCO). Anti-Müllerian hormone (AMH) was suggested to play a pathophysiologic and diagnostic role in this syndrome. The aim of this study was to compare AMH levels among the different phenotypes in relation to clinical, endocrine, and metabolic features. We enrolled 117 women with PCOS (body mass index: 25.89 ± 6.20 kg/m(2), age range: 18-37 years) and 24 controls. Anthropometric characteristics, hirsutism score, ultrasound ovarian features, and hormonal parameters, including AMH, were evaluated. Each participant also underwent an oral glucose tolerance test and an euglycemic-hyperinsulinemic clamp. The prevalence of phenotypes 1 to 4 was 62.4%, 8.6%, 11.1%, and 17.9%, respectively. Body mass index and insulin resistance indexes were similar among the groups. Phenotype 1 showed the highest luteinizing hormone, androgens levels, ovarian volume, and AMH concentrations (9.27 ± 8.17 ng/mL,P< .05) versus phenotype 2 and controls. Phenotype 2 women were hirsute, showed an intermediate free androgen index value, low ovarian volume, and low AMH levels (4.05 ± 4.12 ng/mL). Phenotype 3 showed an intermediate state of HA and slightly augmented AMH levels (5.87 ± 4.35 ng/mL). The clinical and endocrine characteristics of phenotype 4 resembled those of controls, except for higher ovarian volume and AMH levels (7.62 ± 3.85 ng/mL;P< .05). Our results highlight the heterogeneity of the association between increased AMH levels, menstrual dysfunction, and HA in the different PCOS phenotypes, thus offering a key to an understanding of the current controversy on the value of AMH measurement in PCOS. PMID:26718304

  10. Metabolomic phenotyping of a cloned pig model

    DEFF Research Database (Denmark)

    Clausen, Morten Rahr; Christensen, Kirstine Lykke; Hedemann, Mette Skou;

    2011-01-01

    Background Pigs are widely used as models for human physiological changes in intervention studies, because of the close resemblance between human and porcine physiology and the high degree of experimental control when using an animal model. Cloned animals have, in principle, identical genotypes and...... established. Conclusions From the present study we conclude that cloned and normal outbred pigs are phenotypically different. However, it cannot be concluded that the use of cloned animals will reduce the inter-individual variation in intervention studies, though this is based on a limited number of animals....... possibly also phenotypes and this offer an extra level of experimental control which could possibly make them a desirable tool for intervention studies. Therefore, in the present study, we address how phenotype and phenotypic variation is affected by cloning, through comparison of cloned pigs and normal...

  11. Phenotypic profiles of Armenian grape cultivars

    Directory of Open Access Journals (Sweden)

    Aroutiounian Rouben

    2015-01-01

    Full Text Available The conservation and sustainable use of grapevine biodiversity in Armenia is particularly important due to the large number of traditional local varieties. Being partially different from European grapevine gene pool, the material of Armenian local cultivars significantly contributes to the understanding of the genetic variation and is valuable source for target selection. During last years many Armenian grapevine cultivars have been already described and their genotypes determined, but some local varieties and wild accessions remain unidentified and their phenotypic characteristics overlooked. The comprehensive analysis of phenotypes is essential for research, including genetic association studies, cultivar evaluation and selection. The goal of our research was the phenotyping on the base of reproductive, carpological and analytical characteristics of 80 Armenian aboriginal and new grape cultivars. Description of phenotypic profiles is important step towards identification and conservation of genetic resources of Armenian grapes. In future, these data can be applied for breeding of improved grape varieties targeted to fresh consumption and wine production.

  12. Mining skeletal phenotype descriptions from scientific literature.

    Directory of Open Access Journals (Sweden)

    Tudor Groza

    Full Text Available Phenotype descriptions are important for our understanding of genetics, as they enable the computation and analysis of a varied range of issues related to the genetic and developmental bases of correlated characters. The literature contains a wealth of such phenotype descriptions, usually reported as free-text entries, similar to typical clinical summaries. In this paper, we focus on creating and making available an annotated corpus of skeletal phenotype descriptions. In addition, we present and evaluate a hybrid Machine Learning approach for mining phenotype descriptions from free text. Our hybrid approach uses an ensemble of four classifiers and experiments with several aggregation techniques. The best scoring technique achieves an F-1 score of 71.52%, which is close to the state-of-the-art in other domains, where training data exists in abundance. Finally, we discuss the influence of the features chosen for the model on the overall performance of the method.

  13. Investigating the contribution of VAPB/ALS8 loss of function in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Kabashi, Edor; El Oussini, Hajer; Bercier, Valérie; Gros-Louis, François; Valdmanis, Paul N; McDearmid, Jonathan; Mejier, Inge A; Dion, Patrick A; Dupre, Nicolas; Hollinger, David; Sinniger, Jérome; Dirrig-Grosch, Sylvie; Camu, William; Meininger, Vincent; Loeffler, Jean-Philippe; René, Frédérique; Drapeau, Pierre; Rouleau, Guy A; Dupuis, Luc

    2013-06-15

    The mutations P56S and T46I in the gene encoding vesicle-associated membrane protein-associated protein B/C (VAPB) cause ALS8, a familial form of amyotrophic lateral sclerosis (ALS). Overexpression of mutant forms of VAPB leads to cytosolic aggregates, suggesting a gain of function of the mutant protein. However, recent work suggested that the loss of VAPB function could be the major mechanism leading to ALS8. Here, we used multiple genetic and experimental approaches to study whether VAPB loss of function might be sufficient to trigger motor neuron degeneration. In order to identify additional ALS-associated VAPB mutations, we screened the entire VAPB gene in a cohort of ALS patients and detected two mutations (A145V and S160Δ). To directly address the contribution of VAPB loss of function in ALS, we generated zebrafish and mouse models with either a decreased or a complete loss of Vapb expression. Vapb knockdown in zebrafish led to swimming deficits. Mice knocked-out for Vapb showed mild motor deficits after 18 months of age yet had innervated neuromuscular junctions (NMJs). Importantly, overexpression of VAPB mutations were unable to rescue the motor deficit caused by Vapb knockdown in zebrafish and failed to cause a toxic gain-of-function defect on their own. Thus, Vapb loss of function weakens the motor system of vertebrate animal models but is on its own unable to lead to a complete ALS phenotype. Our findings are consistent with the notion that VAPB mutations constitute a risk factor for motor neuron disease through a loss of VAPB function. PMID:23446633

  14. Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring.

    Science.gov (United States)

    Paděrová, J; Holubová, A; Simandlová, M; Puchmajerová, A; Vlčková, M; Malíková, M; Pourová, R; Vejvalková, S; Havlovicová, M; Šenkeříková, M; Ptáková, N; Drábová, J; Geryk, J; Maver, A; Křepelová, A; Macek, M

    2016-09-01

    Kabuki syndrome (KS) is a dominantly inherited disorder mainly due to de novo pathogenic variation in KMT2D or KDM6A genes. Initially, a representative cohort of 14 Czech cases with clinical features suggestive of KS was analyzed by experienced clinical geneticists in collaboration with other specialties, and observed disease features were evaluated according to the 'MLL2-Kabuki score' defined by Makrythanasis et al. Subsequently, the aforementioned genes were Sanger sequenced and copy number variation analysis was performed by MLPA, followed by genome-wide array CGH testing. Pathogenic variants in KMT2D resulting in protein truncation in 43% (6/14; of which 3 are novel) of all cases were detected, while analysis of KDM6A was negative. MLPA analysis was negative in all instances. One female patient bears a 6.6 Mb duplication of the Xp21.2-Xp21.3 region that is probably disease causing. Subjective KS phenotyping identified predictive clinical features associated with the presence of a pathogenic variant in KMT2D. We provide additional evidence that this scoring approach fosters prioritization of patients prior to KMT2D sequencing. We conclude that KMT2D sequencing followed by array CGH is a diagnostic strategy with the highest diagnostic yield. PMID:26841933

  15. Emergent properties of gene evolution: Species as attractors in phenotypic space

    Science.gov (United States)

    Reuveni, Eli; Giuliani, Alessandro

    2012-02-01

    The question how the observed discrete character of the phenotype emerges from a continuous genetic distance metrics is the core argument of two contrasted evolutionary theories: punctuated equilibrium (stable evolution scattered with saltations in the phenotype) and phyletic gradualism (smooth and linear evolution of the phenotype). Identifying phenotypic saltation on the molecular levels is critical to support the first model of evolution. We have used DNA sequences of ∼1300 genes from 6 isolated populations of the budding yeast Saccharomyces cerevisiae. We demonstrate that while the equivalent measure of the genetic distance show a continuum between lineage distance with no evidence of discrete states, the phenotypic space illustrates only two (discrete) possible states that can be associated with a saltation of the species phenotype. The fact that such saltation spans large fraction of the genome and follows by continuous genetic distance is a proof of the concept that the genotype-phenotype relation is not univocal and may have severe implication when looking for disease related genes and mutations. We used this finding with analogy to attractor-like dynamics and show that punctuated equilibrium could be explained in the framework of non-linear dynamics systems.

  16. Comparison of phenotypic and molecular tests to identify lactic acid bacteria

    OpenAIRE

    Paula Mendonça Moraes; Luana Martins Perin; Abelardo Silva Júnior; Luís Augusto Nero

    2013-01-01

    Twenty-nine lactic acid bacteria (LAB) isolates were submitted for identification using Biolog, API50CHL, 16S rDNA sequencing, and species-specific PCR reactions. The identification results were compared, and it was concluded that a polyphasic approach is necessary for proper LAB identification, being the molecular analyzes the most reliable.

  17. High Content Phenotypic Screenings to Identify Inhibitors of Candida albicans Biofilm Formation and Filamentation

    OpenAIRE

    Pierce, Christopher G.; Saville, Stephen P.; Lopez-Ribot, Jose L.

    2014-01-01

    Candida species represent the main cause of opportunistic fungal infections worldwide, and Candida albicans remains the most common etiological agent of candidiasis, now the third to fourth most common nosocomial infection. These infections are typically associated with high morbidity and mortality, mainly due to the limited efficacy of current antifungal drugs. In C. albicans morphogenetic conversions between yeast and filamentous forms and biofilm formation represent two important biologica...

  18. GEE for GWAS using Longitudinal Phenotype Data

    OpenAIRE

    Sitlani, Colleen M.; Rice, Kenneth M.; Lumley, Thomas; McKnight, Barbara; Cupples, L. Adrienne; Avery, Christy L; Noordam, Raymond; Stricker, Bruno H. C.; Whitsel, Eric A.; Psaty, Bruce M.

    2014-01-01

    Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here we discuss one such method – generalized estimating equations...

  19. Next Generation Sequencing Demands Next Generation Phenotyping

    OpenAIRE

    Hennekam, Raoul CM; Biesecker, Leslie G

    2012-01-01

    Next-Generation Sequencing (NGS) is the most powerful diagnostic tool since the roentgenogram. NGS will facilitate diagnosis on a massive scale –allowing interrogation of all genes in a single assay. It has been suggested that NGS will decrease the need for phenotyping in general, and medical geneticists in particular. We argue that NGS will shift focus and approach of phenotyping. We predict that NGS performed for diagnostic purposes will yield variants in several genes, and consequences of ...

  20. Phenotyping of robustness and milk quality

    OpenAIRE

    Berry, D. P.; Mcparland, S.; Bastin, Catherine; Wall, E.; Gengler, Nicolas; Soyeurt, Hélène

    2013-01-01

    A phenotype describes the outcome of the interacting development between the genotype of an individual and its specific environment throughout life. Animal breeding currently exploits large data sets of phenotypic and pedigree information to estimate the genetic merit of animals. Here we describe rapid, low-cost phenomic tools for dairy cattle. We give particular emphasis to infrared spectroscopy of milk because the necessary spectral data are already routinely available on milk samples from ...

  1. Phenotypic spandrel: absolute discrimination and ligand antagonism

    OpenAIRE

    François, Paul; Johnson, Kyle A.; Saunders, Laura N.

    2015-01-01

    We consider the general problem of absolute discrimination between categories of ligands irrespective of their concentration. An instance of this problem is immune discrimination between self and not-self. We connect this problem to biochemical adaptation, and establish that ligand antagonism - the ability of sub threshold ligands to negatively impact response - is a necessary consequence of absolute discrimination.Thus antagonism constitutes a "phenotypic spandrel": a phenotype existing as a...

  2. Important discoveries from analysing bacterial phenotypes

    OpenAIRE

    Bochner, Barry R.; Giovannetti, Luciana; Viti, Carlo

    2008-01-01

    The ability to test hundreds to thousands of cellular phenotypes in a single experiment has opened up new avenues of investigation and exploration and led to important discoveries in very diverse applications of microbiological research and development. The information provided by global phenotyping is complementary to, and often more easily interpretable than information provided by global molecular analytical methods such as gene chips and proteomics. This report summarizes advances present...

  3. Bacteria under SOS evolve anticancer phenotypes

    OpenAIRE

    Weitao Tao; Dallo Shatha F

    2010-01-01

    Abstract Background The anticancer drugs, such as DNA replication inhibitors, stimulate bacterial adhesion and induce the bacterial SOS response. As a variety of bacterial mutants can be generated during SOS, novel phenotypes are likely to be selected under the drug pressure. Presentation of the hypothesis Bacteria growing with cancer cells in the presence of the replication inhibitors undergo the SOS response and evolve advantageous phenotypes for the bacteria to invade the cancer cells in o...

  4. A Regulatory RNA Inducing Transgenerationally Inherited Phenotypes

    DEFF Research Database (Denmark)

    Jensen, Lea Møller

    variation in Arabidopsis enables different regulatory networks and mechanisms to shape the phenotypic characteristics. The thesis describes the identification of regulatory RNA encoded by an enzyme encoding gene. The RNA regulates by inducing transgenerationally inherited phenotypes. The function of the RNA...... is dependent on the genetic background illustrating that polymorphisms are found in either interactors or target genes of the RNA. Furthermore, the RNA provides a mechanistic link between accumulation of glucosinolate and onset of flowering....

  5. Phenex: Ontological Annotation of Phenotypic Diversity

    OpenAIRE

    Balhoff, James P.; Dahdul, Wasila M; Kothari, Cartik R.; Lapp, Hilmar; John G. Lundberg; Mabee, Paula; Midford, Peter E.; Westerfield, Monte; Vision, Todd J

    2010-01-01

    Background Phenotypic differences among species have long been systematically itemized and described by biologists in the process of investigating phylogenetic relationships and trait evolution. Traditionally, these descriptions have been expressed in natural language within the context of individual journal publications or monographs. As such, this rich store of phenotype data has been largely unavailable for statistical and computational comparisons across studies or integration with other ...

  6. SATB2-associated syndrome presenting with Rett-like phenotypes.

    Science.gov (United States)

    Lee, J S; Yoo, Y; Lim, B C; Kim, K J; Choi, M; Chae, J-H

    2016-06-01

    The SATB2-associated syndrome (SAS) was proposed recently, after the SATB2 gene was initially discovered to be associated with isolated cleft palate. This syndrome is characterized by intellectual disability with delayed speech development, facial dysmorphism, cleft or high-arched palate, and dentition problems. Here, we describe two novel SATB2 sequence variants in two unrelated patients presenting with Rett-like phenotypes. We performed trio-based whole-exome sequencing in a 17-month-old girl presenting with severe retardation and Rett-like phenotypes, which revealed a de novo missense variant in SATB2 (p.Glu396Gln). Moreover, targeted sequencing of the SATB2 gene was performed in a 2-year-old girl with severe psychomotor retardation, facial hypotonia, and cleft palate who also exhibited some features of Rett syndrome. A nonsense variant in SATB2 was identified in this patient (p.Arg459*). This study expanded the clinical and genetic spectrum of SAS. SATB2 variants should be considered in cases with psychomotor retardation alone or in any cases with Rett-like phenotypes, regardless of the typical features of SAS such as cleft palate. PMID:26596517

  7. Phenotypic Evolution With and Beyond Genome Evolution.

    Science.gov (United States)

    Félix, M-A

    2016-01-01

    DNA does not make phenotypes on its own. In this volume entitled "Genes and Phenotypic Evolution," the present review draws the attention on the process of phenotype construction-including development of multicellular organisms-and the multiple interactions and feedbacks between DNA, organism, and environment at various levels and timescales in the evolutionary process. First, during the construction of an individual's phenotype, DNA is recruited as a template for building blocks within the cellular context and may in addition be involved in dynamical feedback loops that depend on the environmental and organismal context. Second, in the production of phenotypic variation among individuals, stochastic, environmental, genetic, and parental sources of variation act jointly. While in controlled laboratory settings, various genetic and environmental factors can be tested one at a time or in various combinations, they cannot be separated in natural populations because the environment is not controlled and the genotype can rarely be replicated. Third, along generations, genotype and environment each have specific properties concerning the origin of their variation, the hereditary transmission of this variation, and the evolutionary feedbacks. Natural selection acts as a feedback from phenotype and environment to genotype. This review integrates recent results and concrete examples that illustrate these three points. Although some themes are shared with recent calls and claims to a new conceptual framework in evolutionary biology, the viewpoint presented here only means to add flesh to the standard evolutionary synthesis. PMID:27282029

  8. The International Mouse Phenotyping Consortium: past and future perspectives on mouse phenotyping

    OpenAIRE

    Steve D M Brown; Moore, Mark W.

    2012-01-01

    Determining the function of all mammalian genes remains a major challenge for the biomedical science community in the 21st century. The goal of the International Mouse Phenotyping Consortium (IMPC) over the next 10 years is to undertake broad-based phenotyping of 20,000 mouse genes, providing an unprecedented insight into mammalian gene function. This short article explores the drivers for large-scale mouse phenotyping and provides an overview of the aims and processes involved in IMPC mouse ...

  9. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    OpenAIRE

    Kohler, S.; Doelken, S.C.; Mungall, C.J.; Bauer, S.; Firth, H. V.; Bailleul-Forestier, I.; Black, G C M; Brown, D L; Brudno, M.; Campbell, J.; Fitzpatrick, D R; Eppig, J.T.; Jackson, A.P.; Freson, K.; Girdea, M.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with sev...

  10. Identification of Quantitative Trait Loci for Fibrin Clot Phenotypes. The EuroCLOT Study

    DEFF Research Database (Denmark)

    Williams, Frances M K; Carter, Angela M; Kato, Bernet;

    2009-01-01

    OBJECTIVE: Fibrin makes up the structural basis of an occlusive arterial thrombus, and variability in fibrin phenotype relates to cardiovascular risk. The aims of the current study from the EU consortium EuroCLOT were to (1) determine the heritability of fibrin phenotypes and (2) identify QTLs...... associated with fibrin phenotypes. METHODS AND RESULTS: 447 dizygotic (DZ) and 460 monozygotic (MZ) pairs of healthy UK white female twins and 199 DZ twin pairs from Denmark were studied. D-dimer, an indicator of fibrin turnover, was measured by ELISA and measures of clot formation, morphology, and lysis......-wide linkage analysis revealed 6 significant regions with LOD >3 on 5 chromosomes (5, 6, 9, 16, and 17). CONCLUSIONS: The results indicate a significant genetic contribution to variability in fibrin phenotypes and highlight regions in the human genome which warrant further investigation in relation to ischemic...

  11. Functional connectivity measures as schizophrenia intermediate phenotypes: advances, limitations, and future directions.

    Science.gov (United States)

    Cao, Hengyi; Dixson, Luanna; Meyer-Lindenberg, Andreas; Tost, Heike

    2016-02-01

    The search for quantifiable biological mediators of genetic risk or 'intermediate phenotypes' is an essential strategy in psychiatric neuroscience and a useful tool for exploring the complex relationships between genes, neural circuits and behaviors. In recent years, the examination of connectivity-based intermediate phenotypes has gained increasing popularity in the study of schizophrenia, a brain disorder that manifests in early adulthood and disturbs a wide range of neural network functions. To date, several potential connectivity phenotypes have been identified that link neuroimaging measures of neural circuit interaction to genetic susceptibility for schizophrenia. This paper briefly reviews recent advances, current limitations and future directions in the search for functional connectivity intermediate phenotypes for schizophrenia across different cognitive domains. PMID:26276700

  12. TBC1D24 genotype–phenotype correlation

    Science.gov (United States)

    Balestrini, Simona; Milh, Mathieu; Castiglioni, Claudia; Lüthy, Kevin; Finelli, Mattea J.; Verstreken, Patrik; Cardon, Aaron; Stražišar, Barbara Gnidovec; Holder, J. Lloyd; Lesca, Gaetan; Mancardi, Maria M.; Poulat, Anne L.; Repetto, Gabriela M.; Banka, Siddharth; Bilo, Leonilda; Birkeland, Laura E.; Bosch, Friedrich; Brockmann, Knut; Cross, J. Helen; Doummar, Diane; Félix, Temis M.; Giuliano, Fabienne; Hori, Mutsuki; Hüning, Irina; Kayserili, Hulia; Kini, Usha; Lees, Melissa M.; Meenakshi, Girish; Mewasingh, Leena; Pagnamenta, Alistair T.; Peluso, Silvio; Mey, Antje; Rice, Gregory M.; Rosenfeld, Jill A.; Taylor, Jenny C.; Troester, Matthew M.; Stanley, Christine M.; Ville, Dorothee; Walkiewicz, Magdalena; Falace, Antonio; Fassio, Anna; Lemke, Johannes R.; Biskup, Saskia; Tardif, Jessica; Ajeawung, Norbert F.; Tolun, Aslihan; Corbett, Mark; Gecz, Jozef; Afawi, Zaid; Howell, Katherine B.; Oliver, Karen L.; Berkovic, Samuel F.; Scheffer, Ingrid E.; de Falco, Fabrizio A.; Oliver, Peter L.; Striano, Pasquale; Zara, Federico

    2016-01-01

    Objective: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. Methods: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). Results: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. Conclusions: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes. PMID:27281533

  13. Challenging behavior: Behavioral phenotypes of some genetic syndromes

    Directory of Open Access Journals (Sweden)

    Buha Nataša

    2014-01-01

    Full Text Available Challenging behavior in individuals with mental retardation (MR is relatively frequent, and represents a significant obstacle to adaptive skills. The frequency of specific forms and manifestations of challenging behavior can depend on a variety of personal and environmental factors. There are several prominent theoretical models regarding the etiology of challenging behavior and psychopathology in persons with MR: behavioral, developmental, socio-cultural and biological. The biological model emphasizes the physiological, biochemical and genetic factors as the potential source of challenging behavior. The progress in the field of genetics and neuroscience has opened the opportunity to study and discover the neurobiological basis of phenotypic characteristics. Genetic syndromes associated with MR can be followed by a specific set of problems and disorders which constitutes their behavioral phenotype. The aim of this paper was to present challenging behaviors that manifest in the most frequently studied syndromes: Down syndrome, Fragile X syndrome, Williams syndrome, Prader-Willi syndrome and Angelman syndrome. The concept of behavioral phenotype implies a higher probability of manifesting specific developmental characteristics and specific behaviors in individuals with a certain genetic syndrome. Although the specific set of (possible problems and disorders is distinctive for the described genetic syndromes, the connection between genetics and behavior should be viewed through probabilistic dimension. The probabilistic concept takes into consideration the possibility of intra-syndrome variability in the occurrence, intensity and time onset of behavioral characteristics, at which the higher variability the lower is the specificity of the genetic syndrome. Identifying the specific pattern of behavior can be most important for the process of early diagnosis and prognosis. In addition, having knowledge about behavioral phenotype can be a landmark in

  14. Down syndrome phenotypes: The consequences of chromosomal imbalance

    Energy Technology Data Exchange (ETDEWEB)

    Korenberg, J.R.; Chen, X.N.; Schipper, R.; Sun, Z.; Gonsky, R.; Gerwehr, S.; Graham, J.M. Jr. (Univ. of California, Los Angeles, CA (United States)); Carpenter, N.; Say, B. (H.A. Chapman Institute of Medical Genetics, Tulsa, OK (United States)); Daumer, C. (Univ. of Munich (Germany)) (and others)

    1994-05-24

    Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an Alzheimer-like dementia. Moreover, DS is a model for the study of human aneuploidy. Although usually caused by the presence of an extra chromosome 21, subsets of the phenotypic features of DS may be caused by the duplication of small regions of the chromosome. The physical map of chromosome 21 allows the molecular definition of the regions duplicated in these rare cases of partial trisomy. As a first step in identifying the genes responsible for individual DS features and their pathophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to human chromosome 21. Combining this information with detailed clinical evaluations of these patients, the authors have now constructed a [open quotes]phenotypic map[close quotes] that includes 25 features and assigns regions of 2-20 megabases as likely to contain the genes responsible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. This strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the DS phenotypic features.

  15. All About ALS

    Science.gov (United States)

    ... please review our exit disclaimer . Subscribe All About ALS Understanding a Devastating Disorder In the summer of ... of research dollars—for a fatal disease called ALS. ALS stands for amyotrophic lateral sclerosis. It’s also ...

  16. Identifying Unknown Proteins

    OpenAIRE

    Barker, Winona C.; Dayhoff, Margaret O.

    1983-01-01

    In this paper we discuss ways to identify a protein, both when its amino acid sequence is known and, particularly, prior to the determination of the complete sequence. If a similar sequence is in the Protein Sequence Database, an unknown may be identified on the basis of partial or ambiguous sequence data, or on the basis of amino acid composition. Identification in the early stages of structural determination can save time and scarce resources by preventing duplicate effort or by suggesting ...

  17. An end to endless forms: epistasis, phenotype distribution bias, and nonuniform evolution.

    Directory of Open Access Journals (Sweden)

    Elhanan Borenstein

    2008-10-01

    Full Text Available Studies of the evolution of development characterize the way in which gene regulatory dynamics during ontogeny constructs and channels phenotypic variation. These studies have identified a number of evolutionary regularities: (1 phenotypes occupy only a small subspace of possible phenotypes, (2 the influence of mutation is not uniform and is often canalized, and (3 a great deal of morphological variation evolved early in the history of multicellular life. An important implication of these studies is that diversity is largely the outcome of the evolution of gene regulation rather than the emergence of new, structural genes. Using a simple model that considers a generic property of developmental maps-the interaction between multiple genetic elements and the nonlinearity of gene interaction in shaping phenotypic traits-we are able to recover many of these empirical regularities. We show that visible phenotypes represent only a small fraction of possibilities. Epistasis ensures that phenotypes are highly clustered in morphospace and that the most frequent phenotypes are the most similar. We perform phylogenetic analyses on an evolving, developmental model and find that species become more alike through time, whereas higher-level grades have a tendency to diverge. Ancestral phenotypes, produced by early developmental programs with a low level of gene interaction, are found to span a significantly greater volume of the total phenotypic space than derived taxa. We suggest that early and late evolution have a different character that we classify into micro- and macroevolutionary configurations. These findings complement the view of development as a key component in the production of endless forms and highlight the crucial role of development in constraining biotic diversity and evolutionary trajectories.

  18. Population structure of deep-sea chemolithoautotrophs: identification of phenotypic and genotypic correlations

    Science.gov (United States)

    Mino, S.; Nakagawa, S.; Sawabe, T.; Miyazaki, J.; Makita, H.; Nunoura, T.; Yamamoto, M.; Takai, K.

    2012-12-01

    Deep-sea hydrothermal fields are areas on the seafloor of high biological productivity fueled primarily by microbial chemosynthesis. Chemolithoautotrophic Epsilonproteobacteria and Persephonella with an ability to utilize inorganic substrates such as elemental sulfur and hydrogen are important members in wide range of temperature conditions in deep-sea hydrothermal vents. However, little is known about their population genetic structure such as intraspecific genetic diversity, distribution pattern, and phenotypic characteristics. Previously, using genetic approach based on multi-locus sequence analysis (MLSA), we clarified that Epsilonproteobacteria Group A, B, F, and Persephonella populations were geographically separated, and Epsilonproteobacteria appeared to diverge by mutation rather than recombination. Contrary to genetic evidence for allopatric segregation in deep-sea chemoautotrophs, however, phenotypic evidence has never been found. In addition, analyzing such a phenotypic characteristic may lead to a better understanding of the interactions microbes have with their environment. In this study, we present a metabolomic approach based on matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) to reveal phenotypic biogeographical discrimination. We demonstrated the whole-cell MALDI-TOF MS method on Epsilonproteobacteria and Persephonella populations. These chemoautotrophic strains used in this study were isolated from chimney structures, vent fluids, and hydrothermal sediments. These hydrothermal samples were collected from geographically separated hydrothermal areas of the South Mariana Trough, Okinawa Trough and Central Indian Ridge. Based on mass peaks (signal/noise >10) within the m/z range of 2000-14000, phenotypic analysis was carried out by cluster analysis. The result of phenotypic analysis was compared with the genotypic clusters. The whole-cell MALDI-TOF MS revealed that Persephonella population was identified to

  19. High pressure studies of UFe5Al7 and UFe7Al5 actinide compounds

    International Nuclear Information System (INIS)

    The ternary inter-metallic compounds, UFe5Al7 and UFe7Al5, crystallize in a tetragonal ThMn12 type structure. In the as-cast samples a residual phase of FeAl (∼2%wt) was identified in the grain boundaries. The amount of the residual cubic phase of FeAl was determined by Rietveld analysis and reduced by the annealing process. UFe5Al7 and UFe7Al5 maintain the tetragonal symmetry as a function of pressure, while FeAl keeps the cubic structure as was determined by the Rietveld analysis. The volume-pressure curve calculated from the X-ray analysis gives V/V0=0.87 for UFe5Al7 at 26.0 GPa and 0.89 at 24.6 GPa for UFe7Al5. (author)

  20. Molecular and phenotypic characterization of infectious bursal disease virus isolates.

    Science.gov (United States)

    Dormitorio, T V; Giambrone, J J; Guo, K; Jackwood, D J

    2007-06-01

    Two infectious bursal disease viruses (IBDVs 1174 and V1) were isolated from IBDV-vaccinated broiler flocks in California and Georgia. These flocks had a history of subclinical immunosuppression. These isolates are commonly used in IBDV progeny challenge studies at Auburn, AL, as well as vaccine manufacturer's vaccine efficacy studies, because they come from populated poultry-producing states, and are requested by poultry veterinarians from those states. Nested polymerase chain reaction (PCR) generated viral genome products for sequencing. A 491-bp segment from the VP2 gene, covering the hypervariable region, from each isolate was analyzed and compared with previously sequenced isolates. Sequence analysis showed that they were more closely related to the Delaware (Del) E antigenic variant than they are to the Animal Health Plant Inspection Service (APHIS) standard, both at the nucleotide level (96%, 97%) and at the amino acid level (94%, 97%). Both isolates had the glutamine to lysine shift in amino acid 249 which has been reported to be critical in binding the virus neutralizing Mab B69. Phenotypic studies showed that both isolates produced rapid atrophy of the bursae and weight loss, without the edematous bursal phase, in 2-wk-old commercial broilers having antibody against IBDV. A progeny challenge study showed both isolates produced more atrophy of the bursae (less percentage of protection) than the Del E isolate. Molecular and phenotypic data of these important IBDV isolates help in the improved detection and control of this continually changing and important viral pathogen of chickens. PMID:17626491

  1. Genome-wide association study identifies 74 loci associated with educational attainment

    DEFF Research Database (Denmark)

    Okbay, Aysu; P. Beauchamp, Jonathan; Alan Fontana, Mark;

    2016-01-01

    development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals...

  2. Identifying Knowledge and Communication

    Directory of Open Access Journals (Sweden)

    Eduardo Coutinho Lourenço de Lima

    2006-12-01

    Full Text Available In this paper, I discuss how the principle of identifying knowledge which Strawson advances in ‘Singular Terms and Predication’ (1961, and in ‘Identifying Reference and Truth-Values’ (1964 turns out to constrain communication. The principle states that a speaker’s use of a referring expression should invoke identifying knowledge on the part of the hearer, if the hearer is to understand what the speaker is saying, and also that, in so referring, speakers are attentive to hearers’ epistemic states. In contrasting it with Russell’s Principle (Evans 1982, as well as with the principle of identifying descriptions (Donnellan 1970, I try to show that the principle of identifying knowledge, ultimately a condition for understanding, makes sense only in a situation of conversation. This allows me to conclude that the cooperative feature of communication (Grice 1975 and reference (Clark andWilkes-Gibbs 1986 holds also at the understanding level. Finally, I discuss where Strawson’s views seem to be unsatisfactory, and suggest how they might be improved.

  3. Newly Identified Rydberg Emission Lines in Novae

    Science.gov (United States)

    Lynch, David K.; Rudy, R. J.; Bernstein, L. S.

    2008-09-01

    Newly Identified Rydberg Emission Lines in Novae David K. Lynch, Richard. J. Rudy (The Aerospace Corporation) & Lawrence S. Bernstein (Spectral Sciences, Inc.) Novae spectra in the near infrared frequently show a set of six emission lines that have not been positively identified (Williams, Longmore, & Geballe 1996, MNRAS, 279, 804; Lynch et al. 2001, AJ, 122, 2013; Rudy et al. 2002 ApJ, 573, 794; Lynch et al. 2004 Astron. J. 127, 1089-1097). These lines are at 0.8926, 1.1114, 1.1901, 1.5545, 2.0996 and 2.425 µm ± 0.005 µm. Krautter et al. (1984 A&A 137, 304) suggested that three of the lines were due to rydberg (hydrogenic) transitions in an unspecified atomic species that was in the 4th or 5th ionization stage (core charge = 4 & 5). We believe that Krautter et al.'s explanation is correct based on 4 additional lines that we have identified in the visible and near infrared spectrum of V723 Cassiopeiae. The observed Rydberg lines appear to originate from high angular momentum states with negligible quantum defects. The species cannot be determined with any certainty because in rydberg states, the outer electron sees a nucleus shielded by the inner electrons and together the inner atom appears to have a charge of +1, like hydrogen. As a result, the atom looks hydrogenic and species such as CV, NV, OV, MgV, SiV, etc. have their rydberg transitions at very similar wavelengths. All the lines represent permitted transitions, most likely formed by recombination. Atoms with core charges 4, 5 & 6 are rarely seen in the astrophysical environment because an extremely hot radiation field is necessary to ionize them. Thermonuclear runaways on the surface of a white dwarf can reach millions of degrees K, and thus there are enough X-ray photons available to achieve the necessary high ionization levels.

  4. An Xpert screen to identify carbapenemases

    Directory of Open Access Journals (Sweden)

    Mubin Kazi

    2016-01-01

    Full Text Available To prevent the spread of carbapenemases-producing Enterobacteriaceae (CPE active surveillance, contact isolation and cohorting infected patients should be practiced. Rectal swabs for the Xpert MDRO-assay of 32 patients were included. 71.85% were positive for targets incorporated into the MDRO-assay; whereas 28% were phenotypically not CRE and Xpert negative (9.37% had different mechanism [bla OXA]. The assay identified 59.3%, 9.37% and 3.1% as bla NDM, bla NDM+VIM and bla VIM, respectively. The assay is a screening test that identifies CPE harbouring organism within an hour and can be installed at tertiary-care facilities to screen colonized patients.

  5. Wham: Identifying Structural Variants of Biological Consequence.

    Directory of Open Access Journals (Sweden)

    Zev N Kronenberg

    2015-12-01

    Full Text Available Existing methods for identifying structural variants (SVs from short read datasets are inaccurate. This complicates disease-gene identification and efforts to understand the consequences of genetic variation. In response, we have created Wham (Whole-genome Alignment Metrics to provide a single, integrated framework for both structural variant calling and association testing, thereby bypassing many of the difficulties that currently frustrate attempts to employ SVs in association testing. Here we describe Wham, benchmark it against three other widely used SV identification tools-Lumpy, Delly and SoftSearch-and demonstrate Wham's ability to identify and associate SVs with phenotypes using data from humans, domestic pigeons, and vaccinia virus. Wham and all associated software are covered under the MIT License and can be freely downloaded from github (https://github.com/zeeev/wham, with documentation on a wiki (http://zeeev.github.io/wham/. For community support please post questions to https://www.biostars.org/.

  6. Gain-of-function mutations in the ALS8 causative gene VAPB have detrimental effects on neurons and muscles

    Directory of Open Access Journals (Sweden)

    Mario Sanhueza

    2013-12-01

    Amyotrophic Lateral Sclerosis (ALS is a motor neuron degenerative disease characterized by a progressive, and ultimately fatal, muscle paralysis. The human VAMP-Associated Protein B (hVAPB is the causative gene of ALS type 8. Previous studies have shown that a loss-of-function mechanism is responsible for VAPB-induced ALS. Recently, a novel mutation in hVAPB (V234I has been identified but its pathogenic potential has not been assessed. We found that neuronal expression of the V234I mutant allele in Drosophila (DVAP-V260I induces defects in synaptic structure and microtubule architecture that are opposite to those associated with DVAP mutants and transgenic expression of other ALS-linked alleles. Expression of DVAP-V260I also induces aggregate formation, reduced viability, wing postural defects, abnormal locomotion behavior, nuclear abnormalities, neurodegeneration and upregulation of the heat-shock-mediated stress response. Similar, albeit milder, phenotypes are associated with the overexpression of the wild-type protein. These data show that overexpressing the wild-type DVAP is sufficient to induce the disease and that DVAP-V260I is a pathogenic allele with increased wild-type activity. We propose that a combination of gain- and loss-of-function mechanisms is responsible for VAPB-induced ALS.

  7. Invasion strategies in clonal aquatic plants: Are phenotypic differences caused by phenotypic plasticity or local adaptation?

    DEFF Research Database (Denmark)

    Riis, Tenna; Lambertini, Carla; Olesen, Birgit;

    2010-01-01

    . Methods: Field populations with a large phenotypic variety were sampled in a range of lakes and streams with different chemical and physical properties. The phenotypic plasticity of the species before and after cultivation was studied in a common garden growth experiment, and the genetic diversity of...

  8. Fenótipos clínicos de asma grave Clinical phenotypes of severe asthma

    Directory of Open Access Journals (Sweden)

    Roseliane de Souza Araújo Alves

    2008-09-01

    Full Text Available OBJETIVO: Estabelecer os fenótipos clínicos em portadores de asma grave. MÉTODOS: Foram estudados, retrospectivamente, 111 pacientes em um ambulatório especializado. Os pacientes foram avaliados e acompanhados de maneira sistemática, estabelecendo-se ao final do acompanhamento a adesão e o controle ou não da doença por dados clínicos e funcionais. A resistência ao tratamento foi definida como o não preenchimento, ao final do acompanhamento, por pelo menos seis meses, dos critérios de controle de asma, apesar do uso correto e adesão à medicação. Os fenótipos foram determinados por análise fatorial e comparados por testes diversos. RESULTADOS: Ao final, 88 pacientes foram considerados aderentes e 23 não aderentes. Por análise fatorial do grupo aderente, quatro fenótipos foram determinados: o fenótipo 1 (28 pacientes, formado pelos pacientes resistentes ao tratamento, com maior freqüência de sintomas noturnos, maior número de exacerbações e uso mais freqüente de broncodilatador de resgate; o fenótipo 2 (48 pacientes, formado pelos pacientes com obstrução persistente, com menores valores de relação volume expiratório forçado no primeiro segundo/capacidade vital forçada na avaliação inicial, idade mais avançada e maior tempo de doença; o fenótipo 3 (42 pacientes, representa os pacientes com rinossinusite alérgica, sendo constituído de não fumantes com obstrução predominantemente reversível; e o fenótipo 4 (15 pacientes, formado por casos com história de intolerância à aspirina associado à asma quase fatal. CONCLUSÕES: Um número significativo de portadores de ama grave não adere ao tratamento. Muitos pacientes com asma grave têm obstrução irreversível, mas o fenótipo clínico mais relevante é constituído pelos pacientes resistentes ao tratamento habitual.OBJECTIVE: To characterize clinical phenotypes of severe asthma. METHODS: A total of 111 patients were retrospectively evaluated at a

  9. Regulatory mechanisms link phenotypic plasticity to evolvability.

    Science.gov (United States)

    van Gestel, Jordi; Weissing, Franz J

    2016-01-01

    Organisms have a remarkable capacity to respond to environmental change. They can either respond directly, by means of phenotypic plasticity, or they can slowly adapt through evolution. Yet, how phenotypic plasticity links to evolutionary adaptability is largely unknown. Current studies of plasticity tend to adopt a phenomenological reaction norm (RN) approach, which neglects the mechanisms underlying plasticity. Focusing on a concrete question - the optimal timing of bacterial sporulation - we here also consider a mechanistic approach, the evolution of a gene regulatory network (GRN) underlying plasticity. Using individual-based simulations, we compare the RN and GRN approach and find a number of striking differences. Most importantly, the GRN model results in a much higher diversity of responsive strategies than the RN model. We show that each of the evolved strategies is pre-adapted to a unique set of unseen environmental conditions. The regulatory mechanisms that control plasticity therefore critically link phenotypic plasticity to the adaptive potential of biological populations. PMID:27087393

  10. Constraints on the evolution of phenotypic plasticity

    DEFF Research Database (Denmark)

    Murren, Courtney J; Auld, Josh R.; Callahan, Hilary S;

    2015-01-01

    Phenotypic plasticity is ubiquitous and generally regarded as a key mechanism for enabling organisms to survive in the face of environmental change. Because no organism is infinitely or ideally plastic, theory suggests that there must be limits (for example, the lack of ability to produce an...... optimal trait) to the evolution of phenotypic plasticity, or that plasticity may have inherent significant costs. Yet numerous experimental studies have not detected widespread costs. Explicitly differentiating plasticity costs from phenotype costs, we re-evaluate fundamental questions of the limits to...... the evolution of plasticity and of generalists vs specialists. We advocate for the view that relaxed selection and variable selection intensities are likely more important constraints to the evolution of plasticity than the costs of plasticity. Some forms of plasticity, such as learning, may be...

  11. Delineating the GRIN1 phenotypic spectrum

    DEFF Research Database (Denmark)

    Lemke, Johannes R; Geider, Kirsten; Helbig, Katherine L; Heyne, Henrike O; Schütz, Hannah; Hentschel, Julia; Courage, Carolina; Depienne, Christel; Nava, Caroline; Heron, Delphine; Møller, Rikke S; Hjalgrim, Helle; Lal, Dennis; Neubauer, Bernd A; Nürnberg, Peter; Thiele, Holger; Kurlemann, Gerhard; Arnold, Georgianne L; Bhambhani, Vikas; Bartholdi, Deborah; Pedurupillay, Christeen Ramane J; Misceo, Doriana; Frengen, Eirik; Strømme, Petter; Dlugos, Dennis J; Doherty, Emily S; Bijlsma, Emilia K; Ruivenkamp, Claudia A; Hoffer, Mariette J V; Goldstein, Amy; Rajan, Deepa S; Narayanan, Vinodh; Ramsey, Keri; Belnap, Newell; Schrauwen, Isabelle; Richholt, Ryan; Koeleman, Bobby P C; Sá, Joaquim; Mendonça, Carla; de Kovel, Carolien G F; Weckhuysen, Sarah; Hardies, Katia; De Jonghe, Peter; De Meirleir, Linda; Milh, Mathieu; Badens, Catherine; Lebrun, Marine; Busa, Tiffany; Francannet, Christine; Piton, Amélie; Riesch, Erik; Biskup, Saskia; Vogt, Heinrich; Dorn, Thomas; Helbig, Ingo; Michaud, Jacques L; Laube, Bodo; Syrbe, Steffen

    2016-01-01

    OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional conseque......OBJECTIVE: To determine the phenotypic spectrum caused by mutations in GRIN1 encoding the NMDA receptor subunit GluN1 and to investigate their underlying functional pathophysiology. METHODS: We collected molecular and clinical data from several diagnostic and research cohorts. Functional...... impairment as well as oculomotor and movement disorders being discriminating phenotypic features. Loss of NMDA receptor function appears to be the underlying disease mechanism. The identification of both heterozygous and homozygous mutations blurs the borders of dominant and recessive inheritance of GRIN1...

  12. Rational elicitation of cold-sensitive phenotypes.

    Science.gov (United States)

    Baliga, Chetana; Majhi, Sandipan; Mondal, Kajari; Bhattacharjee, Antara; VijayRaghavan, K; Varadarajan, Raghavan

    2016-05-01

    Cold-sensitive phenotypes have helped us understand macromolecular assembly and biological phenomena, yet few attempts have been made to understand the basis of cold sensitivity or to elicit it by design. We report a method for rational design of cold-sensitive phenotypes. The method involves generation of partial loss-of-function mutants, at either buried or functional sites, coupled with selective overexpression strategies. The only essential input is amino acid sequence, although available structural information can be used as well. The method has been used to elicit cold-sensitive mutants of a variety of proteins, both monomeric and dimeric, and in multiple organisms, namely Escherichia coli, Saccharomyces cerevisiae, and Drosophila melanogaster This simple, yet effective technique of inducing cold sensitivity eliminates the need for complex mutations and provides a plausible molecular mechanism for eliciting cold-sensitive phenotypes. PMID:27091994

  13. Molecular phenotypes associated with anomalous stamen development in Alternanthera philoxeroides

    Directory of Open Access Journals (Sweden)

    Zhu eZhu

    2015-04-01

    Full Text Available Alternanthera philoxeroides is a perennial amphibious weed native to South America but has now spread to diverse parts of the world. A. philoxeroides reproduces both sexually and asexually in its native range, but propagates solely through vegetative means in its introduced range. Traits associated with sexual reproduction become degraded for sexual dysfunction, with flowers possessing either pistillate stamens or male-sterile anthers. Degradations of sexual characters for loss of sexuality commonly take place in clonal plants. The underlying molecular-genetic processes remain largely unknown. We compared the gene expression profiles of abnormal stamens with that of normal stamens by RNA-Seq analysis, and identified a large number of differentially expressed genes between abnormal and normal stamens. In accordance with flower morphology, the expression of B-class MADS-box genes (ApAP3, ApTM6 and ApPI was markedly reduced in pistillate stamens. However, most of the genes involved in meiosis were expressed normally in stamens with male-sterile anthers. In addition to verifying the expression patterns of genes previously known to be related to stamen and pollen grain development, we also identified previously unknown molecular phenotypes associated with sexual dysfunction in A. philoxeroides, that is helpful for dissecting the molecular mechanisms underpinning various male-sterile phenotypes and the molecular processes underlying the transition from sexuality to asexuality in clonal plants.

  14. Recurrent duplications of 17q12 associated with variable phenotypes.

    Science.gov (United States)

    Mitchell, Elyse; Douglas, Andrew; Kjaegaard, Susanne; Callewaert, Bert; Vanlander, Arnaud; Janssens, Sandra; Yuen, Amy Lawson; Skinner, Cindy; Failla, Pinella; Alberti, Antonino; Avola, Emanuela; Fichera, Marco; Kibaek, Maria; Digilio, Maria C; Hannibal, Mark C; den Hollander, Nicolette S; Bizzarri, Veronica; Renieri, Alessandra; Mencarelli, Maria Antonietta; Fitzgerald, Tomas; Piazzolla, Serena; van Oudenhove, Elke; Romano, Corrado; Schwartz, Charles; Eichler, Evan E; Slavotinek, Anne; Escobar, Luis; Rajan, Diana; Crolla, John; Carter, Nigel; Hodge, Jennelle C; Mefford, Heather C

    2015-12-01

    The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi-institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability. PMID:26420380

  15. Identification of sorghum hybrids with high phenotypic stability using GGE biplot methodology.

    Science.gov (United States)

    Teodoro, P E; Almeida Filho, J E; Daher, R F; Menezes, C B; Cardoso, M J; Godinho, V P C; Torres, F E; Tardin, F D

    2016-01-01

    The aim of this study was to identify sorghum hybrids that have both high yield and phenotypic stability in Brazilian environments. Seven trials were conducted between February and March 2011. The experimental design was a randomized complete block with 25 treatments and three replicates. The treatments consisted of 20 simple pre-commercial hybrids and five witnesses of grain sorghum. Sorghum genotypes were analyzed by the genotype main effects + genotype environment interaction (GGE) biplot method if significant genotype x environment interaction, adaptability, and phenotypic stability were detected. GGE biplot methodology identified two groups of environments, the first composed of Água Comprida-MG, Montividiu-GO, and Vilhena- RO and the second of Guaíra-SP and Sete Lagoas-MG. The BRS 308 and 1G282 genotypes were found to have high grain yield, adaptability, and phenotypic stability and are thus indicated for cultivation in the first and second groups of environments, respectively. PMID:27323167

  16. Phenotypic plasticity can facilitate adaptive evolution in gene regulatory circuits

    OpenAIRE

    Martin Olivier C; Espinosa-Soto Carlos; Wagner Andreas

    2011-01-01

    Abstract Background Many important evolutionary adaptations originate in the modification of gene regulatory circuits to produce new gene activity phenotypes. How do evolving populations sift through an astronomical number of circuits to find circuits with new adaptive phenotypes? The answer may often involve phenotypic plasticity. Phenotypic plasticity allows a genotype to produce different - alternative - phenotypes after non-genetic perturbations that include gene expression noise, environ...

  17. Phenotypic plasticity can facilitate adaptive evolution in gene regulatory circuits

    OpenAIRE

    Espinosa-Soto, C.; Martin, O. C.; Wagner, A

    2011-01-01

    BACKGROUND: Many important evolutionary adaptations originate in the modification of gene regulatory circuits to produce new gene activity phenotypes. How do evolving populations sift through an astronomical number of circuits to find circuits with new adaptive phenotypes? The answer may often involve phenotypic plasticity. Phenotypic plasticity allows a genotype to produce different - alternative - phenotypes after non-genetic perturbations that include gene expression noise, environment...

  18. Inference of gene-phenotype associations via protein-protein interaction and orthology.

    Directory of Open Access Journals (Sweden)

    Panwen Wang

    Full Text Available One of the fundamental goals of genetics is to understand gene functions and their associated phenotypes. To achieve this goal, in this study we developed a computational algorithm that uses orthology and protein-protein interaction information to infer gene-phenotype associations for multiple species. Furthermore, we developed a web server that provides genome-wide phenotype inference for six species: fly, human, mouse, worm, yeast, and zebrafish. We evaluated our inference method by comparing the inferred results with known gene-phenotype associations. The high Area Under the Curve values suggest a significant performance of our method. By applying our method to two human representative diseases, Type 2 Diabetes and Breast Cancer, we demonstrated that our method is able to identify related Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathways. The web server can be used to infer functions and putative phenotypes of a gene along with the candidate genes of a phenotype, and thus aids in disease candidate gene discovery. Our web server is available at http://jjwanglab.org/PhenoPPIOrth.

  19. Elevated oxidative membrane damage associated with genetic modifiers of Lyst-mutant phenotypes.

    Directory of Open Access Journals (Sweden)

    Colleen M Trantow

    2010-07-01

    Full Text Available LYST is a large cytosolic protein that influences the biogenesis of lysosome-related organelles, and mutation of the encoding gene, LYST, can cause Chediak-Higashi syndrome. Recently, Lyst-mutant mice were recognized to also exhibit an iris disease resembling exfoliation syndrome, a common cause of glaucoma in humans. Here, Lyst-mutant iris phenotypes were used in a search for genes that influence Lyst pathways. In a candidate gene-driven approach, albino Lyst-mutant mice homozygous for a mutation in Tyr, whose product is key to melanin synthesis within melanosomes, exhibited complete rescue of Lyst-mutant iris phenotypes. In a genetic background-driven approach using a DBA/2J strain of congenic mice, an interval containing Tyrp1 enhanced Lyst-dependent iris phenotypes. Thus, both experimental approaches implicated the melanosome, an organelle that is a potential source of oxidative stress, as contributing to the disease phenotype. Confirming an association with oxidative damage, Lyst mutation resulted in genetic context-sensitive changes in iris lipid hydroperoxide levels, being lowest in albino and highest in DBA/2J mice. Surprisingly, the DBA/2J genetic background also exposed a late-onset neurodegenerative phenotype involving cerebellar Purkinje-cell degeneration. These results identify an association between oxidative damage to lipid membranes and the severity of Lyst-mutant phenotypes, revealing a new mechanism that contributes to pathophysiology involving LYST.

  20. Significance of Lewis Phenotyping Using Saliva and Gastric Tissue: Comparison with the Lewis Phenotype Inferred from Lewis and Secretor Genotypes

    Directory of Open Access Journals (Sweden)

    Yun Ji Hong

    2014-01-01

    , and le59 alleles was 74.6%, 21.3%, 3.1%, and 1.0%, respectively, among 418 alleles. The saliva Lewis phenotype was completely consistent with the Lewis phenotype inferred from Lewis and Secretor genotypes, but that of gastric mucosa could not be predicted from genotypes. Lewis phenotyping using erythrocytes is only adequate for transfusion needs. Saliva testing for the Lewis phenotype is a more reliable method for determining the peripheral Lewis phenotype of an individual and the gastric Lewis phenotype must be used for the study on the association between Helicobacter pylori and the Lewis phenotype.

  1. Internally readable identifying tag

    International Nuclear Information System (INIS)

    A method of identifying non-metallic objects by means of X-ray equipment is described in detail. A small metal pin with a number of grooves cut in a pre-determined equi-spaced pattern is implanted into the non-metallic object and by decoding the groove patterns using X-ray equipment, the object is uniquely identified. A specific example of such an application is in studying the migratory habits of fish. The pin inserted into the snout of the fish is 0.010 inch in diameter, 0.040 inch in length with 8 possible positions for grooves if spaced 0.005 inch apart. With 6 of the groove positions available for data, the capacity is 26 or 64 combinations; clearly longer pins would increase the data capacity. This method of identification is a major advance over previous techniques which necessitated destruction of the fish in order to recover the identification tag. (UK)

  2. Identifying Fiscal Inflation

    OpenAIRE

    De Graeve, Ferre; Queijo von Heideken, Virginia

    2013-01-01

    Fiscal theorists warn about the risk of future inflation as a consequence of current fiscal imbalances in the US. Because actual inflation remains historically low and data on inflation expectations do not corroborate such risks, warnings for fiscal inflation are often ignored in policy and academic circles. This paper shows that a canonical NK- DSGE model enables identifying an anticipated component of inflation expectations that is closely related to fiscal policy. Estimation results sugges...

  3. Studies on SiC(p) reinforced Al-Al sub 3 Ni eutectic matrix composites

    International Nuclear Information System (INIS)

    An investigation on processing of Al-5.69wt% Ni eutectic with SiC particulate composites is reported. The intermetallic composites are prepared by elemental powder metallurgy route and sintered at two different temperatures, i.e., 600 degree C and 620 degree C. Results show that the metal matrix was Al-Al sub 3 Ni eutectic. The phase analysis by XRD identified the presence of Al sub 3 Ni and Al as dominant phases together with silicon and Al sub 4 C sub 3 phase as minor phases. The Al sub 4 C sub 3 and Si phases are formed during sintering due to SiC-Al interface reaction. SEM micrographs also reveal the formation of microvoid surrounding the SiC particle

  4. Peruvian Maca (Lepidium peruvianum): (I) Phytochemical and Genetic Differences in Three Maca Phenotypes.

    Science.gov (United States)

    Meissner, Henry O; Mscisz, Alina; Mrozikiewicz, Mieczyslaw; Baraniak, Marek; Mielcarek, Sebastian; Kedzia, Bogdan; Piatkowska, Ewa; Jólkowska, Justyna; Pisulewski, Pawel

    2015-09-01

    Glucosinolates were previously reported as physiologically-important constituents present in Peruvian Maca (Lepidium peruvianum Chacon) and linked to various therapeutic functions of differently-colored Peruvian Maca hypocotyls. In two separate Trials, three colours of Maca hypocotyls "Black", "Red" and "Yellow" (termed "Maca phenotypes"), were selected from mixed crops of Peruvian Maca for laboratory studies as fresh and after being dried. Individual Maca phenotypes were cultivated in the highlands of the Peruvian Andes at 4,200m a.s.l. (Junin and Ninacaca). Glucosinolate levels, chromatographic HPLC profiles and DNA variability in the investigated Maca phenotypes are presented. Genotypic profiles were determined by the ISSR-PCR and RAPD techniques. Compared to the Black and Red phenotypes, the Yellow phenotype contained much lower Glucosinolate levels measured against Glucotropaeolin and m-methoxy-glucotropaeolin standards, and exhibited different RAPD and ISSR-PCR reactions. The Red Maca phenotype showed the highest concentrations of Glucosinolates as compared to the Black and Yellow Maca. It appears that the traditional system used by natives of the Peruvian Andean highlands in preparing Maca as a vegetable dish (boiling dried Maca after soaking in water), to supplement their daily meals, is as effective as laboratory methods - for extracting Glucosinolates, which are considered to be one of the key bioactive constituents responsible for therapeutic functions of Peruvian Maca phenotypes. It is reasonable to assume that the HPLC and DNA techniques combined, or separately, may assist in determining ID and "Fingerprints" identifying individual Peruvian Maca phenotypes, hence confirming the authenticity of marketable Maca products. The above assumptions warrant further laboratory testing. PMID:26508907

  5. Phenotype as Agent for Epigenetic Inheritance.

    Science.gov (United States)

    Torday, John S; Miller, William B

    2016-01-01

    The conventional understanding of phenotype is as a derivative of descent with modification through Darwinian random mutation and natural selection. Recent research has revealed Lamarckian inheritance as a major transgenerational mechanism for environmental action on genomes whose extent is determined, in significant part, by germ line cells during meiosis and subsequent stages of embryological development. In consequence, the role of phenotype can productively be reconsidered. The possibility that phenotype is directed towards the effective acquisition of epigenetic marks in consistent reciprocation with the environment during the life cycle of an organism is explored. It is proposed that phenotype is an active agent in niche construction for the active acquisition of epigenetic marks as a dominant evolutionary mechanism rather than a consequence of Darwinian selection towards reproductive success. The reproductive phase of the life cycle can then be appraised as a robust framework in which epigenetic inheritance is entrained to affect growth and development in continued reciprocal responsiveness to environmental stresses. Furthermore, as first principles of physiology determine the limits of epigenetic inheritance, a coherent justification can thereby be provided for the obligate return of all multicellular eukaryotes to the unicellular state. PMID:27399791

  6. Radiofrequency treatment alters cancer cell phenotype

    Science.gov (United States)

    Ware, Matthew J.; Tinger, Sophia; Colbert, Kevin L.; Corr, Stuart J.; Rees, Paul; Koshkina, Nadezhda; Curley, Steven; Summers, H. D.; Godin, Biana

    2015-07-01

    The importance of evaluating physical cues in cancer research is gradually being realized. Assessment of cancer cell physical appearance, or phenotype, may provide information on changes in cellular behavior, including migratory or communicative changes. These characteristics are intrinsically different between malignant and non-malignant cells and change in response to therapy or in the progression of the disease. Here, we report that pancreatic cancer cell phenotype was altered in response to a physical method for cancer therapy, a non-invasive radiofrequency (RF) treatment, which is currently being developed for human trials. We provide a battery of tests to explore these phenotype characteristics. Our data show that cell topography, morphology, motility, adhesion and division change as a result of the treatment. These may have consequences for tissue architecture, for diffusion of anti-cancer therapeutics and cancer cell susceptibility within the tumor. Clear phenotypical differences were observed between cancerous and normal cells in both their untreated states and in their response to RF therapy. We also report, for the first time, a transfer of microsized particles through tunneling nanotubes, which were produced by cancer cells in response to RF therapy. Additionally, we provide evidence that various sub-populations of cancer cells heterogeneously respond to RF treatment.

  7. Cognitive Phenotype of Velocardiofacial Syndrome: A Review

    Science.gov (United States)

    Furniss, Frederick; Biswas, Asit B.; Gumber, Rohit; Singh, Niraj

    2011-01-01

    The behavioural phenotype of velocardiofacial syndrome (VCFS), one of the most common human multiple anomaly syndromes, includes developmental disabilities, frequently including intellectual disability (ID) and high risk of diagnosis of psychotic disorders including schizophrenia. VCFS may offer a model of the relationship between ID and risk of…

  8. Phenotyping animal models of diabetic neuropathy

    DEFF Research Database (Denmark)

    Biessels, G J; Bril, V; Calcutt, N A;

    2014-01-01

    NIDDK, JDRF, and the Diabetic Neuropathy Study Group of EASD sponsored a meeting to explore the current status of animal models of diabetic peripheral neuropathy. The goal of the workshop was to develop a set of consensus criteria for the phenotyping of rodent models of diabetic neuropathy. The...

  9. Genetical metabolomics: closing in on phenotypes

    NARCIS (Netherlands)

    Keurentjes, J.J.B.

    2009-01-01

    One of the long-standing goals in plant biology has been to link genotypic variation to natural variation in plant development and adaptive traits. From recent studies it has become clear that a complex interacting network is underlying phenotypic diversity. A major role in this regulatory mechanism

  10. Advances in Phenotyping of Functional Traits

    Science.gov (United States)

    In plants, functional traits are morphological, biochemical, physiological, structural, phenological, or behavioral characteristics that are expressed in phenotypes of individual plants,that are relevant to the plant’s role in the ecosystem or its agronomic performance. By themselves, functional tra...

  11. Phenotyping for Abiotic Stress Tolerance in Maize

    Institute of Scientific and Technical Information of China (English)

    Benhilda Masuka; Jose Luis Araus; Biswanath Das; Kai Sonder; Jill E. Cairns

    2012-01-01

    The ability to quickly develop germplasm having tolerance to several complex polygenic inherited abiotic and biotic stresses combined is critical to the resilience of cropping systems in the face of climate change.Molecular breeding offers the tools to accelerate cereal breeding; however,suitable phenotyping protocols are essential to ensure that the much-anticipated benefits of molecular breeding can be realized.To facilitate the full potential of molecular tools,greater emphasis needs to be given to reducing the within-experimental site variability,application of stress and characterization of the environment and appropriate phenotyping tools.Yield is a function of many processes throughout the plant cycle,and thus integrative traits that encompass crop performance over time or organization level (i.e.canopy level) will provide a better alternative to instantaneous measurements which provide only a snapshot of a given plant process.Many new phenotyping tools based on remote sensing are now available including non-destructive measurements of growth-related parameters based on spectral reflectance and infrared thermometry to estimate plant water status.Here we describe key field phenotyping protocols for maize with emphasis on tolerance to drought and low nitrogen.

  12. Behavioural Phenotypes in Disability Research: Historical Perspectives

    Science.gov (United States)

    Goodey, C. F.

    2006-01-01

    Western medicine has a long history of accounting for behaviour by reducing the body to ultimate explanatory entities. In pre-modern medicine these were invisible "animal spirits" circulating the body. In modern medicine, they are "genes". Both raise questions. The psychological phenotype is defined by human consensus, varying according to time…

  13. Data and animal management software for large-scale phenotype screening.

    Science.gov (United States)

    Ching, Keith A; Cooke, Michael P; Tarantino, Lisa M; Lapp, Hilmar

    2006-04-01

    The mouse N-ethyl-N-nitrosourea (ENU) mutagenesis program at the Genomics Institute of the Novartis Research Foundation (GNF) uses MouseTRACS to analyze phenotype screens and manage animal husbandry. MouseTRACS is a Web-based laboratory informatics system that electronically records and organizes mouse colony operations, prints cage cards, tracks inventory, manages requests, and reports Institutional Animal Care and Use Committee (IACUC) protocol usage. For efficient phenotype screening, MouseTRACS identifies mutants, visualizes data, and maps mutations. It displays and integrates phenotype and genotype data using likelihood odds ratio (LOD) plots of genetic linkage between genotype and phenotype. More detailed mapping intervals show individual single nucleotide polymorphism (SNP) markers in the context of phenotype. In addition, dynamically generated pedigree diagrams and inventory reports linked to screening results summarize the inheritance pattern and the degree of penetrance. MouseTRACS displays screening data in tables and uses standard charts such as box plots, histograms, scatter plots, and customized charts looking at clustered mice or cross pedigree comparisons. In summary, MouseTRACS enables the efficient screening, analysis, and management of thousands of animals to find mutant mice and identify novel gene functions. MouseTRACS is available under an open source license at http://www.mousetracs.sourceforge.net. PMID:16596450

  14. Research to Identify Effective Antifungal Agents, 1992 Annual Report.

    Energy Technology Data Exchange (ETDEWEB)

    Schreck, Carl

    1993-03-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990 and Schreck et al. 1991). The objectives of the present study were to select and evaluate up to 10 candidate fungicides.

  15. New Interview and Observation Measures of the Broader Autism Phenotype: Group Differentiation

    Science.gov (United States)

    de Jonge, Maretha; Parr, Jeremy; Rutter, Michael; Wallace, Simon; Kemner, Chantal; Bailey, Anthony; van Engeland, Herman; Pickles, Andrew

    2015-01-01

    To identify the broader autism phenotype (BAP), the Family History Interview subject and informant versions and an observational tool (Impression of Interviewee), were developed. This study investigated whether the instruments differentiated between parents of children with autism, and parents of children with Down syndrome (DS). The BAP scores of…

  16. An interview study of phenotypic characterization of genetically-modified mice.

    NARCIS (Netherlands)

    Thon, R.; Vondeling, H.; Lassen, J.; Hansen, A.K.; Ritskes-Hoitinga, M.

    2009-01-01

    An interview study was carried out with the aim of clarifying the reasons for the limited use of phenotypic characterization of genetically-modified mice (GMM) and identifying issues hindering its implementation. A total of 15 users of GMM participated in semi-structured face-to-face interviews, whi

  17. An interview study of phenotypic characterization of genetically-modified mice

    NARCIS (Netherlands)

    Thon, R.; Vondeling, H.; Lassen, J.; Hansen, A.K.; Ritskes-Hoitinga, M.

    2009-01-01

    An interview study was carried out with the aim of clarifying the reasons for the limited use of phenotypic characterization of genetically-modified mice (GMM) and identifying issues hindering its implementation. A total of 15 users of GMM participated in semi-structured face-to-face interviews, whi

  18. Fetal microglial in vitro phenotype depends on prior in vivo inflammation

    Directory of Open Access Journals (Sweden)

    Marina Cortes

    2015-08-01

    Discussion. We identified a unique HMOX1down and FBPup phenotype of microglia exposed to the double-hit suggesting interplay of inflammatory and metabolic pathways as a memory of prior inflammatory insult. These findings suggest new therapeutic targets for early postnatal intervention to prevent brain injury.

  19. Quantitative phenotyping of powdery mildew resistance in grapevine reveals differences in host resistance biology

    Science.gov (United States)

    The recent demonstration of race-specific resistance to Erysiphe necator has encouraged grapevine breeders to identify and introgress quantitative resistance genes exhibiting complementary mechanisms. In 2012, we established a phenotyping center (VitisGenPM) for detailed evaluation of resistance to...

  20. New interview and observation measures of the broader autism phenotype : group differentiation

    NARCIS (Netherlands)

    de Jonge, Maretha; Parr, Jeremy; Rutter, Michael; Wallace, Simon; Kemner, Chantal; Bailey, Anthony; van Engeland, Herman; Pickles, Andrew

    2015-01-01

    To identify the broader autism phenotype (BAP), the Family History Interview subject and informant versions and an observational tool (Impression of Interviewee), were developed. This study investigated whether the instruments differentiated between parents of children with autism, and parents of ch

  1. Research to Identify Effective Antifungal Agents, 1993 Annual Report.

    Energy Technology Data Exchange (ETDEWEB)

    Schreck, Carl

    1993-10-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990, 1991, and 1992). The objectives of the present study were to select and evaluate candidate fungicides.

  2. Research to Identify Effective Antifungal Agents, 1991 Annual Report.

    Energy Technology Data Exchange (ETDEWEB)

    Schreck, Carl

    1991-09-01

    This study is a continuation of ``Research to Identify Effective Antifungal Agents'' sponsored by Bonneville Power Administration (Schreck et al. 1990). The objectives of the present study was to evaluate up to 10 candidate fungicides.

  3. Transcriptome sequencing in prostate cancer identifies inter-tumor heterogeneity

    Directory of Open Access Journals (Sweden)

    Janet Mendonca

    2015-06-01

    Full Text Available Given the dearth of gene mutations in prostate cancer, [1] ,[2] it is likely that genomic rearrangements play a significant role in the evolution of prostate cancer. However, in the search for recurrent genomic alterations, "private alterations" have received less attention. Such alterations may provide insights into the evolution, behavior, and clinical outcome of an individual tumor. In a recent report in "Genome Biology" Wyatt et al. [3] defines unique alterations in a cohort of high-risk prostate cancer patient with a lethal phenotype. Utilizing a transcriptome sequencing approach they observe high inter-tumor heterogeneity; however, the genes altered distill into three distinct cancer-relevant pathways. Their analysis reveals the presence of several non-ETS fusions, which may contribute to the phenotype of individual tumors, and have significance for disease progression.

  4. Next-generation sequencing of 28 ALS-related genes in a Japanese ALS cohort.

    Science.gov (United States)

    Nakamura, Ryoichi; Sone, Jun; Atsuta, Naoki; Tohnai, Genki; Watanabe, Hazuki; Yokoi, Daichi; Nakatochi, Masahiro; Watanabe, Hirohisa; Ito, Mizuki; Senda, Jo; Katsuno, Masahisa; Tanaka, Fumiaki; Li, Yuanzhe; Izumi, Yuishin; Morita, Mitsuya; Taniguchi, Akira; Kano, Osamu; Oda, Masaya; Kuwabara, Satoshi; Abe, Koji; Aiba, Ikuko; Okamoto, Koichi; Mizoguchi, Kouichi; Hasegawa, Kazuko; Aoki, Masashi; Hattori, Nobutaka; Tsuji, Shoji; Nakashima, Kenji; Kaji, Ryuji; Sobue, Gen

    2016-03-01

    We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the first extensive genetic screening of Japanese ALS patients. These findings are useful for developing genetic screening and counseling strategies for such patients. PMID:26742954

  5. Orientation relationship of eutectoid FeAl and FeAl2

    Science.gov (United States)

    Scherf, A.; Kauffmann, A.; Kauffmann-Weiss, S.; Scherer, T.; Li, X.; Stein, F.; Heilmaier, M.

    2016-01-01

    Fe–Al alloys in the aluminium range of 55–65 at.% exhibit a lamellar microstructure of B2-ordered FeAl and triclinic FeAl2, which is caused by a eutectoid decomposition of the high-temperature Fe5Al8 phase, the so-called ∊ phase. The orientation relationship of FeAl and FeAl2 has previously been studied by Bastin et al. [J. Cryst. Growth (1978 ▸), 43, 745] and Hirata et al. [Philos. Mag. Lett. (2008 ▸), 88, 491]. Since both results are based on different crystallographic data regarding FeAl2, the data are re-evaluated with respect to a recent re-determination of the FeAl2 phase provided by Chumak et al. [Acta Cryst. (2010 ▸), C66, i87]. It is found that both orientation relationships match subsequent to a rotation operation of 180° about a 〈112〉 crystallographic axis of FeAl or by applying the inversion symmetry of the FeAl2 crystal structure as suggested by the Chumak data set. Experimental evidence for the validity of the previously determined orientation relationships was found in as-cast fully lamellar material (random texture) as well as directionally solidified material (∼〈110〉FeAl || solidification direction) by means of orientation imaging microscopy and global texture measurements. In addition, a preferential interface between FeAl and FeAl2 was identified by means of trace analyses using cross sectioning with a focused ion beam. On the basis of these habit planes the orientation relationship between the two phases can be described by (01)FeAl || (114) and [111]FeAl || [10]. There is no evidence for twinning within FeAl lamellae or alternating orientations of FeAl lamellae. Based on the determined orientation and interface data, an atomistic model of the structure relationship of Fe5Al8, FeAl and FeAl2 in the vicinity of the eutectoid decomposition is derived. This model is analysed with respect to the strain which has to be accommodated at the interface of FeAl and FeAl2. PMID:27047304

  6. Cotton phenotyping with lidar from a track-mounted platform

    Science.gov (United States)

    French, Andrew N.; Gore, Michael A.; Thompson, Alison

    2016-05-01

    High-Throughput Phenotyping (HTP) is a discipline for rapidly identifying plant architectural and physiological responses to environmental factors such as heat and water stress. Experiments conducted since 2010 at Maricopa, Arizona with a three-fold sensor group, including thermal infrared radiometers, active visible/near infrared reflectance sensors, and acoustic plant height sensors, have shown the validity of HTP with a tractor-based system. However, results from these experiments also show that accuracy of plant phenotyping is limited by the system's inability to discriminate plant components and their local environmental conditions. This limitation may be overcome with plant imaging and laser scanning which can help map details in plant architecture and sunlit/shaded leaves. To test the capability for mapping cotton plants with a laser system, a track-mounted platform was deployed in 2015 over a full canopy and defoliated cotton crop consisting of a scanning LIDAR driven by Arduinocontrolled stepper motors. Using custom Python and Tkinter code, the platform moved autonomously along a pipe-track at 0.1 m/s while collecting LIDAR scans at 25 Hz (0.1667 deg. beam). These tests showed that an autonomous LIDAR platform can reduce HTP logistical problems and provide the capability to accurately map cotton plants and cotton bolls. A prototype track-mounted platform was developed to test the use of LIDAR scanning for High- Throughput Phenotyping (HTP). The platform was deployed in 2015 at Maricopa, Arizona over a senescent cotton crop. Using custom Python and Tkinter code, the platform moved autonomously along a pipe-track at <1 m/s while collecting LIDAR scans at 25 Hz (0.1667 deg. beam). Scanning data mapped the canopy heights and widths, and detected cotton bolls.

  7. Multidimensional Neuropathic Pain Phenotypes after Spinal Cord Injury.

    Science.gov (United States)

    Widerström-Noga, Eva; Felix, Elizabeth R; Adcock, James P; Escalona, Maydelis; Tibbett, Jacqueline

    2016-03-01

    Identifying clinical neuropathic pain phenotypes is a first step to better understand the underlying pain mechanisms after spinal cord injury (SCI). The primary purpose of the present study was to characterize multidimensional neuropathic pain phenotypes based on quantitative sensory testing (QST), pain intensity, and utilization of catastrophizing coping strategies. Thermal perception, thermal pain, and vibratory perception thresholds were assessed above and below the level of injury (LOI) in 101 persons with SCI and neuropathic pain, 18 persons with SCI and no neuropathic pain, and 50 able-bodied, pain-free controls. Cluster analysis of QST z-scores below the LOI, pain intensity ratings, and the Coping Strategies Questionnaire (CSQ) catastrophizing subscale scores in subjects with neuropathic pain resulted in two phenotypes: severe neuropathic pain (SNP) with greater pain intensity (7.39 ± 1.57) and thermal and vibratory sensitivity compared with the moderate neuropathic pain (MNP; 5.40 ± 1.43). A factor analysis including all CSQ subscales, the Neuropathic Pain Symptom Inventory (NPSI) total score, and thermal pain sensitivity above and below the LOI resulted in three factors: (1) adaptive pain coping including increasing activities, diverting attention, and reinterpreting pain sensations; (2) catastrophizing, neuropathic pain, and thermal sensitivity including greater NPSI total score, thermal pain sensitivity below the LOI, and catastrophizing; and (3) general pain sensitivity including greater thermal pain sensitivity above the LOI and lower catastrophizing. Our results suggest that neuropathic pain symptom severity post-SCI is significantly associated with residual spinothalamic tract function below the LOI and catastrophizing pain coping. PMID:26414803

  8. EEG alpha phenotypes: linkage analyses and relation to alcohol dependence in an American Indian community study

    Directory of Open Access Journals (Sweden)

    Phillips Evelyn

    2010-03-01

    Full Text Available Abstract Background Evidence for a high degree of heritability of EEG alpha phenotypes has been demonstrated in twin and family studies in a number of populations. However, information on linkage of this phenotype to specific chromosome locations is still limited. This study's aims were to map loci linked to EEG alpha phenotypes and to determine if there was overlap with loci previously mapped for alcohol dependence in an American Indian community at high risk for substance dependence. Methods Each participant gave a blood sample and completed a structured diagnostic interview using the Semi Structured Assessment for the Genetics of Alcoholism. Bipolar EEGs were collected and spectral power determined in the alpha (7.5-12.0 Hz frequency band for two composite scalp locations previously identified by principal components analyses (bilateral fronto-central and bilateral centro-parietal-occipital. Genotypes were determined for a panel of 791 micro-satellite polymorphisms in 410 members of multiplex families using SOLAR. Results Sixty percent of this study population had a lifetime diagnosis of alcohol dependence. Analyses of multipoint variance component LOD scores, for the EEG alpha power phenotype, revealed two loci that had a LOD score of 3.0 or above for the fronto-central scalp region on chromosomes 1 and 6. Additionally, 4 locations were identified with LOD scores above 2.0 on chromosomes 4, 11, 14, 16 for the fronto-central location and one on chromosome 2 for the centro-parietal-occipital location. Conclusion These results corroborate the importance of regions on chromosome 4 and 6 highlighted in prior segregation studies in this and other populations for alcohol dependence-related phenotypes, as well as other areas that overlap with other substance dependence phenotypes identified in previous linkage studies in other populations. These studies additionally support the construct that EEG alpha recorded from fronto-central scalp areas may

  9. Endemic species have highly integrated phenotypes, environmental distributions and phenotype-environment relationships

    NARCIS (Netherlands)

    Hermant, M.; Prinzing, A.; Vernon, P.; Convey, P.; Hennion, F.

    2013-01-01

    Keywords: Abiotic environmental gradients; endemism level; functional biogeography; island biogeography; Kerguelen Islands; life-history traits; multi-species comparison; phenotypic integration; range size; sub-Antarctic Abstract Aim: Why are some species geographically restricted? Ecological explan

  10. Health-related phenotypes and longevity in Danish twins

    DEFF Research Database (Denmark)

    Kulminski, Alexander M; Arbeev, Konstantin G; Culminskaya, Irina V;

    2009-01-01

    Aging studies can be facilitated by refocusing from longevity phenotypes to their proxies (intermediate phenotypes). Robust selection of the intermediate phenotypes requires data on such phenotypes and life span measured in the same individuals, which is not always the case in aging studies. A...... promising approach is to select intermediate phenotypes using information on longevity measured in related individuals. We evaluated feasibility of this approach focusing on 32 geriatric diseases as potential intermediate phenotypes of longevity assessed in the Longitudinal Study of Aging Danish Twins. Our...

  11. Aussprache als motorische Fertigkeit

    DEFF Research Database (Denmark)

    Bonner, Maria

    2013-01-01

    Authentische Aussprache gilt im Fremdsprachenunterricht als schwer erreichbares Ziel, fremdsprachlicher Akzent wird als nahezu unvermeidbar gesehen. Weder die Hypothese einer kritischen Periode für den Erwerb einer authentischen Aussprache noch das Konzept der Fossilierung im Sprachlernprozess...

  12. Amyotrophic Lateral Sclerosis (ALS)

    Science.gov (United States)

    ... benefit of 16 months before onset of severe respiratory failure. Other treatments are designed to relieve symptoms and ... of ALS. Most people with ALS die from respiratory failure, usually within 3 to 5 years from the ...

  13. Initial Symptoms of ALS

    Science.gov (United States)

    ... Chapters Certified Centers and Clinics Support Groups About ALS About Us Our Research In Your Community Advocate ... Diagnosis En español Symptoms The initial symptoms of ALS can be quite varied in different people. One ...

  14. Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

    DEFF Research Database (Denmark)

    van Hecke, Oliver; Kamerman, Peter R; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L H; Bennett, Michael I; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S; Raja, Srinivasa N; Rice, Andrew S C; Seltzer, Zeʼev; Thorgeirsson, Thorgeir E; Yarnitsky, David; Smith, Blair H

    2015-01-01

    phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity......" neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration...

  15. Identification of Markers Associated with Highly Aggressive Metastatic Phenotypes Using Quantitative Comparative Proteomics

    DEFF Research Database (Denmark)

    Terp, Mikkel Green; Lund, Rikke Raaen; Jensen, Ole Nørregaard;

    phenotypes. To identify proteins associated with cancer cell aggressiveness, we used comparative quantitative liquid chromatography-tandem mass spectrometry (LC-MS/MS) proteome analysis of a unique metastasis model comprised of three isogenic human breast cancer cell lines that are equally tumorigenic in...... per se. Our study provides novel insights into key proteins associated with the metastatic potential of breast cancer cells and identified LRRC59, CD59 and CSPG4 as candidates that merit further study....

  16. Identification of genomic regions associated with phenotypic variation between dog breeds using selection mapping.

    OpenAIRE

    Vaysse, Amaury; Ratnakumar, Abhirami; Derrien, Thomas; Axelsson, Erik; Rosengren Pielberg, Gerli; Sigurdsson, Snaevar; Fall, Tove; Seppälä, Eija; Hansen, Mark,; Lawley, Cindy; Karlsson, Elinor; Bannasch, Danika; Vilà, Carles; Lohi, Hannes; Galibert, Francis

    2011-01-01

    The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Ge...

  17. Identification of Genomic Regions Associated with Phenotypic Variation between Dog Breeds using Selection Mapping

    OpenAIRE

    Vaysse, Amaury; Ratnakumar, Abhirami; Derrien, Thomas; Axelsson, Erik; Rosengren Pielberg, Gerli; Sigurdsson, Snaevar; Fall, Tove; Seppälä, Eija H; Hansen, Mark S. T.; Lawley, Cindy T.; Karlsson, Elinor K.; Bannasch, Danika; Vilà, Carles; Lohi, Hannes; Galibert, Francis

    2011-01-01

    The extraordinary phenotypic diversity of dog breeds has been sculpted by a unique population history accompanied by selection for novel and desirable traits. Here we perform a comprehensive analysis using multiple test statistics to identify regions under selection in 509 dogs from 46 diverse breeds using a newly developed high-density genotyping array consisting of >170,000 evenly spaced SNPs. We first identify 44 genomic regions exhibiting extreme differentiation across multiple breeds. Ge...

  18. Spare capacity and phenotypic flexibility in the digestive system of a migratory bird: defining the limits of animal design

    OpenAIRE

    McWilliams, Scott R.; William H Karasov

    2014-01-01

    Flexible phenotypes enable animals to live in environments that change over space and time, and knowing the limits to and the required time scale for this flexibility provides insights into constraints on energy and nutrient intake, diet diversity and niche width. We quantified the level of immediate and ultimate spare capacity, and thus the extent of phenotypic flexibility, in the digestive system of a migratory bird in response to increased energy demand, and identified the digestive constr...

  19. Elevated Dehydroepiandrosterone Sulfate Levels as the Reproductive Phenotype in the Brothers of Women with Polycystic Ovary Syndrome

    OpenAIRE

    Legro, Richard S.; Kunselman, Allen R.; DEMERS, LAWRENCE; Wang, Steve C.; Bentley-Lewis, Rhonda; Dunaif, Andrea

    2002-01-01

    There is an inherited susceptibility to polycystic ovary syndrome (PCOS). Some investigators have suggested that premature male-pattern balding is a male phenotype in PCOS families, but this remains controversial. We recently reported evidence for an autosomal monogenic abnormality in ovarian and adrenal steroidogenesis in the sisters of women with PCOS. We performed this study to determine whether we could identify a clinical or biochemical phenotype in the brothers of women with PCOS. One h...

  20. Belief propagation in genotype-phenotype networks.

    Science.gov (United States)

    Moharil, Janhavi; May, Paul; Gaile, Daniel P; Blair, Rachael Hageman

    2016-03-01

    Graphical models have proven to be a valuable tool for connecting genotypes and phenotypes. Structural learning of phenotype-genotype networks has received considerable attention in the post-genome era. In recent years, a dozen different methods have emerged for network inference, which leverage natural variation that arises in certain genetic populations. The structure of the network itself can be used to form hypotheses based on the inferred direct and indirect network relationships, but represents a premature endpoint to the graphical analyses. In this work, we extend this endpoint. We examine the unexplored problem of perturbing a given network structure, and quantifying the system-wide effects on the network in a node-wise manner. The perturbation is achieved through the setting of values of phenotype node(s), which may reflect an inhibition or activation, and propagating this information through the entire network. We leverage belief propagation methods in Conditional Gaussian Bayesian Networks (CG-BNs), in order to absorb and propagate phenotypic evidence through the network. We show that the modeling assumptions adopted for genotype-phenotype networks represent an important sub-class of CG-BNs, which possess properties that ensure exact inference in the propagation scheme. The system-wide effects of the perturbation are quantified in a node-wise manner through the comparison of perturbed and unperturbed marginal distributions using a symmetric Kullback-Leibler divergence. Applications to kidney and skin cancer expression quantitative trait loci (eQTL) data from different mus musculus populations are presented. System-wide effects in the network were predicted and visualized across a spectrum of evidence. Sub-pathways and regions of the network responded in concert, suggesting co-regulation and coordination throughout the network in response to phenotypic changes. We demonstrate how these predicted system-wide effects can be examined in connection with

  1. The Human Phenotype Ontology project: linking molecular biology and disease through phenotype data

    Science.gov (United States)

    Köhler, Sebastian; Doelken, Sandra C.; Mungall, Christopher J.; Bauer, Sebastian; Firth, Helen V.; Bailleul-Forestier, Isabelle; Black, Graeme C. M.; Brown, Danielle L.; Brudno, Michael; Campbell, Jennifer; FitzPatrick, David R.; Eppig, Janan T.; Jackson, Andrew P.; Freson, Kathleen; Girdea, Marta; Helbig, Ingo; Hurst, Jane A.; Jähn, Johanna; Jackson, Laird G.; Kelly, Anne M.; Ledbetter, David H.; Mansour, Sahar; Martin, Christa L.; Moss, Celia; Mumford, Andrew; Ouwehand, Willem H.; Park, Soo-Mi; Riggs, Erin Rooney; Scott, Richard H.; Sisodiya, Sanjay; Vooren, Steven Van; Wapner, Ronald J.; Wilkie, Andrew O. M.; Wright, Caroline F.; Vulto-van Silfhout, Anneke T.; de Leeuw, Nicole; de Vries, Bert B. A.; Washingthon, Nicole L.; Smith, Cynthia L.; Westerfield, Monte; Schofield, Paul; Ruef, Barbara J.; Gkoutos, Georgios V.; Haendel, Melissa; Smedley, Damian; Lewis, Suzanna E.; Robinson, Peter N.

    2014-01-01

    The Human Phenotype Ontology (HPO) project, available at http://www.human-phenotype-ontology.org, provides a structured, comprehensive and well-defined set of 10,088 classes (terms) describing human phenotypic abnormalities and 13,326 subclass relations between the HPO classes. In addition we have developed logical definitions for 46% of all HPO classes using terms from ontologies for anatomy, cell types, function, embryology, pathology and other domains. This allows interoperability with several resources, especially those containing phenotype information on model organisms such as mouse and zebrafish. Here we describe the updated HPO database, which provides annotations of 7,278 human hereditary syndromes listed in OMIM, Orphanet and DECIPHER to classes of the HPO. Various meta-attributes such as frequency, references and negations are associated with each annotation. Several large-scale projects worldwide utilize the HPO for describing phenotype information in their datasets. We have therefore generated equivalence mappings to other phenotype vocabularies such as LDDB, Orphanet, MedDRA, UMLS and phenoDB, allowing integration of existing datasets and interoperability with multiple biomedical resources. We have created various ways to access the HPO database content using flat files, a MySQL database, and Web-based tools. All data and documentation on the HPO project can be found online. PMID:24217912

  2. A Systematic Review of Phenotypic Features Associated With Cardiac Troponin I Mutations in Hereditary Cardiomyopathies

    DEFF Research Database (Denmark)

    Mogensen, Jens; Hey, Thomas; Lambrecht, Sascha

    2015-01-01

    BACKGROUND: Genetic investigations have established that mutations in proteins of the contractile unit of the myocardium, known as the sarcomere, may be associated with hypertrophic cardiomyopathy (HCM), restrictive cardiomyopathy (RCM), and dilated cardiomyopathy (DCM). It has become clinical...... in relation to phenotypic features reported to be associated with mutations in cardiac troponin I (cTnI; TNNI3), which is a recognized sarcomeric disease gene in all 3 cardiomyopathies. RESULTS: The results of this review did not identify specific genotype-phenotype relations in HCM or DCM, and c...

  3. Can structural neuroimaging be used to define phenotypes and course of schizophrenia?

    Science.gov (United States)

    Kerns, John G; Lauriello, John

    2012-09-01

    This article examines whether structural neuroimaging measures have been found to predict outcome in schizophrenia and whether changes in neuroimaging measures have been found to correlate with poor outcome in the disorder. Overall, there is little compelling evidence that structural neuroimaging measures in either first-episode or chronic patients predict future outcome. Progressive brain changes might reflect a neuroimaging phenotype associated with a worse course of the disorder. At the same time, there are many fruitful avenues that future research could take in an attempt to better predict future outcome or to identify specific imaging phenotypes associated with outcome. PMID:22929870

  4. Markov chain Monte Carlo linkage analysis of a complex qualitative phenotype.

    Science.gov (United States)

    Hinrichs, A; Lin, J H; Reich, T; Bierut, L; Suarez, B K

    1999-01-01

    We tested a new computer program, LOKI, that implements a reversible jump Markov chain Monte Carlo (MCMC) technique for segregation and linkage analysis. Our objective was to determine whether this software, designed for use with continuously distributed phenotypes, has any efficacy when applied to the discrete disease states of the simulated data from the Mordor data from GAW Problem 1. Although we were able to identify the genomic location for two of the three quantitative trait loci by repeated application of the software, the MCMC sampler experienced significant mixing problems indicating that the method, as currently formulated in LOKI, was not suitable for the discrete phenotypes in this data set. PMID:10597502

  5. Classification of dendritic cell phenotypes from gene expression data

    Directory of Open Access Journals (Sweden)

    Zolezzi Francesca

    2011-08-01

    Full Text Available Abstract Background The selection of relevant genes for sample classification is a common task in many gene expression studies. Although a number of tools have been developed to identify optimal gene expression signatures, they often generate gene lists that are too long to be exploited clinically. Consequently, researchers in the field try to identify the smallest set of genes that provide good sample classification. We investigated the genome-wide expression of the inflammatory phenotype in dendritic cells. Dendritic cells are a complex group of cells that play a critical role in vertebrate immunity. Therefore, the prediction of the inflammatory phenotype in these cells may help with the selection of immune-modulating compounds. Results A data mining protocol was applied to microarray data for murine cell lines treated with various inflammatory stimuli. The learning and validation data sets consisted of 155 and 49 samples, respectively. The data mining protocol reduced the number of probe sets from 5,802 to 10, then from 10 to 6 and finally from 6 to 3. The performances of a set of supervised classification models were compared. The best accuracy, when using the six following genes --Il12b, Cd40, Socs3, Irgm1, Plin2 and Lgals3bp-- was obtained by Tree Augmented Naïve Bayes and Nearest Neighbour (91.8%. Using the smallest set of three genes --Il12b, Cd40 and Socs3-- the performance remained satisfactory and the best accuracy was with Support Vector Machine (95.9%. These data mining models, using data for the genes Il12b, Cd40 and Socs3, were validated with a human data set consisting of 27 samples. Support Vector Machines (71.4% and Nearest Neighbour (92.6% gave the worst performances, but the remaining models correctly classified all the 27 samples. Conclusions The genes selected by the data mining protocol proposed were shown to be informative for discriminating between inflammatory and steady-state phenotypes in dendritic cells. The

  6. Doublecortin May Play a Role in Defining Chondrocyte Phenotype

    Directory of Open Access Journals (Sweden)

    Dongxia Ge

    2014-04-01

    Full Text Available Embryonic development of articular cartilage has not been well understood and the role of doublecortin (DCX in determination of chondrocyte phenotype is unknown. Here, we use a DCX promoter-driven eGFP reporter mouse model to study the dynamic gene expression profiles in mouse embryonic handplates at E12.5 to E13.5 when the condensed mesenchymal cells differentiate into either endochondral chondrocytes or joint interzone cells. Illumina microarray analysis identified a variety of genes that were expressed differentially in the different regions of mouse handplate. The unique expression patterns of many genes were revealed. Cytl1 and 3110032G18RIK were highly expressed in the proximal region of E12.5 handplate and the carpal region of E13.5 handplate, whereas Olfr538, Kctd15, and Cited1 were highly expressed in the distal region of E12.5 and the metacarpal region of E13.5 handplates. There was an increasing gradient of Hrc expression in the proximal to distal direction in E13.5 handplate. Furthermore, when human DCX protein was expressed in human adipose stem cells, collagen II was decreased while aggrecan, matrilin 2, and GDF5 were increased during the 14-day pellet culture. These findings suggest that DCX may play a role in defining chondrocyte phenotype.

  7. Quantitative phenotypic and pathway profiling guides rational drug combination strategies

    Directory of Open Access Journals (Sweden)

    NeilOCarragher

    2014-05-01

    Full Text Available Advances in target-based drug discovery strategies have enabled drug discovery groups in academia and industry to become very effective at generating molecules that are potent and selective against single targets. However, it has become apparent from disappointing results in recent clinical trials that a major challenge to the development of successful targeted therapies for treating complex multifactorial diseases is overcoming heterogeneity in target mechanism among patients and inherent or acquired drug resistance. Consequently, reductionist target directed drug-discovery approaches are not appropriately tailored towards identifying and optimizing multi-targeted therapeutics or rational drug combinations for complex disease. In this article, we describe the application of emerging high-content phenotypic profiling and analysis tools to support robust evaluation of drug combination performance following dose-ratio matrix screening. We further describe how the incorporation of high-throughput reverse phase protein microarrays with phenotypic screening can provide rational drug combination hypotheses but also confirm the mechanism-of-action of novel drug combinations, to facilitate future preclinical and clinical development strategies.

  8. Aarskog-Scott syndrome: phenotypic and genetic heterogeneity

    Directory of Open Access Journals (Sweden)

    Ignacio Briceno

    2016-03-01

    Full Text Available Aarskog-Scott syndrome (AAS is a rare developmental disorder which primarily affects males and has a relative prevalence of 1 in 25,000 in the general population. AAS patients usually present with developmental complications including short stature and facial, skeletal and urogenital anomalies. The spectrum of genotype-phenotype correlations in AAS is unclear and mutations of the FGD1 gene on the proximal short arm of chromosome X account for only 20% of the incidence of the disorder. Failure to identify pathogenic variants in patients referred for FGD1 screening suggests heterogeneity underlying pathophysiology of the condition. Furthermore, overlapping features of AAS with several other developmental disorders increase the complexity of diagnosis. Cytoskeletal signaling may be involved in the pathophysiology of AAS. The FGD1 protein family has a role in activation of CDC42 (Cell Division Control protein 42 homolog which has a core function in remodeling of extracellular matrix and the transcriptional activation of many modulators of development. Therefore, mutations in components in the EGFR1 (Epidermal Growth Factor Receptor 1 signaling pathway, to which CDC42 belongs, may contribute to pathophysiology. Parallel sequencing strategies (so-called next generation sequencing or high throughput sequencing enables simultaneous production of millions of sequencing reads that enormously facilitate cost-effective identification of cryptic mutations in heterogeneous monogenic disorders. Here we review the source of phenotypic and genetic heterogeneity in the context of AAS and discuss the applicability of next generation sequencing for identification of novel mutations underlying AAS.

  9. DNA methylation: conducting the orchestra from exposure to phenotype?

    Science.gov (United States)

    Leenen, Fleur A D; Muller, Claude P; Turner, Jonathan D

    2016-01-01

    DNA methylation, through 5-methyl- and 5-hydroxymethylcytosine (5mC and 5hmC), is considered to be one of the principal interfaces between the genome and our environment, and it helps explain phenotypic variations in human populations. Initial reports of large differences in methylation level in genomic regulatory regions, coupled with clear gene expression data in both imprinted genes and malignant diseases, provided easily dissected molecular mechanisms for switching genes on or off. However, a more subtle process is becoming evident, where small (disease phenotypes. This has resulted in two clear methylation paradigms. The latter "subtle change" paradigm is rapidly becoming the epigenetic hallmark of complex disease phenotypes, although we are currently hampered by a lack of data addressing the true biological significance and meaning of these small differences. Our initial expectation of rapidly identifying mechanisms linking environmental exposure to a disease phenotype led to numerous observational/association studies being performed. Although this expectation remains unmet, there is now a growing body of literature on specific genes, suggesting wide ranging transcriptional and translational consequences of such subtle methylation changes. Data from the glucocorticoid receptor (NR3C1) has shown that a complex interplay between DNA methylation, extensive 5'UTR splicing, and microvariability gives rise to the overall level and relative distribution of total and N-terminal protein isoforms generated. Additionally, the presence of multiple AUG translation initiation codons throughout the complete, processed mRNA enables translation variability, hereby enhancing the translational isoforms and the resulting protein isoform diversity, providing a clear link between small changes in DNA methylation and significant changes in protein isoforms and cellular locations. Methylation changes in the NR3C1 CpG island alters the NR3C1 transcription and eventually protein

  10. A novel SOD1-ALS mutation separates central and peripheral effects of mutant SOD1 toxicity

    OpenAIRE

    Joyce, Peter I.; McGoldrick, Philip; Saccon, Rachele A.; Weber, William, L.; Fratta, Pietro; West, Steven J.; Zhu, Ning; Carter, Sarah; Phatak, Vinaya; Stewart, Michelle; Simon, Michelle; Kumar, Saumya; Heise, Ines; Bros-Facer, Virginie; Dick, James

    2014-01-01

    Transgenic mouse models expressing mutant superoxide dismutase 1 (SOD1) have been critical in furthering our understanding of amyotrophic lateral sclerosis (ALS). However, such models generally overexpress the mutant protein, which may give rise to phenotypes not directly relevant to the disorder. Here, we have analysed a novel mouse model that has a point mutation in the endogenous mouse Sod1 gene; this mutation is identical to a pathological change in human familial ALS (fALS) which results...

  11. Identifying Phronotypes in Psychiatry

    Directory of Open Access Journals (Sweden)

    F. AndrewKozel

    2010-10-01

    Full Text Available Refinements in the methods of diagnosis for psychiatric disorders are critically needed. These new methods should be based on objectively measured brain characteristics that provide clinically useful information. Studying the brain with respect to psychiatric disorders, however, faces numerous challenges. Utilizing techniques learned in other areas of medicine to deal with symptoms that lead to complex disorders can provide insight into improving diagnostic models in psychiatry. Specifically, many areas of medicine use objective measures of an organ’s function or characteristic to guide clinical management of particular subjective complaints. In psychiatry, an objectively measured brain characteristic that provides clinically useful information is proposed to be that person’s “phronotype.” Important requirements to developing phronotypes are discussed. Identifying phronotypes in psychiatry will require a specific investigative approach that must be grounded in rigorous scientific methodology. Successfully developing such markers will have a profound impact on clinical care, clinical research, basic science research, and most importantly the lives of those suffering from these illnesses.

  12. SigniSite: Identification of residue-level genotype-phenotype correlations in protein multiple sequence alignments.

    Science.gov (United States)

    Jessen, Leon Eyrich; Hoof, Ilka; Lund, Ole; Nielsen, Morten

    2013-07-01

    Identifying which mutation(s) within a given genotype is responsible for an observable phenotype is important in many aspects of molecular biology. Here, we present SigniSite, an online application for subgroup-free residue-level genotype-phenotype correlation. In contrast to similar methods, SigniSite does not require any pre-definition of subgroups or binary classification. Input is a set of protein sequences where each sequence has an associated real number, quantifying a given phenotype. SigniSite will then identify which amino acid residues are significantly associated with the data set phenotype. As output, SigniSite displays a sequence logo, depicting the strength of the phenotype association of each residue and a heat-map identifying 'hot' or 'cold' regions. SigniSite was benchmarked against SPEER, a state-of-the-art method for the prediction of specificity determining positions (SDP) using a set of human immunodeficiency virus protease-inhibitor genotype-phenotype data and corresponding resistance mutation scores from the Stanford University HIV Drug Resistance Database, and a data set of protein families with experimentally annotated SDPs. For both data sets, SigniSite was found to outperform SPEER. SigniSite is available at: http://www.cbs.dtu.dk/services/SigniSite/. PMID:23761454

  13. Temporal lobe epilepsy and GEFS+ phenotypes associated with SCN1B mutations.

    Science.gov (United States)

    Scheffer, Ingrid E; Harkin, Louise A; Grinton, Bronwyn E; Dibbens, Leanne M; Turner, Samantha J; Zielinski, Marta A; Xu, Ruwei; Jackson, Graeme; Adams, Judith; Connellan, Mary; Petrou, Steven; Wellard, R Mark; Briellmann, Regula S; Wallace, Robyn H; Mulley, John C; Berkovic, Samuel F

    2007-01-01

    SCN1B, the gene encoding the sodium channel beta 1 subunit, was the first gene identified for generalized epilepsy with febrile seizures plus (GEFS+). Only three families have been published with SCN1B mutations. Here, we present four new families with SCN1B mutations and characterize the associated phenotypes. Analysis of SCN1B was performed on 402 individuals with various epilepsy syndromes. Four probands with missense mutations were identified. Detailed electroclinical phenotyping was performed on all available affected family members including quantitative MR imaging in those with temporal lobe epilepsy (TLE). Two new families with the original C121W SCN1B mutation were identified; novel mutations R85C and R85H were each found in one family. The following phenotypes occurred in the six families with SCN1B missense mutations: 22 febrile seizures, 20 febrile seizures plus, five TLE, three other GEFS+ phenotypes, two unclassified and ten unaffected individuals. All individuals with confirmed TLE had the C121W mutation; two underwent temporal lobectomy (one with hippocampal sclerosis and one without) and both are seizure free. We confirm the role of SCN1B in GEFS+ and show that the GEFS+ spectrum may include TLE alone. TLE with an SCN1B mutation is not a contraindication to epilepsy surgery. PMID:17020904

  14. Species identification of invasive yeasts including Candida in Pakistan: limitations of phenotypic methods

    Science.gov (United States)

    Farooqi, Joveria; Jabeen, Kauser; Saeed, Noureen; Zafar, Afia; Brandt, Mary Eleanor; Hasan, Rumina

    2015-01-01

    Objective To compare phenotypic and genotypic methods of yeast identification. Methods The in-vitro cross-sectional study was conducted from January 2006 to May 2009. Invasive yeasts isolated at the clinical microbiology laboratory at the Aga Khan University (AKU), Karachi, Pakistan, were identified. Speciation by phenotypic and molecular methods was compared. All yeasts isolated during the study period from blood and other invasive sites were identified using standard methods. Isolates were shipped to Mycotic Diseases Branch, Centres for Disease Control and Prevention, Atlanta, Georgia, USA, for identification by Luminex flow cytometric multianalyte profiling (xMAP) system. Ribosomal ITS2 DNA sequencing was performed on isolates not identified by Luminex. Result Of the 214 invasive yeasts evaluated, Candida species were 209 (97.7%) while the frequency of non-Candida species was 5 (2.3%). Overall agreement between phenotypic and molecular identification was 81.3%, 90.3% amongst the more common Candida species, and only 38.8% amongst the uncommon yeasts. Conclusion Phenotypic methods of identification proved adequate for common Candida species, but were deficient in recognising rare Candida and non-Candida yeasts, highlighting the importance of molecular methods for identification. PMID:23866432

  15. Evolution of environmental cues for phenotypic plasticity.

    Science.gov (United States)

    Chevin, Luis-Miguel; Lande, Russell

    2015-10-01

    Phenotypically plastic characters may respond to multiple variables in their environment, but the evolutionary consequences of this phenomenon have rarely been addressed theoretically. We model the evolution of linear reaction norms in response to several correlated environmental variables, in a population undergoing stationary environmental fluctuations. At evolutionary equilibrium, the linear combination of environmental variables that acts as a developmental cue for the plastic trait is the multivariate best linear predictor of changes in the optimum. However, the reaction norm with respect to any single environmental variable may exhibit nonintuitive patterns. Apparently maladaptive, or hyperadaptive plasticity can evolve with respect to single environmental variables, and costs of plasticity may increase, rather than reduce, plasticity in response to some variables. We also find conditions for the evolution of an indirect environmental indicator that affects expression of a plastic phenotype, despite not influencing natural selection on it. PMID:26292649

  16. Histomorphological Phenotyping of the Adult Mouse Brain.

    Science.gov (United States)

    Mikhaleva, Anna; Kannan, Meghna; Wagner, Christel; Yalcin, Binnaz

    2016-01-01

    This article describes a series of standard operating procedures for morphological phenotyping of the mouse brain using basic histology. Many histological studies of the mouse brain use qualitative approaches based on what the human eye can detect. Consequently, some phenotypic information may be missed. Here we describe a quantitative approach for the assessment of brain morphology that is simple and robust. A total of 78 measurements are made throughout the brain at specific and well-defined regions, including the cortex, the hippocampus, and the cerebellum. Experimental design and timeline considerations, including strain background effects, the importance of sectioning quality, measurement variability, and efforts to correct human errors are discussed. © 2016 by John Wiley & Sons, Inc. PMID:27584555

  17. A Rechargeable Al/S Battery with an Ionic-Liquid Electrolyte.

    Science.gov (United States)

    Gao, Tao; Li, Xiaogang; Wang, Xiwen; Hu, Junkai; Han, Fudong; Fan, Xiulin; Suo, Liumin; Pearse, Alex J; Lee, Sang Bok; Rubloff, Gary W; Gaskell, Karen J; Noked, Malachi; Wang, Chunsheng

    2016-08-16

    Aluminum metal is a promising anode material for next generation rechargeable batteries owing to its abundance, potentially dendrite-free deposition, and high capacity. The rechargeable aluminum/sulfur (Al/S) battery is of great interest owing to its high energy density (1340 Wh kg(-1) ) and low cost. However, Al/S chemistry suffers poor reversibility owing to the difficulty of oxidizing AlSx . Herein, we demonstrate the first reversible Al/S battery in ionic-liquid electrolyte with an activated carbon cloth/sulfur composite cathode. Electrochemical, spectroscopic, and microscopic results suggest that sulfur undergoes a solid-state conversion reaction in the electrolyte. Kinetics analysis identifies that the slow solid-state sulfur conversion reaction causes large voltage hysteresis and limits the energy efficiency of the system. PMID:27417442

  18. Sleep Duration and Breast Cancer Phenotype

    OpenAIRE

    Ali Khawaja; Santosh Rao; Li Li; Thompson, Cheryl L.

    2013-01-01

    Emerging evidence suggests that short sleep is associated with an increased risk of cancer; however, little has been done to study the role of sleep on tumor characteristics. In this study, we evaluated the relationship between sleep duration and tumor phenotype in 972 breast cancer patients. Sleep duration was inversely associated with tumor grade (univariate P = 0.032), particularly in postmenopausal women (univariate P = 0.018). This association did not reach statistical significance after...

  19. Prions, protein homeostasis, and phenotypic diversity

    OpenAIRE

    Halfmann, Randal; Alberti, Simon; Lindquist, Susan

    2010-01-01

    Prions are fascinating but often misunderstood protein aggregation phenomena. The traditional association of the mammalian prion protein with disease has overshadowed a potentially more interesting attribute of prions: their ability to create protein-based molecular memories. In fungi, prions alter the relationship between genotype and phenotype in a heritable way that diversifies clonal populations. Recent findings in yeast indicate that prions might be much more common than previously real...

  20. Lewis phenotype, secretor status, and coeliac disease.

    OpenAIRE

    Dickey, W; Wylie, J D; Collins, J S; Porter, K G; Watson, R G; McLoughlin, J C

    1994-01-01

    Patients who cannot secrete ABO and Lewis blood group antigens into body fluids, an ability controlled by a single gene on chromosome 19, are known to be at increased risk of certain autoimmune diseases associated with human leucocyte antigen (HLA) markers. This study investigated the possibility of an association with coeliac disease using red cell Lewis (Le) blood group phenotype to infer secretor status. Among 73 patients with coeliac disease who had Le a or b antigen, 48% were non-secreto...

  1. Connectomic intermediate phenotypes for psychiatric disorders

    Directory of Open Access Journals (Sweden)

    Alex eFornito

    2012-04-01

    Full Text Available Psychiatric disorders are phenotypically heterogeneous entities with a complex genetic basis. To mitigate this complexity, many investigators study so-called intermediate phenotypes that putatively provide a more direct index of the physiological effects of candidate genetic risk variants than overt psychiatric syndromes. Magnetic resonance imaging (MRI is a particularly popular technique for measuring such phenotypes because it allows interrogation of diverse aspects of brain structure and function in vivo. Much of this work however, has focused on relatively simple measures that quantify variations in the physiology or tissue integrity of specific brain regions in isolation, contradicting an emerging consensus that most major psychiatric disorders do not arise from isolated dysfunction in one or a few brain regions, but rather from disturbed interactions within and between distributed neural circuits; i.e., they are disorders of brain connectivity. The recent proliferation of new MRI techniques for comprehensively mapping the entire connectivity architecture of the brain, termed the human connectome, has provided a rich repertoire of tools for understanding how genetic variants implicated in mental disorder impact distinct neural circuits. In this article, we review research using these connectomic techniques to understand how genetic variation influences the connectivity and topology of human brain networks. We highlight recent evidence from twin and imaging genetics studies suggesting that the penetrance of candidate risk variants for mental illness, such as those in SLC6A4, MAOA, ZNF804A and APOE, may be higher for intermediate phenotypes characterised at the level of distributed neural systems than at the level of spatially localised brain regions. The findings indicate that imaging connectomics provides a powerful framework for understanding how genetic risk for psychiatric disease is expressed through altered structure and function of

  2. Color change, phenotypic plasticity, and camouflage

    OpenAIRE

    Martin eStevens

    2016-01-01

    The ability to change appearance over a range of timescales is widespread in nature, existing in many invertebrate and vertebrate groups. This can include color change occurring in seconds, minutes, and hours, to longer term changes associated with phenotypic plasticity and development. A major function is for camouflage against predators because color change and plasticity enables animals to match their surroundings and potentially reduce the risk of predation. Recently, we published finding...

  3. Phenotypic impact of genomic structural variation

    DEFF Research Database (Denmark)

    Weischenfeldt, Joachim; Symmons, Orsolya; Spitz, François;

    2013-01-01

    Genomic structural variants have long been implicated in phenotypic diversity and human disease, but dissecting the mechanisms by which they exert their functional impact has proven elusive. Recently however, developments in high-throughput DNA sequencing and chromosomal engineering technology have...... delineating disease-causing elements that are affected by structural variants, and we discuss future directions for research on the functional consequences of structural variants....

  4. Mutator phenotypes due to DNA replication infidelity

    OpenAIRE

    Arana, Mercedes E.; Kunkel, Thomas A.

    2010-01-01

    This article considers the fidelity of DNA replication performed by eukaryotic DNA polymerases involved in replicating the nuclear genome. DNA replication fidelity can vary widely depending on the DNA polymerase, the composition of the error, the flanking sequence, the presence of DNA damage and the ability to correct errors. As a consequence, defects in processes that determine DNA replication fidelity can confer strong mutator phenotypes whose specificity can help determine the molecular na...

  5. Innate lymphocyte cells in asthma phenotypes

    OpenAIRE

    Ozyigit, Leyla Pur; MORITA, Hideaki; Akdis, Mubeccel

    2015-01-01

    T helper type 2 (TH2) cells were previously thought to be the main initiating effector cell type in asthma; however, exaggerated TH2 cell activities alone were insufficient to explain all aspects of asthma. Asthma is a heterogeneous syndrome comprising different phenotypes that are characterized by their different clinical features, treatment responses, and inflammation patterns. The most-studied subgroups of asthma include TH2-associated early-onset allergic asthma, late-onset persistent eos...

  6. Lung cancer stem cells—characteristics, phenotype

    OpenAIRE

    Hardavella, Georgia; George, Rachel; Sethi, Tariq

    2016-01-01

    Lung cancer remains a major cause of cancer-related deaths worldwide with unfavourable prognosis mainly due to the late stage of disease at presentation. High incidence and disease recurrence rates are a fact despite advances in treatment. Ongoing experimental and clinical observations suggest that the malignant phenotype in lung cancer is sustained by lung cancer stem cells (CSCs) which are putative stem cells situated throughout the airways that have the potential of initiating lung cancer ...

  7. Phenotype development in TgHD minipigs

    Czech Academy of Sciences Publication Activity Database

    Ellederová, Zdeňka; Vidinská, Daniela; Mačáková, Monika; Kučerová, S.; Bohuslavová, Božena; Sedláčková, M.; Lišková, Irena; Valeková, Ivona; Baxa, Monika; Ardan, Taras; Juhás, Štefan; Motlík, Jan

    2015-01-01

    Roč. 78, Suppl 2 (2015), s. 11-11. ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124; GA MŠk(CZ) 7F14308 Institutional support: RVO:67985904 Keywords : phenotype * minipig model of Huntington´s disease * reproductive failure Subject RIV: EB - Genetics ; Molecular Biology

  8. The Social Phenotype of Williams Syndrome

    OpenAIRE

    Järvinen, Anna; Korenberg, Julie R; Bellugi, Ursula

    2013-01-01

    Williams syndrome (WS) offers an exciting model for social neuroscience because its genetic basis is well-defined, and the unique phenotype reflects dimensions of prosocial behaviors. WS is associated with a strong drive to approach strangers, a gregarious personality, heightened social engagement yet difficult peer interactions, high non-social anxiety, unusual bias toward positive affect, and diminished sensitivity to fear. New neurobiological evidence points toward alterations in structure...

  9. Identifying features of 'pathological demand avoidance' using the Diagnostic Interview for Social and Communication Disorders (DISCO).

    Science.gov (United States)

    O'Nions, Elizabeth; Gould, Judith; Christie, Phil; Gillberg, Christopher; Viding, Essi; Happé, Francesca

    2016-04-01

    The term 'pathological demand avoidance' (PDA) was coined by Elizabeth Newson to describe children within the autism spectrum who exhibit obsessive resistance to everyday demands and requests (Newson et al., Arch Dis Child 88:595-600, 2003). Clinical accounts describe avoidance strategies including apparently strategic use of distraction or socially shocking behaviour, and obsessive need for control, reflected in domineering behaviour to peers and adults. Educational and management approaches effective for PDA reportedly differ from those for 'typical' autism spectrum disorders (ASD), and include novelty, humour and flexibility. Identification of PDA in individuals with ASD may have important implications for management (Eaton and Banting, J Learn Disabil Offending Behav 3:150-157, 2012). Despite increasing interest, no clinician-rated instrument for PDA has been developed. Here, items relevant to PDA were identified from the Diagnostic Interview for Social and Communication Disorder (DISCO) (Wing et al., J Child Psychol Psychiatry 43:307-325, 2002). The most PDA-specific subset of relevant DISCO items was selected, based on low endorsement in general across a sample of 153 individuals assessed for possible ASD using the DISCO. Having selected 11 DISCO PDA items for the measure, a subset of individuals with a high number of these features was identified (N = 27). Consistent with Newson's descriptions, this high scoring group was characterised by lack of co-operation, use of apparently manipulative behaviour, socially shocking behaviour, difficulties with other people, anxiety and sudden behavioural changes from loving to aggression. All but one case met criteria for an ASD. This study brings the field a step closer to a clinician-rated measure of PDA features and highlights the need for further elucidation of the PDA phenotype. PMID:26224583

  10. Estimating the variation, autocorrelation, and environmental sensitivity of phenotypic selection

    NARCIS (Netherlands)

    Chevin, Luis-Miguel; Visser, Marcel E.; Tufto, Jarle

    2015-01-01

    Despite considerable interest in temporal and spatial variation of phenotypic selection, very few methods allow quantifying this variation while correctly accounting for the error variance of each individual estimate. Furthermore, the available methods do not estimate the autocorrelation of phenotyp

  11. Dissecting phenotypic variation among AIS patients

    International Nuclear Information System (INIS)

    We have created genital skin fibroblast cell lines directly from three patients in a Chinese family affected by androgen insensitivity syndrome (AIS). All patients in the family share an identical AR Arg840Cys mutant but show different disease phenotypes. By using the cell lines, we find that the mutation has not influenced a normal androgen-binding capacity at 37 deg C but has reduced the affinity for androgens and may cause thermolability of the androgen-receptor complex. The impaired nuclear trafficking of the androgen receptor in the cell lines is highly correlated with the severity of donors' disease phenotype. The transactivity of the mutant is substantially weakened and the extent of the reduced transactivity reflects severity of the donors' disease symptom. Our data reveal that although etiology of AIS is monogenic and the mutant may alter the major biological functions of its wild allele, the function of the mutant AR can also be influenced by the different genetic backgrounds and thus explains the divergent disease phenotypes

  12. Reinforcing targeted therapeutics with phenotypic stability factors.

    Science.gov (United States)

    Yaswen, Paul

    2014-01-01

    Deregulated cell cycle progression can often be traced to intrinsic defects in specific regulatory proteins in cancer cells. Knowledge of these primary defects has led to targeted approaches that exploit the defects and spare normal cells. However, the success of such targeted approaches is still hit-or-miss. Genetic and epigenetic variability inherent in most tumors often results in phenotypic heterogeneity that, in turn, results in de novo or acquired resistance to therapeutic agents. The ability of cells to compensate and adapt to the inhibition of a specific cell cycle mediator is not remarkable. What is novel and of great potential importance is that the ability of cells to exhibit such adaptability varies markedly. "Phenotypic stability factors" that restrict the ability of cells to undergo epithelial-mesenchymal transitions (EMT) may dictate the success or failure of targeted therapies by interfering with compensatory changes such as deregulation of CDK2 activity. Identification of existing and new agents that induce and maintain phenotypic stability factors will inform and enable synergistic approaches to the eradication of even the most aggressive tumors. PMID:25483053

  13. MPHASYS: a mouse phenotype analysis system

    Directory of Open Access Journals (Sweden)

    Mian I

    2007-06-01

    Full Text Available Abstract Background Systematic, high-throughput studies of mouse phenotypes have been hampered by the inability to analyze individual animal data from a multitude of sources in an integrated manner. Studies generally make comparisons at the level of genotype or treatment thereby excluding associations that may be subtle or involve compound phenotypes. Additionally, the lack of integrated, standardized ontologies and methodologies for data exchange has inhibited scientific collaboration and discovery. Results Here we introduce a Mouse Phenotype Analysis System (MPHASYS, a platform for integrating data generated by studies of mouse models of human biology and disease such as aging and cancer. This computational platform is designed to provide a standardized methodology for working with animal data; a framework for data entry, analysis and sharing; and ontologies and methodologies for ensuring accurate data capture. We describe the tools that currently comprise MPHASYS, primarily ones related to mouse pathology, and outline its use in a study of individual animal-specific patterns of multiple pathology in mice harboring a specific germline mutation in the DNA repair and transcription-specific gene Xpd. Conclusion MPHASYS is a system for analyzing multiple data types from individual animals. It provides a framework for developing data analysis applications, and tools for collecting and distributing high-quality data. The software is platform independent and freely available under an open-source license 1.

  14. Phenotypic Variability in the Coccolithophore Emiliania huxleyi.

    Science.gov (United States)

    Blanco-Ameijeiras, Sonia; Lebrato, Mario; Stoll, Heather M; Iglesias-Rodriguez, Debora; Müller, Marius N; Méndez-Vicente, Ana; Oschlies, Andreas

    2016-01-01

    Coccolithophores are a vital part of oceanic phytoplankton assemblages that produce organic matter and calcium carbonate (CaCO3) containing traces of other elements (i.e. Sr and Mg). Their associated carbon export from the euphotic zone to the oceans' interior plays a crucial role in CO2 feedback mechanisms and biogeochemical cycles. The coccolithophore Emiliania huxleyi has been widely studied as a model organism to understand physiological, biogeochemical, and ecological processes in marine sciences. Here, we show the inter-strain variability in physiological and biogeochemical traits in 13 strains of E. huxleyi from various biogeographical provinces obtained from culture collections commonly used in the literature. Our results demonstrate that inter-strain genetic variability has greater potential to induce larger phenotypic differences than the phenotypic plasticity of single strains cultured under a broad range of variable environmental conditions. The range of variation found in physiological parameters and calcite Sr:Ca highlights the need to reconsider phenotypic variability in paleoproxy calibrations and model parameterizations to adequately translate findings from single strain laboratory experiments to the real ocean. PMID:27348427

  15. Olfactory phenotypic expression unveils human aging

    Science.gov (United States)

    Mazzatenta, Andrea; Cellerino, Alessandro; Origlia, Nicola; Barloscio, Davide; Sartucci, Ferdinando; Giulio, Camillo Di; Domenici, Luciano

    2016-01-01

    The mechanism of the natural aging of olfaction and its declinein the absence of any overt disease conditions remains unclear. Here, we investigated this mechanism through measurement of one of the parameters of olfactory function, the absolute threshold, in a healthy population from childhood to old age. The absolute olfactory threshold data were collected from an Italian observational study with 622 participants aged 5-105 years. A subjective testing procedure of constant stimuli was used, which was also compared to the ‘staircase’ method, with the calculation of the reliability. The n-butanol stimulus was used as an ascending series of nine molar concentrations that were monitored using an electronic nose. The data were analyzed using nonparametric statistics because of the multimodal distribution. We show that the age-related variations in the absolute olfactory threshold are not continuous; instead, there are multiple olfactory phenotypes. Three distinct age-related phenotypes were defined, termed as ‘juvenile’, ‘mature’ and ‘elder’. The frequency of these three phenotypes depends on age. Our data suggest that the sense of smell does not decrease linearly with aging. Our findings provide the basis for further understanding of olfactory loss as an anticipatory sign of aging and neurodegenerative processes. PMID:27027240

  16. Trisomic and allelic differences influence phenotypic variability during development of Down syndrome mice.

    Science.gov (United States)

    Deitz, Samantha L; Roper, Randall J

    2011-12-01

    Individuals with full or partial Trisomy 21 (Ts21) present with clinical features collectively referred to as Down syndrome (DS), although DS phenotypes vary in incidence and severity between individuals. Differing genetic and phenotypic content in individuals with DS as well as mouse models of DS facilitate the understanding of the correlation between specific genes and phenotypes associated with Ts21. The Ts1Rhr mouse model is trisomic for 33 genes (the "Down syndrome critical region" or DSCR) hypothesized to be responsible for many clinical DS features, including craniofacial dysmorphology with a small mandible. Experiments with Ts1Rhr mice showed that the DSCR was not sufficient to cause all DS phenotypes by identifying uncharacteristic craniofacial abnormalities not found in individuals with DS or other DS mouse models. We hypothesized that the origins of the larger, dysmorphic mandible observed in adult Ts1Rhr mice develop from larger embryonic craniofacial precursors. Because of phenotypic variability seen in subsequent studies with Ts1Rhr mice, we also hypothesized that genetic background differences would alter Ts1Rhr developmental phenotypes. Using Ts1Rhr offspring from two genetic backgrounds, we found differences in mandibular precursor volume as well as total embryonic volume and postnatal body size of Ts1Rhr and nontrisomic littermates. Additionally, we observed increased relative expression of Dyrk1a and differential expression of Ets2 on the basis of the genetic background in the Ts1Rhr mandibular precursor. Our results suggest that trisomic gene content and allelic differences in trisomic or nontrisomic genes influence variability in gene expression and developmental phenotypes associated with DS. PMID:21926299

  17. Lessons and Implications from Genome-Wide Association Studies (GWAS Findings of Blood Cell Phenotypes

    Directory of Open Access Journals (Sweden)

    Nathalie Chami

    2014-01-01

    Full Text Available Genome-wide association studies (GWAS have identified reproducible genetic associations with hundreds of human diseases and traits. The vast majority of these associated single nucleotide polymorphisms (SNPs are non-coding, highlighting the challenge in moving from genetic findings to mechanistic and functional insights. Nevertheless, large-scale (epigenomic studies and bioinformatic analyses strongly suggest that GWAS hits are not randomly distributed in the genome but rather pinpoint specific biological pathways important for disease development or phenotypic variation. In this review, we focus on GWAS discoveries for the three main blood cell types: red blood cells, white blood cells and platelets. We summarize the knowledge gained from GWAS of these phenotypes and discuss their possible clinical implications for common (e.g., anemia and rare (e.g., myeloproliferative neoplasms human blood-related diseases. Finally, we argue that blood phenotypes are ideal to study the genetics of complex human traits because they are fully amenable to experimental testing.

  18. Haptoglobin Phenotype Predicts a Low Heart Rate Variability in Patients with Chronic Kidney Disease

    DEFF Research Database (Denmark)

    Svensson, My; Strandhave, Charlotte; Krarup, H.B.;

    F-PO1096 Haptoglobin Phenotype Predicts a Low Heart Rate Variability in Patients with Chronic Kidney Disease My Svensson,1 Charlotte Strandhave,1 Henrik My Svensson,1 Charlotte Strandhave,1 HenrikKrarup,2 Jeppe H. Christensen.1 1Department of Nephrology, Aalborg Hospital, Aalborg, Denmark; 2...... phenotype-dependent antioxidant capacity where Hp 2-2 exhibits a low antioxidant ability, increasing the risk of cardiovascular disease. An attenuated heart rate variability (HRV) may be an important predictor of mortality in patients with chronic kidney disease (CKD). In the present study, we examined......Department of Clinical Biochemistry, Aalborg Hospital, Aalborg, Denmark. Introduction Three major phenotypes for the haptoglobin (Hp) gene has been identified: Hp 1-1, Hp 2-2, and the heterozygous Hp 2-1. Hp 2-2 is associated with a poor outcome in patients with cardiovascular disease. This may be due to a...

  19. Investigating the Social Phenotype in Williams Syndrome: Methodological Challenges

    OpenAIRE

    H. Tager Flusberg

    2009-01-01

    The earliest descriptions of individuals with WS remarked on their unusual sociability, interest and engagement with other people, especially strangers. For the past 15 years researchers have focused their investigations on elucidating this aspect of the WS phenotype addressing several key questions: Is the social phenotype unique to WS? How can we define the social phenotype of WS? What are the cognitive mechanisms that underlie the social phenotype? What is the neurobiological ba...

  20. Computational approaches to identify functional genetic variants in cancer genomes

    Science.gov (United States)

    Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris; Ritchie, Graham R.S.; Creixell, Pau; Karchin, Rachel; Vazquez, Miguel; Fink, J. Lynn; Kassahn, Karin S.; Pearson, John V.; Bader, Gary; Boutros, Paul C.; Muthuswamy, Lakshmi; Ouellette, B.F. Francis; Reimand, Jüri; Linding, Rune; Shibata, Tatsuhiro; Valencia, Alfonso; Butler, Adam; Dronov, Serge; Flicek, Paul; Shannon, Nick B.; Carter, Hannah; Ding, Li; Sander, Chris; Stuart, Josh M.; Stein, Lincoln D.; Lopez-Bigas, Nuria

    2014-01-01

    The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor, but only a minority drive tumor progression. We present the result of discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype. PMID:23900255

  1. Computational approaches to identify functional genetic variants in cancer genomes

    DEFF Research Database (Denmark)

    Gonzalez-Perez, Abel; Mustonen, Ville; Reva, Boris;

    2013-01-01

    The International Cancer Genome Consortium (ICGC) aims to catalog genomic abnormalities in tumors from 50 different cancer types. Genome sequencing reveals hundreds to thousands of somatic mutations in each tumor but only a minority of these drive tumor progression. We present the result of discu...... discussions within the ICGC on how to address the challenge of identifying mutations that contribute to oncogenesis, tumor maintenance or response to therapy, and recommend computational techniques to annotate somatic variants and predict their impact on cancer phenotype....

  2. Identifying indicators of soil suppressiveness to fungal diseases

    OpenAIRE

    Siegel, Katarzyna; Aime, Sébastien; Chapelle, Emilie; Edel Hermann, Veronique; Raaijmakers, Jos M; Lemanceau, Philippe; Steinberg, Christian

    2013-01-01

    Soils suppressive to soil-borne diseases are defined by a low disease incidence in spite of the presence of a virulent pathogen and a susceptible plant. In many cases, the inhibition of the disease development relies on the activity of the resident soil microbiome. To identify taxonomic microbial indicators linked to the suppressiveness phenotype of soils, culture independent-based methods have been employed to analyse and compare microbial dynamics in two different soils suppressive to eithe...

  3. Hormones and phenotypic plasticity: Implications for the evolution of integrated adaptive phenotypes

    Institute of Scientific and Technical Information of China (English)

    Sean C.LEMA; Jun KITANO

    2013-01-01

    It is generally accepted that taxa exhibit genetic variation in phenotypic plasticity,but many questions remain unanswered about how divergent plastic responses evolve under dissimilar ecological conditions.Hormones are signaling molecules that act as proximate mediators of phenotype expression by regulating a variety of cellular,physiological,and behavioral responses.Hormones not only change cellular and physiological states but also influence gene expression directly or indirectly,thereby linking environmental conditions to phenotypic development.Studying how hormonal pathways respond to environmental variation and how those responses differ between individuals,populations,and species can expand our understanding of the evolution of phenotypic plasticity.Here,we explore the ways that the study of hormone signaling is providing new insights into the underlying proximate bases for individual,population or species variation in plasticity.Using several studies as exemplars,we examine how a 'norm of reaction' approach can be used in investigations of hormone-mediated plasticity to inform the following:1) how environmental cues affect the component hormones,receptors and enzymes that comprise any endocrine signaling pathway,2) how genetic and epigenetic variation in endocrine-associated genes can generate variation in plasticity among these diverse components,and 3) how phenotypes mediated by the same hormone can be coupled and decoupled via independent plastic responses of signaling components across target tissues.Future studies that apply approaches such as reaction norms and network modeling to questions concerning how hormones link environmental stimuli to ecologically-relevant phenotypic responses should help unravel how phenotypic plasticity evolves.

  4. Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations

    Science.gov (United States)

    van Hecke, Oliver; Kamerman, Peter R.; Attal, Nadine; Baron, Ralf; Bjornsdottir, Gyda; Bennett, David L.H.; Bennett, Michael I.; Bouhassira, Didier; Diatchenko, Luda; Freeman, Roy; Freynhagen, Rainer; Haanpää, Maija; Jensen, Troels S.; Raja, Srinivasa N.; Rice, Andrew S.C.; Seltzer, Ze'ev; Thorgeirsson, Thorgeir E.; Yarnitsky, David; Smith, Blair H.

    2015-01-01

    Abstract For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic “entry level” set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of “possible” neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC “entry level” set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability. PMID:26469320

  5. Discovery and optimisation studies of antimalarial phenotypic hits

    Science.gov (United States)

    Mital, Alka; Murugesan, Dinakaran; Kaiser, Marcel; Yeates, Clive; Gilbert, Ian H.

    2015-01-01

    There is an urgent need for the development of new antimalarial compounds. As a result of a phenotypic screen, several compounds with potent activity against the parasite Plasmodium falciparum were identified. Characterization of these compounds is discussed, along with approaches to optimise the physicochemical properties. The in vitro antimalarial activity of these compounds against P. falciparum K1 had EC50 values in the range of 0.09–29 μM, and generally good selectivity (typically >100-fold) compared to a mammalian cell line (L6). One example showed no significant activity against a rodent model of malaria, and more work is needed to optimise these compounds. PMID:26408453

  6. Phenotype-Driven Plasma Biobanking Strategies and Methods

    Directory of Open Access Journals (Sweden)

    Erica A. Bowton

    2015-05-01

    Full Text Available Biobank development and integration with clinical data from electronic medical record (EMR databases have enabled recent strides in genomic research and personalized medicine. BioVU, Vanderbilt’s DNA biorepository linked to de-identified clinical EMRs, has proven fruitful in its capacity to extensively appeal to numerous areas of biomedical and clinical research, supporting the discovery of genotype-phenotype interactions. Expanding on experiences in BioVU creation and development, we have recently embarked on a parallel effort to collect plasma in addition to DNA from blood specimens leftover after routine clinical testing at Vanderbilt. This initiative offers expanded utility of BioVU by combining proteomic and metabolomic approaches with genomics and/or clinical outcomes, widening the breadth for potential research and subsequent future impact on clinical care. Here, we describe the considerations and components involved in implementing a plasma biobank program from a feasibility assessment through pilot sample collection.

  7. Rumen microbial communities influence metabolic phenotypes in lambs

    DEFF Research Database (Denmark)

    Morgavi, Diego P.; Rahahao-Paris, Estelle; Popova, Milka;

    2015-01-01

    and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted) that differentially restricted......The rumen microbiota is an essential part of ruminants forging their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota...... the acquisition of microbes. Rumen microbiota, fermentation parameters, digestibility and growth were monitored for up to 31 weeks of age. Microbiota assembled in isolation from other ruminants lacked protozoa and had low bacterial and archaeal diversity whereas digestibility was not affected. Exposure to adult...

  8. Phenotypic variation of native chicken populations in northwest Ethiopia.

    Science.gov (United States)

    Halima, Hassen; Neser, F W C; van Marle-Koster, E; de Kock, A

    2007-10-01

    Seven indigenous chicken populations were identified and characterized from four administrative zones in northwest Ethiopia. A total of three hundred chickens were characterized under field conditions for qualitative and quantitative traits following standard chicken descriptors. Large phenotypic variability among chicken populations was observed for plumage color. About 25.49, 22.3, and 16.4 % of the chickens have white, grayish and red plumage colors, respectively. The rest showed a considerable heterogeneity like black, multicolor, black with white tips, red brownish and white with red striped plumage colors. The following characteristics were also displayed: plain head shape (51.18%), yellow shank color (64.42%) and pea comb (50.72%). About 97.52% of the chickens did not have feathers on their legs. Variations were also observed on quantitative characters such as shank length, egg size and body weight and other reproductive traits characterized on intensive management system. PMID:17969713

  9. Digital Identifier Systems: Comparative Evaluation

    OpenAIRE

    Hamid Reza Khedmatgozar; Mehdi Alipour-Hafezi; Payam Hanafizadeh

    2015-01-01

    Identifier is one of the main elements in identifying an object in digital environment. Digital identifier systems were developed followed by a lot of problems such as violation of persistency and uniqueness of physical identifiers and URL in digital environment. These identifiers try to guarantee uniqueness and persistency of hostnames by using indirect names for Domain Name System (DNS). The main objective of this research is to identify qualified digital identifier system among other syste...

  10. Myelin alters the inflammatory phenotype of macrophages by activating PPARs

    OpenAIRE

    Bogie, Jeroen; Jorissen, Winde; Mailleux, Jo; Vanmierlo, Tim; van Horssen, Jack; Hellings, Niels; Stinissen, Piet; Hendriks, J. J. A.; Nijland, Philip G.; Zelcer, Noam

    2013-01-01

    Background Foamy macrophages, containing myelin degradation products, are abundantly found in active multiple sclerosis (MS) lesions. Recent studies have described an altered phenotype of macrophages after myelin internalization. However, mechanisms by which myelin affects the phenotype of macrophages and how this phenotype influences lesion progression remain unclear. Results We demonstrate that myelin as well as phosphatidylserine (PS), a phospholipid found in myelin, reduce nitri...

  11. Detection of rare blood group, Bombay (Oh phenotype patients and management by acute normovolemic hemodilution

    Directory of Open Access Journals (Sweden)

    Manisha Shrivastava

    2015-01-01

    Full Text Available Background: Due to lack of correct blood grouping practices, the rare Bombay Oh phenotype may be missed, subjecting patients to the risk of severe hemolytic transfusion reaction. In the absence of blood donor registry, transfusion management of patients needing immediate surgery is a challenge. This study presents detection of rare Bombay Oh phenotype patients and their management by acute peri-operative acute normovolemic hemodilution (ANH in a hospital from central India. Materials and Methods: Blood grouping of patients and blood donors with a standard tube method was carried out and samples identified as rare Bombay phenotype were confirmed by saliva inhibition test. Surgical management of cases needing transfusion was done by ANH, as per the British Committee for Standards in Hematology guidelines. Results: The incidence of Bombay phenotype was 0.002% or 1 in 51,924 in the study. Amongst three cases (patients identified as Bombay phenotype, one was Bombay Oh, Rh negative. Two cases were missed in the first instance and one case actually did not require transfusion. In the absence of a blood donor registry for Bombay phenotype, the cases needing transfusion were successfully managed with ANH in the operation theatre. Conclusion: A simple test like blood grouping should be done with serious intention with incorporation of both forward and reverse grouping, so that no patient receives wrong blood leading to fatal hemolysis due to transfusion. ANH is a cost-effective transfusion option for suitable patients. Appropriate clinical decision making, use of strategies to decrease peri-operative blood losses and cost-effective country based planning could be more widely applied to improve clinical transfusion practice.

  12. Analysis of phenotype array data from Biolog MicroPlatesTM

    Institute of Scientific and Technical Information of China (English)

    John Bissett; Carol Ann Nolan

    2004-01-01

    @@ Biolog MicroPlatesTM are employed to characterize Trichoderma isolates based on differential assimilation of test substrates and redox reactions in a 96-well test plate. The Biolog method is potentially advantageous in being relatively simple, fast and economical, and data acquisition can be automated using a microplate reader and applicable software. Several research applications of the Biolog system are presented: i) "monophenetic groups" from cluster analyses of phenotype array data are investigated for previously undetected new species in Trichoderma, ii) metabolic characters differentiating species are identified, and multivariate analyses performed to complement molecular data in validating new species and significant variants, and iii) phenotype array data for more than 1200 Trichoderma strains are analysed to select strains that might be exploited for bioconversions and commercial production of enzymes. Phenotype arrays are much more sensitive to strain level variation than molecular techniques, however, phenotype array data do not consistently reflect phylogenies constructed from molecular data. Nevertheless, the Biolog phenotype array is an economical alternative method for surveying biological diversity, and provides data that complements molecular data in phylogenetic studies.

  13. Association Between the Hypertriglyceridemic Waist Phenotype, Prediabetes, and Diabetes Mellitus Among Adults in Puerto Rico.

    Science.gov (United States)

    Díaz-Santana, Mary Vanellys; Suárez Pérez, Erick L; Ortiz Martínez, Ana P; Guzmán Serrano, Manuel; Pérez Cardona, Cynthia M

    2016-02-01

    This study assessed the association of the hypertriglyceridemic waist (HTGW) phenotype with prediabetes and diabetes (DM) in a group of Hispanics. Analysis of a cross-sectional study of 858 adults residing in Puerto Rico that collected data on blood pressure, biochemical, and anthropometric measurements was performed. HTGW phenotype was defined as elevated triglycerides and elevated waist circumference. Prediabetes was defined as a fasting glucose of 100-125 mg/dL and DM as a fasting glucose ≥126 mg/dL or prior diagnosis. Prevalence of HTGW, prediabetes, and DM was 27.9, 38.0, and 21.6 %, respectively. Subjects with the HTGW phenotype had higher adjusted odds of prediabetes (POR 5.55; 95 % CI 3.38-9.13) and DM (POR 7.28; 95 % CI 3.63-14.63) compared to those without the phenotype. The association for prediabetes was stronger for women than among men. HTGW phenotype was strongly associated with prediabetes and DM, reinforcing the need to further assess its performance as a screening tool to identify at-risk individuals for cardiometabolic conditions. PMID:24519258

  14. Fc block treatment, dead cells exclusion, and cell aggregates discrimination concur to prevent phenotypical artifacts in the analysis of subpopulations of tumor-infiltrating CD11b(+) myelomonocytic cells.

    Science.gov (United States)

    Kuonen, Francois; Touvrey, Cedric; Laurent, Julien; Ruegg, Curzio

    2010-11-01

    It is well established that cancer cells can recruit CD11b(+) myeloid cells to promote tumor angiogenesis and tumor growth. Increasing interest has emerged on the identification of subpopulations of tumor-infiltrating CD11b(+) myeloid cells using flow cytometry techniques. In the literature, however, discrepancies exist on the phenotype of these cells (Coffelt et al., Am J Pathol 2010;176:1564-1576). Since flow cytometry analysis requires particular precautions for accurate sample preparation and trustable data acquisition, analysis, and interpretation, some discrepancies might be due to technical reasons rather than biological grounds. We used the syngenic orthotopic 4T1 mammary tumor model in immunocompetent BALB/c mice to analyze and compare the phenotype of CD11b(+) myeloid cells isolated from peripheral blood and from tumors, using six-color flow cytometry. We report here that the nonspecific antibody binding through Fc receptors, the presence of dead cells and cell doublets in tumor-derived samples concur to generate artifacts in the phenotype of tumor-infiltrating CD11b(+) subpopulations. We show that the heterogeneity of tumor-infiltrating CD11b(+) subpopulations analyzed without particular precautions was greatly reduced upon Fc block treatment, dead cells, and cell doublets exclusion. Phenotyping of tumor-infiltrating CD11b(+) cells was particularly sensitive to these parameters compared to circulating CD11b(+) cells. Taken together, our results identify Fc block treatment, dead cells, and cell doublets exclusion as simple but crucial steps for the proper analysis of tumor-infiltrating CD11b(+) cell populations. PMID:20824631

  15. TGIF Mutations in Human Holoprosencephaly: Correlation between Genotype and Phenotype.

    Science.gov (United States)

    Keaton, A A; Solomon, B D; Kauvar, E F; El-Jaick, K B; Gropman, A L; Zafer, Y; Meck, J M; Bale, S J; Grange, D K; Haddad, B R; Gowans, G C; Clegg, N J; Delgado, M R; Hahn, J S; Pineda-Alvarez, D E; Lacbawan, F; Vélez, J I; Roessler, E; Muenke, M

    2010-01-01

    Holoprosencephaly (HPE), which results from failed or incomplete midline forebrain division early in gestation, is the most common forebrain malformation. The etiology of HPE is complex and multifactorial. To date, at least 12 HPE-associated genes have been identified, including TGIF (transforming growth factor beta-induced factor), located on chromosome 18p11.3. TGIF encodes a transcriptional repressor of retinoid responses involved in TGF-β signaling regulation, including Nodal signaling. TGIF mutations are reported in approximately 1-2% of patients with non-syndromic, non-chromosomal HPE. We combined data from our comprehensive studies of HPE with a literature search for all individuals with HPE and evidence of mutations affecting TGIF in order to establish the genotypic and phenotypic range. We describe 2 groups of patients: 34 with intragenic mutations and 21 with deletions of TGIF. These individuals, which were ascertained from our research group, in collaboration with other centers, and through a literature search, include 38 probands and 17 mutation-positive relatives. The majority of intragenic mutations occur in the TGIF homeodomain. Patients with mutations affecting TGIFrecapitulate the entire phenotypic spectrum observed in non-chromosomal, non-syndromic HPE. We identified a statistically significant difference between the 2 groups with respect to inheritance, as TGIF deletions were more likely to be de novo in comparison to TGIF mutations (χ(2) ((2)) = 6.97, p(permutated) = 0.0356). In addition, patients with TGIF deletions were also found to more commonly present with manifestations beyond the craniofacial and neuroanatomical features associated with HPE (p = 0.0030). These findings highlight differences in patients with intragenic mutations versus deletions affecting TGIF, and draw attention to the homeodomain region, which appears to be particularly relevant to HPE. These results may be useful for genetic counseling of affected patients. PMID

  16. Plasma exosome profiles from dairy cows with divergent fertility phenotypes.

    Science.gov (United States)

    Mitchell, M D; Scholz-Romero, K; Reed, S; Peiris, H N; Koh, Y Q; Meier, S; Walker, C G; Burke, C R; Roche, J R; Rice, G; Salomon, C

    2016-09-01

    Cell-to-cell communication in physiological and pathological conditions may be influenced by neighboring cells, distant tissues, or local environmental factors. Exosomes are specific subsets of extracellular vesicles that internalize and deliver their content to near and distant sites. Exosomes may play a role in the maternal-embryo crosstalk vital for the recognition and maintenance of a pregnancy; however, their role in dairy cow reproduction has not been established. This study aimed to characterize the exosome profile in the plasma of 2 strains of dairy cow with divergent fertility phenotypes. Plasma was obtained and characterized on the basis of genetic ancestry as fertile (FERT; 92% North American genetics, North American Holstein-Friesian strain, n=8). Exosomes were isolated by differential and buoyant density centrifugation and characterized by size distribution (nanoparticle tracking analysis, NanoSight NS500, NanoSight Ltd., Amesbury, UK), the presence of CD63 (Western blot), and their morphology (electron microscopy). The total number of exosomes was determined by quantifying the immunoreactive CD63 (ExoELISA kit, System Biosciences), and the protein content established by mass spectrometry. Enriched exosome fractions were identified as cup-shape vesicles with diameters around 100 nm and positive for the CD63 marker. The concentration of exosomes was 50% greater in FERT cows. Mass spectrometry identified 104 and 117 proteins in FERT and SUBFERT cows, of which 23 and 36 were unique, respectively. Gene ontology analysis revealed enrichment for proteins involved in immunomodulatory processes and cell-to-cell communication. Although the role of exosomes in dairy cow reproduction remains to be elucidated, their quantification and content in models with divergent fertility phenotypes could provide novel information to support both physiological and genetic approaches to improving dairy cow fertility. PMID:27372594

  17. Cloning of the Arabidopsis WIGGUM gene identifies a role for farnesylation in meristem development

    OpenAIRE

    Ziegelhoffer, Eva C.; Medrano, Leonard J.; Meyerowitz, Elliot M.

    2000-01-01

    Control of cellular proliferation in plant meristems is important for maintaining the correct number and position of developing organs. One of the genes identified in the control of floral and apical meristem size and floral organ number in Arabidopsis thaliana is WIGGUM. In wiggum mutants, one of the most striking phenotypes is an increase in floral organ number, particularly in the sepals and petals, correlating with an increase in the width of young floral meristems. Additional phenotypes ...

  18. The gray phenotype and tristable phenotypic transitions in the human fungal pathogen Candida tropicalis.

    Science.gov (United States)

    Zhang, Yulong; Tao, Li; Zhang, Qiuyu; Guan, Guobo; Nobile, Clarissa J; Zheng, Qiushi; Ding, Xuefen; Huang, Guanghua

    2016-08-01

    Phenotypic plasticity, the ability to switch between different morphological types, plays critical roles in environmental adaptation, leading to infections, and allowing for sexual reproduction in pathogenic Candida species. Candida tropicalis, which is both an emerging human fungal pathogen and an environmental fungus, can switch between two heritable cell types termed white and opaque. In this study, we report the discovery of a novel phenotype in C. tropicalis, named the gray phenotype. Similar to Candida albicans and Candida dubliniensis, white, gray, and opaque cell types of C. tropicalis also form a tristable switching system, where gray cells are relatively small and elongated. In C. tropicalis, gray cells exhibit intermediate levels of mating competency and virulence in a mouse systemic infection model compared to the white and opaque cell types, express a set of cell type-enriched genes, and exhibit both common and species-specific biological features. The key regulators of white-opaque transitions, Wor1 and Efg1, are not required for the gray phenotype. A comparative study of the gray phenotypes in C. tropicalis, C. albicans, and C. dubliniensis provides clues to explain the virulence properties and niche preferences of C. tropicalis. PMID:27246518

  19. Significance of Lewis Phenotyping Using Saliva and Gastric Tissue: Comparison with the Lewis Phenotype Inferred from Lewis and Secretor Genotypes

    OpenAIRE

    Yun Ji Hong; Sang Mee Hwang; Taek Soo Kim; Eun Young Song; Kyoung Un Park; Junghan Song; Kyou-Sup Han

    2014-01-01

    Lewis phenotypes using various types of specimen were compared with the Lewis phenotype predicted from Lewis and Secretor genotypes. This is the first logical step in explaining the association between the Lewis expression and Helicobacter pylori. We performed a study of the followings on 209 patients who underwent routine gastroscopy: erythrocyte and saliva Lewis phenotyping, gastric Lewis phenotyping by the tissue array, and the Lewis and Secretor genes genotyping. The results of phenotypin...

  20. TILLING in two-rowed spring barley: mutation frequencies and phenotypes

    International Nuclear Information System (INIS)

    TILLING (Targeting Induced Local Lesions IN Genomes) searches the genomes of mutagenized organisms for mutations in a chosen gene, and allows functional analysis in the context of the whole organism. Moreover, TILLING extends reverse genetics to mutation breeding, since it can generate large allelic series of economically interesting genes. As part of the GABI-TILL consortium (GABI II) we have established a TILLING platform for the two-rowed, malting barley cultivar 'Barke'. The population comprises 10,492 M2 plants, and the respective DNA was arranged in 8-fold two dimensional (2D)-pools for mutation screening. Mutations were detected by following the original TILLING procedure of Cel I based hetero-duplex analysis. By screening ten gene fragments for mutations in 7,348 M2 lines 81 mutations were identified, yielding an average mutation frequency of approximately 1 mutation per 0.5 Mb. Seventy-nine percent of these mutations were located in coding regions of the analysed gene fragments of which 45% represented missense alleles inducing a change of amino acid in the protein. Five percent of the mutations provided truncation mutations either by elimination of a splice junction or by insertion of a premature stop codon. For instance for the vrs1 gene (Komatsuda et al. 2007), which is the major factor that controls row-type morphology of the barley spike, thirty-one mutations were identified by screening a 1,270bp fragment. Three of the identified mutants either exhibited a 6-rowed or an intermediate phenotype. One mutant displayed a spikelet morphology that was significantly altered compared to 'Barke' wild-type. The barley TILLING activity is going to be extended into the GABI-Future program. Additionally, tests to improve mutation frequency in barley will be undertaken. Furthermore, attempts for generating an instantly homozygous TILLING-Population by Barley microspore culture mutagenesis are underway in co-operation with the group of Jochen Kumlehn (Co-PI GABI

  1. Association between the Hypertriglyceridemic Waist Phenotype, Prediabetes, and Diabetes Mellitus in Rural Chinese Population: A Cross-Sectional Study

    Directory of Open Access Journals (Sweden)

    Shuang Chen

    2016-03-01

    Full Text Available Background: The objective was to evaluate the association of the hypertriglyceridemic waist (HTGW phenotype with prediabetes and diabetes (DM in rural Chinese population. Methods: In a cross-sectional study, 11,579 adults (5361 men and 6218 women aged 35 years or older were recruited from rural areas of China. Anthropometric measurements, laboratory examinations and self-reported information were collected by trained personnel. The HTGW phenotype was defined as elevated triglycerides and elevated waist circumference. We used logistic regression analysis to evaluate the associations of interest. Results: Adults with the HTGW phenotype had a significantly higher prevalence of prediabetes and diabetes than those without the HTGW phenotype. Compared with the normal waist-normal triglycerides (NWNT group, those in the HTGW group had a higher adjusted odds ratio of diabetes (OR: 2.10; 95% CI: 1.62–2.73. The association for diabetes was stronger for men (OR: 2.27; 95% CI: 1.52–3.40 than for women (OR: 1.86; 95% CI: 1.32–2.63. However, multivariate analysis indicated that the HTGW phenotype was not associated with prediabetes. Conclusions: This study demonstrated that the HTGW phenotype was associated with diabetes in a large rural Chinese population, and suggested this phenotype as a simple screening tool to identify adults with cardiometabolic conditions.

  2. Significance of Lewis phenotyping using saliva and gastric tissue: comparison with the Lewis phenotype inferred from Lewis and secretor genotypes.

    Science.gov (United States)

    Hong, Yun Ji; Hwang, Sang Mee; Kim, Taek Soo; Song, Eun Young; Park, Kyoung Un; Song, Junghan; Han, Kyou-Sup

    2014-01-01

    Lewis phenotypes using various types of specimen were compared with the Lewis phenotype predicted from Lewis and Secretor genotypes. This is the first logical step in explaining the association between the Lewis expression and Helicobacter pylori. We performed a study of the followings on 209 patients who underwent routine gastroscopy: erythrocyte and saliva Lewis phenotyping, gastric Lewis phenotyping by the tissue array, and the Lewis and Secretor genes genotyping. The results of phenotyping were as follows [Le(a-b-), Le(a+b-), Le(a-b+), and Le(a+b+), respectively, in order]: erythrocyte (12.4%, 25.8%, 61.2%, and 0.5%); saliva (2.4%, 27.3%, 70.3%, and 0.0%); gastric mucosa (8.1%, 6.7%, 45.5%, and 39.7%). The frequency of Le, le (59/508) , le (59/1067) , and le (59) alleles was 74.6%, 21.3%, 3.1%, and 1.0%, respectively, among 418 alleles. The saliva Lewis phenotype was completely consistent with the Lewis phenotype inferred from Lewis and Secretor genotypes, but that of gastric mucosa could not be predicted from genotypes. Lewis phenotyping using erythrocytes is only adequate for transfusion needs. Saliva testing for the Lewis phenotype is a more reliable method for determining the peripheral Lewis phenotype of an individual and the gastric Lewis phenotype must be used for the study on the association between Helicobacter pylori and the Lewis phenotype. PMID:24783214

  3. Plant phenomics and the need for physiological phenotyping across scales to narrow the genotype-to-phenotype knowledge gap

    Czech Academy of Sciences Publication Activity Database

    Grosskinsky, D. K.; Svensgaard, J.; Christensen, S.; Roitsch, Thomas

    2015-01-01

    Roč. 66, č. 18 (2015), s. 5429-5440. ISSN 0022-0957 Institutional support: RVO:67179843 Keywords : External phenotype * genome –environment–management interaction * genome –phenome map * internal phenotype * phenomics * physiological traits * physiology * plant phenotyping * predictors Subject RIV: EH - Ecology, Behaviour Impact factor: 5.526, year: 2014

  4. Volver al desarrollo

    Directory of Open Access Journals (Sweden)

    Jaime Ornelas Delgado

    2012-01-01

    Full Text Available El desarrollo, categoría empleada para expresar el crecimiento económico, surge durante la "guerra fría" y si bien fue propuesta por teóricos metropolitanos, se asumió en Latinoamérica como parte de los instrumentos disponibles para lograr el crecimiento y alternativa al socialismo. El desarrollo mantuvo su vigencia entre 1945 y 1975, cuando al advenimiento del neoliberalismo fue paulatinamente retirado de la agenda de las preocupaciones nacionales e internacionales. Al iniciarse el siglo xxi, el fracaso del mercado autorregulado trajo de nueva cuenta al debate los problemas del desarrollo, lo que obliga a revisarlo críticamente, tanto como al concepto mismo para mostrar su carácter colonial, si se quiere construir caminos ajenos al neoliberal y superar los problemas que han hecho de Latinoamérica una de las regiones más desiguales del mundo.

  5. A Marfan syndrome gene expression phenotype in cultured skin fibroblasts

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    Emond Mary

    2007-09-01

    Full Text Available Abstract Background Marfan syndrome (MFS is a heritable connective tissue disorder caused by mutations in the fibrillin-1 gene. This syndrome constitutes a significant identifiable subtype of aortic aneurysmal disease, accounting for over 5% of ascending and thoracic aortic aneurysms. Results We used spotted membrane DNA macroarrays to identify genes whose altered expression levels may contribute to the phenotype of the disease. Our analysis of 4132 genes identified a subset with significant expression differences between skin fibroblast cultures from unaffected controls versus cultures from affected individuals with known fibrillin-1 mutations. Subsequently, 10 genes were chosen for validation by quantitative RT-PCR. Conclusion Differential expression of many of the validated genes was associated with MFS samples when an additional group of unaffected and MFS affected subjects were analyzed (p-value -6 under the null hypothesis that expression levels in cultured fibroblasts are unaffected by MFS status. An unexpected observation was the range of individual gene expression. In unaffected control subjects, expression ranges exceeding 10 fold were seen in many of the genes selected for qRT-PCR validation. The variation in expression in the MFS affected subjects was even greater.

  6. Identification of interspecies interactions affecting Porphyromonas gingivalis virulence phenotypes

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    Elizabeth L. Tenorio

    2011-10-01

    Full Text Available Background: Periodontitis is recognized as a complex polymicrobial disease, however, the impact of the bacterial interactions among the 700–1,000 different species of the oral microbiota remains poorly understood. We conducted an in vitro screen for oral bacteria that mitigate selected virulence phenotypes of the important periodontal pathogen, Porphyromonas gingivalis. Methods: We isolated and identified oral anaerobic bacteria from subgingival plaque of dental patients. When cocultured with P. gingivalis W83, specific isolates reduced the cytopathogenic effects of P. gingivalis on oral epithelial cells. Results: In an initial screen of 103 subgingival isolates, we identified 19 distinct strains from nine species of bacteria (including Actinomyces naeslundii, Streptococcus oralis, Streptococcus mitis, and Veilonella dispar that protect oral epithelial cells from P. gingivalis-induced cytotoxicity. We found that some of these strains inhibited P. gingivalis growth in plate assays through the production of organic acids, whereas some decreased the gingipain activity of P. gingivalis in coculture or mixing experiments. Conclusion: In summary, we identified 19 strains isolated from human subgingival plaque that interacted with P. gingivalis, resulting in mitigation of its cytotoxicity to oral epithelial cells, inhibition of growth, and/or reduction of gingipain activity. Understanding the mechanisms of interaction between bacteria in the oral microbial community may lead to the development of new probiotic agents and new strategies for interrupting the development of periodontal disease.

  7. Comparative Metabolomic and Lipidomic Analysis of Phenotype Stratified Prostate Cells.

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    Tanya C Burch

    Full Text Available Prostate cancer (PCa is the most prevalent cancer amongst men and the second most common cause of cancer related-deaths in the USA. Prostate cancer is a heterogeneous disease ranging from indolent asymptomatic cases to very aggressive life threatening forms. The goal of this study was to identify differentially expressed metabolites and lipids in prostate cells with different tumorigenic phenotypes. We have used mass spectrometry metabolomic profiling, lipidomic profiling, bioinformatic and statistical methods to identify, quantify and characterize differentially regulated molecules in five prostate derived cell lines. We have identified potentially interesting species of different lipid subclasses including phosphatidylcholines (PCs, phosphatidylethanolamines (PEs, glycerophosphoinositols (PIs and other metabolites that are significantly upregulated in prostate cancer cells derived from distant metastatic sites. Transcriptomic and biochemical analysis of key enzymes that are involved in lipid metabolism demonstrate the significant upregulation of choline kinase alpha in the metastatic cells compared to the non-malignant and non-metastatic cells. This suggests that different de novo lipogenesis and other specific signal transduction pathways are activated in aggressive metastatic cells as compared to normal and non-metastatic cells.

  8. Identification of phases in the interaction layer between U-Mo-Zr/Al and U-Mo-Zr/Al-Si

    International Nuclear Information System (INIS)

    Out-of-pile diffusion experiments were performed between U-7wt.% Mo-1wt.% Zr and Al or Al A356 (7,1wt.% Si) at 550 deg. C. In this work morphological characterization and phase identification on both interaction layer are presented. They were carried out by the use of different techniques: optical and scanning electron microscopy, X-Ray diffraction and WDS microanalysis. In the interaction layer U-7wt.% Mo-1wt.% Zr/Al, the phases UAl3, UAl4, Al20Mo2U and Al43Mo4U6 were identified. In the interaction layer U-7wt.% Mo-1wt.% Zr/Al A356, the phases U(Al, Si) with 25at.% Si and Si5U3 were identified. This last phase, with a higher Si concentration, was identified with XRD Synchrotron radiation performed at the National Synchrotron Light Laboratory (LNLS), Campinas, Brasil. (author)

  9. Copy number variations and cognitive phenotypes in unselected populations

    Science.gov (United States)

    Männik, Katrin; Mägi, Reedik; Macé, Aurélien; Cole, Ben; Guyatt, Anna; Shihab, Hashem A.; Maillard, Anne M.; Alavere, Helene; Kolk, Anneli; Reigo, Anu; Mihailov, Evelin; Leitsalu, Liis; Ferreira, Anne-Maud; Nõukas, Margit; Teumer, Alexander; Salvi, Erika; Cusi, Daniele; McGue, Matt; Iacono, William G.; Gaunt, Tom R.; Beckmann, Jacques S.; Jacquemont, Sébastien; Kutalik, Zoltán; Pankratz, Nathan; Timpson, Nicholas; Metspalu, Andres; Reymond, Alexandre

    2015-01-01

    Importance The association of rare copy number variants (CNVs) with complex disorders is almost exclusively evaluated using clinically ascertained cohorts. As a result, the contribution of these genetic variants to cognitive phenotypes in the general population remains unclear. Objectives - To investigate the clinical features of genomic disorders in adult carriers without clinical pre-selection. - To assess the genome-wide burden of rare CNVs on carriers’ educational attainment and intellectual disability prevalence in the general population. Design, Setting, and Participants The population biobank of Estonia (EGCUT) contains 52,000 participants, or 5% of the Estonian adults, enrolled in 2002-2010. General practitioners examined participants and filled out a questionnaire of health- and lifestyle-related questions, as well as reported diagnoses. As EGCUT is representative of the country's population, we investigated a random sample of 7877 individuals for CNV analysis and genotype-phenotype associations with education and disease traits. Main Outcomes and Measures Phenotypes of genomic disorders in the general population, prevalence of autosomal CNVs, and association of the latter variants with decreased educational attainment and increased prevalence of intellectual disability. Results We identified 56 carriers of genomic disorders. Their phenotypes are reminiscent of those described for carriers of identical rearrangements ascertained in clinical cohorts. We also generated a genome-wide map of rare (frequency ≤0.05%) autosomal CNVs and identified 10.5% of the screened general population (n=831) as carriers of CNVs ≥250kb. Carriers of deletions ≥250kb or duplications ≥1Mb show, compared to the Estonian population, a greater prevalence of intellectual disability (P=0.0015, OR=3.16, (95%CI: 1.51-5.98); P=0.0083, OR=3.67, (95%CI: 1.29-8.54), respectively), reduced mean education attainment (a proxy for intelligence; P=1.06e-04; P=5.024e-05, respectively

  10. Jalta als Heterotopie

    OpenAIRE

    Schmid, Ulrich

    2013-01-01

    Jalta ist ein Ort, der sich im europäischen Kulturgedächtnis sowohl historisch als auch literarisch als "radikal anderer Ort" - als " Heterotopie" - festgesetzt hat. An der Konferenz von Jalta wurde 1945 eine neue Weltordnung geschaffen in der Hoffnung auf eine bessere Welt. Auch in den Werken von Anton ?echov, vor allem in denjenigen, die in Jalta entstanden sind, wird von einer anderen und besseren Welt geträumt.

  11. Pornographie als Metapher

    Directory of Open Access Journals (Sweden)

    Caroline Schubarth

    2010-02-01

    Full Text Available In diesem Artikel werden unterschiedliche metaphorische Verwendungen des Pornografiebegriffs und deren Implikationen untersucht. Während die Existenz von Pornografie der feministischen Anti-Porno-Bewegung als Erklärung für die anhaltende Diskriminierung von Frauen in westlichen Gesellschaften dient, nutzen rechtskonservative Kräfte den Pornografievorwurf als Rechtfertigung für die Zensur von als deviant empfundenen Identitäten und sexuellen Praktiken.

  12. Pornographie als Metapher

    OpenAIRE

    Caroline Schubarth

    2010-01-01

    In diesem Artikel werden unterschiedliche metaphorische Verwendungen des Pornografiebegriffs und deren Implikationen untersucht. Während die Existenz von Pornografie der feministischen Anti-Porno-Bewegung als Erklärung für die anhaltende Diskriminierung von Frauen in westlichen Gesellschaften dient, nutzen rechtskonservative Kräfte den Pornografievorwurf als Rechtfertigung für die Zensur von als deviant empfundenen Identitäten und sexuellen Praktiken.This article...

  13. Iron Metabolism Disturbance in a French Cohort of ALS Patients

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    Charlotte Veyrat-Durebex

    2014-01-01

    Full Text Available Objective. The aim of this study was to assess iron status in a cohort of amyotrophic lateral sclerosis (ALS patients compared to controls in order to evaluate these parameters as a risk factor or a modifying factor of ALS. Methods. We collected serum iron, ferritin, transferrin, total iron-binding capacity, and transferrin saturation coefficient (TSC from 104 ALS patients at the time of diagnosis and from 145 controls. We reported phenotypic characteristics and evolution parameters such as ALSFRS-R and forced vital capacity at diagnosis and after one year of follow-up. In a first step we compared iron status between ALS patients and controls, and then we evaluated the relation between iron status and disease evolution of ALS patients using univariate and multivariate analysis. Results. We observed increased concentrations of serum iron (P=0.002 and ferritin (P<0.0001 and increased TSC (P=0.017 in ALS patients. We also showed an association between markers of iron status and high body weight loss in ALS patients. The multivariate analysis of survival highlighted a significant relation between ferritin level and disease duration (P=0.038. Conclusion. This is the first study showing a higher concentration of serum iron in ALS patients, strengthening the involvement of a deregulation of iron metabolism in ALS.

  14. Sobre Al-Qarmuniyya

    OpenAIRE

    Fierro Bello, María Isabel

    1990-01-01

    [ES] En dos tradiciones escatológicas relativas a al-Andalus y recogidas por 'Abd al-Malik h Haha en su Ta'rg se hace referencia a Carmona. La mención de esta ciudad en dichas tradiciones debe ser puesta en relación con dos episodios de la historia de al-Andalus que tuvieron lugar antes de la muerte de Ibn Habib: la batalla de Carmona en época de 'Abd al-Rahman y la concentración de tropas omeyas en el mismo lugar durante el ataque normando en los años 229-30/844-5.

  15. Invasion strategies in clonal aquatic plants: are phenotypic differences caused by phenotypic plasticity or local adaptation?

    Science.gov (United States)

    Riis, Tenna; Lambertini, Carla; Olesen, Birgit; Clayton, John S.; Brix, Hans; Sorrell, Brian K.

    2010-01-01

    Background and Aims The successful spread of invasive plants in new environments is often linked to multiple introductions and a diverse gene pool that facilitates local adaptation to variable environmental conditions. For clonal plants, however, phenotypic plasticity may be equally important. Here the primary adaptive strategy in three non-native, clonally reproducing macrophytes (Egeria densa, Elodea canadensis and Lagarosiphon major) in New Zealand freshwaters were examined and an attempt was made to link observed differences in plant morphology to local variation in habitat conditions. Methods Field populations with a large phenotypic variety were sampled in a range of lakes and streams with different chemical and physical properties. The phenotypic plasticity of the species before and after cultivation was studied in a common garden growth experiment, and the genetic diversity of these same populations was also quantified. Key Results For all three species, greater variation in plant characteristics was found before they were grown in standardized conditions. Moreover, field populations displayed remarkably little genetic variation and there was little interaction between habitat conditions and plant morphological characteristics. Conclusions The results indicate that at the current stage of spread into New Zealand, the primary adaptive strategy of these three invasive macrophytes is phenotypic plasticity. However, while limited, the possibility that genetic diversity between populations may facilitate ecotypic differentiation in the future cannot be excluded. These results thus indicate that invasive clonal aquatic plants adapt to new introduced areas by phenotypic plasticity. Inorganic carbon, nitrogen and phosphorous were important in controlling plant size of E. canadensis and L. major, but no other relationships between plant characteristics and habitat conditions were apparent. This implies that within-species differences in plant size can be explained

  16. Against Genetic Tests for Athletic Talent: The Primacy of the Phenotype.

    Science.gov (United States)

    Loland, Sigmund

    2015-09-01

    New insights into the genetics of sport performance lead to new areas of application. One area is the use of genetic tests to identify athletic talent. Athletic performances involve a high number of complex phenotypical traits. Based on the ACCE model (review of Analytic and Clinical validity, Clinical utility, and Ethical, legal and social implications), a critique is offered of the lack of validity and predictive power of genetic tests for talent. Based on the ideal of children's right to an open future, a moral argument is given against such tests on children and young athletes. A possible role of genetic tests in sport is proposed in terms of identifying predisposition for injury. In meeting ACCE requirements, such tests could improve individualised injury prevention and increase athlete health. More generally, limitations of science are discussed in the identification of talent and in the understanding of complex human performance phenotypes. An alternative approach to talent identification is proposed in terms of ethically sensitive, systematic and evidence-based holistic observation over time of relevant phenotypical traits by experienced observers. Talent identification in sport should be based on the primacy of the phenotype. PMID:26121951

  17. A major deletion in the cucumber mitochondrial genome sorts with the MSC phenotype.

    Science.gov (United States)

    Lilly, J W; Bartoszewski, G; Malepszy, S; Havey, M J

    2001-09-01

    The cucumber mitochondrial genome is unique because of its large size, paternal transmission, and the existence of a paternally transmitted mosaic (MSC) phenotype spontaneously appearing after independent tissue culture experiments. Transmission studies eliminated paternal imprinting as the genetic basis for the MSC phenotype. We identified a 13 kb region (JLV5-DEL) in the wild-type mitochondrial genome that was absent from three MSC lines. This deleted region was paternally transmitted with the MSC phenotype through the F3 and test-cross generations. Southern hybridizations and PCR amplifications using primers within the JLV5 region revealed that rare wild-type sorters possessed the wild-type region. MSC plants possess the wild-type region at levels (approximately 0.002) below detection by standard PCR reactions and Southern hybridizations, using genomic DNA. Sequence analysis of the wild-type contig revealed no homologies to mitochondrial genes and no open reading frames within JLV5-DEL. PCR amplifications across JLV5-DEL using MSC mtDNA revealed that the loss of this region was not a simple deletion and may be associated with a rearrangement. Because no genic regions were identified within the wild-type JLV5 region, the specific lesion conditioning the MSC phenotype may be associated with the putative rearrangement or another mutation that occurred during tissue culture or exists substoichiometrically in the parental line and is transmitted together with JLV5 within the same mitochondrion. PMID:11680824

  18. Phenotypical Expression of Maize Seedlings from Lines with the “Tallos Gemelos” Trait

    Directory of Open Access Journals (Sweden)

    Ma. Lorena Meraz-Fonseca

    2015-01-01

    Full Text Available In the Colegio de Postgraduados in Mexico, we have generated lines of maize (Zea mays L. with the particularity that from a seed two or more stalks emerge and develop normally, calling that character “tallos gemelos.” This trait possibly modifies the proportions of the constituent tissues of the seed and could increase the nutritional and nutraceutical quality of the grain. The aim of this study was to evaluate the germination percentage and quantify and describe the types of phenotypic expression of seedling with twin stalks in the lines. 100 seeds of each of the 26 S5 lines tested were used. At 15 days after planting in a greenhouse, the seedlings were classified based on their morphology. The results showed that, on average, the lines had 81.3% of emergence and 51% of twin stalks. Eight types of phenotypic expression in seedlings were identified and described with the character “tallos gemelos”; Type II showed the highest proportion (59.5%. The phenotypical expressions identified in seedlings with the “tallos gemelos” trait are evidence of epigenetic mechanisms, since they present one of the features of epimutants, which is that they are reversible, that is; they can return to the original phenotype, in the present circumstance to normal plants (single stalk.

  19. Kin recognition and the 'armpit effect': evidence of self-referent phenotype matching.

    Science.gov (United States)

    Mateo, J M; Johnston, R E

    2000-04-01

    In species with multiple paternity or maternity, animals may best assess their relatedness to unfamiliar conspecifics by comparing their own phenotype(s) with those of unidentified individuals. Yet whether animals can recognize kin through self-matching is controversial. Because golden hamsters (Mesocricetus auratus) mate multiply and can produce multiply sired litters, they were tested for their ability to use self-matching for kin recognition. Hamsters that were reared only with non-kin since birth responded differentially to odours of unfamiliar relatives and non-relatives. Postnatal association with kin was not necessary for this discrimination. Prenatal learning was unlikely because of delayed production and perception of social odours. To our knowledge, this is the first demonstration that a vertebrate can use its own phenotype for kin-recognition purposes without prior experience with kin. By using itself as a referent, rather than its siblings or parents, a golden hamster may be better able to direct nepotism towards the most appropriate individuals. Kin discrimination via self-inspection may be especially important in nepotistic contexts (to identify most closely related conspecifics), whereas inclusion of the phenotypes of close kin as referents may be favoured in mate-choice contexts (to identify all related individuals). PMID:10821615

  20. Methods for Analyzing Multivariate Phenotypes in Genetic Association Studies

    Directory of Open Access Journals (Sweden)

    Qiong Yang

    2012-01-01

    Full Text Available Multivariate phenotypes are frequently encountered in genetic association studies. The purpose of analyzing multivariate phenotypes usually includes discovery of novel genetic variants of pleiotropy effects, that is, affecting multiple phenotypes, and the ultimate goal of uncovering the underlying genetic mechanism. In recent years, there have been new method development and application of existing statistical methods to such phenotypes. In this paper, we provide a review of the available methods for analyzing association between a single marker and a multivariate phenotype consisting of the same type of components (e.g., all continuous or all categorical or different types of components (e.g., some are continuous and others are categorical. We also reviewed causal inference methods designed to test whether the detected association with the multivariate phenotype is truly pleiotropy or the genetic marker exerts its effects on some phenotypes through affecting the others.

  1. Temporal abstraction-based clinical phenotyping with Eureka!

    Science.gov (United States)

    Post, Andrew R; Kurc, Tahsin; Willard, Richie; Rathod, Himanshu; Mansour, Michel; Pai, Akshatha Kalsanka; Torian, William M; Agravat, Sanjay; Sturm, Suzanne; Saltz, Joel H

    2013-01-01

    Temporal abstraction, a method for specifying and detecting temporal patterns in clinical databases, is very expressive and performs well, but it is difficult for clinical investigators and data analysts to understand. Such patterns are critical in phenotyping patients using their medical records in research and quality improvement. We have previously developed the Analytic Information Warehouse (AIW), which computes such phenotypes using temporal abstraction but requires software engineers to use. We have extended the AIW's web user interface, Eureka! Clinical Analytics, to support specifying phenotypes using an alternative model that we developed with clinical stakeholders. The software converts phenotypes from this model to that of temporal abstraction prior to data processing. The model can represent all phenotypes in a quality improvement project and a growing set of phenotypes in a multi-site research study. Phenotyping that is accessible to investigators and IT personnel may enable its broader adoption. PMID:24551400

  2. Whole-Genome Sequencing Analysis Accurately Predicts Antimicrobial Resistance Phenotypes in Campylobacter spp.

    Science.gov (United States)

    Zhao, S; Tyson, G H; Chen, Y; Li, C; Mukherjee, S; Young, S; Lam, C; Folster, J P; Whichard, J M; McDermott, P F

    2016-01-01

    The objectives of this study were to identify antimicrobial resistance genotypes for Campylobacter and to evaluate the correlation between resistance phenotypes and genotypes using in vitro antimicrobial susceptibility testing and whole-genome sequencing (WGS). A total of 114 Campylobacter species isolates (82 C. coli and 32 C. jejuni) obtained from 2000 to 2013 from humans, retail meats, and cecal samples from food production animals in the United States as part of the National Antimicrobial Resistance Monitoring System were selected for study. Resistance phenotypes were determined using broth microdilution of nine antimicrobials. Genomic DNA was sequenced using the Illumina MiSeq platform, and resistance genotypes were identified using assembled WGS sequences through blastx analysis. Eighteen resistance genes, including tet(O), blaOXA-61, catA, lnu(C), aph(2″)-Ib, aph(2″)-Ic, aph(2')-If, aph(2″)-Ig, aph(2″)-Ih, aac(6')-Ie-aph(2″)-Ia, aac(6')-Ie-aph(2″)-If, aac(6')-Im, aadE, sat4, ant(6'), aad9, aph(3')-Ic, and aph(3')-IIIa, and mutations in two housekeeping genes (gyrA and 23S rRNA) were identified. There was a high degree of correlation between phenotypic resistance to a given drug and the presence of one or more corresponding resistance genes. Phenotypic and genotypic correlation was 100% for tetracycline, ciprofloxacin/nalidixic acid, and erythromycin, and correlations ranged from 95.4% to 98.7% for gentamicin, azithromycin, clindamycin, and telithromycin. All isolates were susceptible to florfenicol, and no genes associated with florfenicol resistance were detected. There was a strong correlation (99.2%) between resistance genotypes and phenotypes, suggesting that WGS is a reliable indicator of resistance to the nine antimicrobial agents assayed in this study. WGS has the potential to be a powerful tool for antimicrobial resistance surveillance programs. PMID:26519386

  3. Behavioral Analysis of Dopaminergic Activation in Zebrafish and Rats Reveals Similar Phenotypes.

    Science.gov (United States)

    Ek, Fredrik; Malo, Marcus; Åberg Andersson, Madelene; Wedding, Christoffer; Kronborg, Joel; Svensson, Peder; Waters, Susanna; Petersson, Per; Olsson, Roger

    2016-05-18

    Zebrafish is emerging as a complement to mammals in behavioral studies; however, there is a lack of comparative studies with rodents and humans to establish the zebrafish as a predictive translational model. Here we present a detailed phenotype evaluation of zebrafish larvae, measuring 300-3000 variables and analyzing them using multivariate analysis to identify the most important ones for further evaluations. The dopamine agonist apomorphine has previously been shown to have a complex U-shaped dose-response relationship in the variable distance traveled. In this study, we focused on breaking down distance traveled into more detailed behavioral phenotypes for both zebrafish and rats and identified in the multivariate analysis low and high dose phenotypes with characteristic behavioral features. Further analysis of single parameters also identified an increased activity at the lowest concentration indicative of a U-shaped dose-response. Apomorphine increased the distance of each swim movement (bout) at both high and low doses, but the underlying behavior of this increase is different; at high dose, both bout duration and frequency increased whereas bout max speed was higher at low dose. Larvae also displayed differences in place preference. The low dose phenotype spent more time in the center, indicative of an anxiolytic effect, while the high-dose phenotype had a wall preference. These dose-dependent effects corroborated findings in a parallel rat study and previous observations in humans. The translational value of pharmacological zebrafish studies was further evaluated by comparing the amino acid sequence of the dopamine receptors (D1-D4), between zebrafish, rats and humans. Humans and zebrafish share 100% of the amino acids in the binding site for D1 and D3 whereas D2 and D4 receptors share 85-95%. Molecular modeling of dopamine D2 and D4 receptors indicated that nonconserved amino acids have limited influence on important ligand-receptor interactions. PMID

  4. Epigenetic Inheritance of a Cocaine Resistance Phenotype

    OpenAIRE

    Vassoler, Fair M.; White, Samantha L; Schmidt, Heath D.; Sadri-Vakili, Ghazaleh; Pierce, R Christopher

    2012-01-01

    A heritable phenotype resulting from the self-administration of cocaine in rats was delineated. We observed delayed acquisition and reduced maintenance of cocaine self-administration in male, but not female, offspring of sires that self-administered cocaine. Brain-derived neurotrophic factor (BDNF) mRNA and protein were increased in the medial prefrontal cortex (mPFC) and there was an increased association of acetylated histone H3 with BDNF promoters only in the male offspring of cocaine-expe...

  5. Understanding the basis for Down syndrome phenotypes.

    Directory of Open Access Journals (Sweden)

    2006-03-01

    Full Text Available Down syndrome is a collection of features that are caused by trisomy for human Chromosome 21. While elevated transcript levels of the more than 350 genes on the chromosome are primarily responsible, it is likely that multiple genetic mechanisms underlie the numerous ways in which development and function diverge in individuals with trisomy 21 compared to euploid individuals. We consider genotype-phenotype interactions with the goal of producing working concepts that will be useful for approaches to ameliorate the effects of trisomy.

  6. Moyamoya angiopathy - Is there a Western phenotype?

    Science.gov (United States)

    Hever, Pennylouise; Alamri, Alexander; Tolias, Christos

    2015-12-01

    Moyamoya disease (MMD) is a chronic cerebrovascular disease involving progressive bilateral stenosis of the intracranial segments of the internal carotid arteries. It results in the development of a rich, but friable collateral supply, prone to rupture. The disease is well described in Japanese literature and was originally thought to be a predozminantly Eastern disease. However, the recent literature describes a Western phenotype that may present with a different clinical course. This review aims to describe the variations in the epidemiology of the MMD between Eastern and Western populations, the possible reasons for them and highlight their implications for clinical practise and future research. PMID:26473792

  7. A single point-mutation within the melanophilin gene causes the lavender plumage colour dilution phenotype in the chicken

    Directory of Open Access Journals (Sweden)

    Tixier-Boichard Michèle

    2008-01-01

    Full Text Available Abstract Background The lavender phenotype in the chicken causes the dilution of both black (eumelanin and red/brown (phaeomelanin pigments. Defects in three genes involved in intracellular melanosomal transport, previously described in mammals, give rise to similar diluted pigmentation phenotypes as those seen in lavender chickens. Results We have used a candidate-gene approach based on an expectation of homology with mammals to isolate a gene involved in pigmentation in chicken. Comparative sequence analysis of candidate genes in the chicken identified a strong association between a mutation in the MLPH gene and the diluted pigmentation phenotype. This mutation results in the amino acid change R35W, at a site also associated with similar phenotypes in mice, humans and cats. Conclusion This is the first time that an avian species with a mutation in the MLPH gene has been reported.

  8. Genome-Wide Association Study Identifies Loci for Salt Tolerance during Germination in Autotetraploid Alfalfa (Medicago sativa L.) Using Genotyping-by-Sequencing.

    Science.gov (United States)

    Yu, Long-Xi; Liu, Xinchun; Boge, William; Liu, Xiang-Ping

    2016-01-01

    Salinity is one of major abiotic stresses limiting alfalfa (Medicago sativa L.) production in the arid and semi-arid regions in US and other counties. In this study, we used a diverse panel of alfalfa accessions previously described by Zhang et al. (2015) to identify molecular markers associated with salt tolerance during germination using genome-wide association study (GWAS) and genotyping-by-sequencing (GBS). Phenotyping was done by germinating alfalfa seeds under different levels of salt stress. Phenotypic data of adjusted germination rates and SNP markers generated by GBS were used for marker-trait association. Thirty six markers were significantly associated with salt tolerance in at least one level of salt treatments. Alignment of sequence tags to the Medicago truncatula genome revealed genetic locations of the markers on all chromosomes except chromosome 3. Most significant markers were found on chromosomes 1, 2, and 4. BLAST search using the flanking sequences of significant markers identified 14 putative candidate genes linked to 23 significant markers. Most of them were repeatedly identified in two or three salt treatments. Several loci identified in the present study had similar genetic locations to the reported QTL associated with salt tolerance in M. truncatula. A locus identified on chromosome 6 by this study overlapped with that by drought in our previous study. To our knowledge, this is the first report on mapping loci associated with salt tolerance during germination in autotetraploid alfalfa. Further investigation on these loci and their linked genes would provide insight into understanding molecular mechanisms by which salt and drought stresses affect alfalfa growth. Functional markers closely linked to the resistance loci would be useful for MAS to improve alfalfa cultivars with enhanced resistance to drought and salt stresses. PMID:27446182

  9. Heat Shock Protein 47: A Novel Biomarker of Phenotypically Altered Collagen-Producing Cells

    International Nuclear Information System (INIS)

    Heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that helps the molecular maturation of various types of collagens. A close association between increased expression of HSP47 and the excessive accumulation of collagens is found in various human and experimental fibrotic diseases. Increased levels of HSP47 in fibrotic diseases are thought to assist in the increased assembly of procollagen, and thereby contribute to the excessive deposition of collagens in fibrotic areas. Currently, there is not a good universal histological marker to identify collagen-producing cells. Identifying phenotypically altered collagen-producing cells is essential for the development of cell-based therapies to reduce the progression of fibrotic diseases. Since HSP47 has a single substrate, which is collagen, the HSP47 cellular expression provides a novel universal biomarker to identify phenotypically altered collagen-producing cells during wound healing and fibrosis. In this brief article, we explained why HSP47 could be used as a universal marker for identifying phenotypically altered collagen-producing cells

  10. Peruvian Maca (Lepidium peruvianum): (II) Phytochemical Profiles of Four Prime Maca Phenotypes Grown in Two Geographically-Distant Locations

    Science.gov (United States)

    O. Meissner, Henry; Mscisz, Alina; Piatkowska, Ewa; Baraniak, Marek; Mielcarek, Sebastian; Kedzia, Bogdan; Holderna-Kedzia, Elzbieta; Pisulewski, Pawel

    2016-01-01

    Peruvian Maca crops (Lepidium peruvianum), grown in two geographically-distant cultivation sites located at similar altitudes in the highlands of the Peruvian Andes (Junin at 4,200 m a.s.l. and Ancash 4,150 m a.s.l.), were used in the study. Four prime Maca phenotypes, distinguished by hypocotyl colours labelled as “Yellow”, “Purple”, “Red” and “Black” were selected to determine distribution in levels and corresponding ratios between individual Glucosinolates (Glucotropaeolin and m-methylglucotropaeolin) in an attempt to identify four Peruvian Maca phenotypes from analyses of powdered hypocotyls. There were highly significant differences (P<0.01) in hypocotyl weight/size of four Maca phenotypes harvested in two locations. The Junin crop represented a mostly “large” class (13.3 g) with “small” size hypocotyls (7.2 g), while a “small” class was predominant in Ancash (3.5 g). Powdered Yellow Maca showed significantly higher (P<0.001) microbial contamination than the other three, with Black Maca being the least infected. Only minor, statistically-confirmed differences were detected in nutritive characteristics between the four Maca phenotypes grown in Junin, however highly significant differences (P<0.01) in Glucosinolates existed between the Red and Black Maca grown in Junin and Ancash. Irrespective of the cultivation location, Red phenotypes showed the highest content of Total Glucosinolates, followed by Black and Purple, with the Yellow phenotype showing consistently lower levels. Highly significant P<0.01) differences determined in ratios of individual Glucosinolates between four Maca phenotypes grown in two locations, confirms an earlier assumption that sums of individual Glucosinolates, their ratios and profiles, may be feasible to explore in analytically identifying individual Maca phenotypes in pulverised marketed Maca products.

  11. Al-Anon/Alateen

    Science.gov (United States)

    Find an Al-Anon meeting Español | Français 2018 Int'l Convention Home About Group Meetings What If I'm not ready ... a meeting? What can I expect at an Al-Anon meeting? What was my first meeting like? ...

  12. Evolution of ConAl clusters and chemisorption of hydrogen on ConAl clusters

    International Nuclear Information System (INIS)

    The growth behavior of ConAl (n = 1–15) and the chemisorptions of hydrogen on the ground state geometries have been studied using the density functional theory (DFT) within the generalized gradient approximation (GGA). The growth pattern for ConAl is Al-substituted Con+1 clusters, and it keeps the similar frameworks of the most stable Con+1 clusters except for n = 2, 3, and 6. The Al atom substitutes the surface atom of the Con+1 clusters for n ≤ 13. Starting from n = 14, the Al atom completely falls into the center of the Co-frame. The dissociation energy, the second-order energy differences, and the HOMO–LUMO gaps indicate that the magic numbers of the calculated ConAl clusters are 7, 9, and 13, corresponding to the high symmetrical structures. To my knowledge, this is the first time that a systematic study of chemisorption of hydrogen on cobalt aluminum clusters. The twofold bridge site is identified to be the most favorable chemisorptions site for one hydrogen adsorption on ConAl (n = 1–6, 8, 10), and two hydrogen adsorption on ConAl (n = 1–7), while threefold hollow site is preferred for one hydrogen adsorption on ConAl (n = 7, 9, 11–15) and two hydrogen adsorption on ConAl (n = 8–10, 12–15) clusters. The ground state structure of two hydrogen adsorption on Co11Al is exceptional. In general, the binding energy of both H and 2H of ConAl (n = 1–12) is found to increase with the cluster size. And the result shows that large binding energies of the hydrogen atoms and large fragmentation energies for Co11AlH and Co12AlH make these species behaving like magic clusters.

  13. A vestibular phenotype for Waardenburg syndrome?

    Science.gov (United States)

    Black, F. O.; Pesznecker, S. C.; Allen, K.; Gianna, C.

    2001-01-01

    OBJECTIVE: To investigate vestibular abnormalities in subjects with Waardenburg syndrome. STUDY DESIGN: Retrospective record review. SETTING: Tertiary referral neurotology clinic. SUBJECTS: Twenty-two adult white subjects with clinical diagnosis of Waardenburg syndrome (10 type I and 12 type II). INTERVENTIONS: Evaluation for Waardenburg phenotype, history of vestibular and auditory symptoms, tests of vestibular and auditory function. MAIN OUTCOME MEASURES: Results of phenotyping, results of vestibular and auditory symptom review (history), results of vestibular and auditory function testing. RESULTS: Seventeen subjects were women, and 5 were men. Their ages ranged from 21 to 58 years (mean, 38 years). Sixteen of the 22 subjects sought treatment for vertigo, dizziness, or imbalance. For subjects with vestibular symptoms, the results of vestibuloocular tests (calorics, vestibular autorotation, and/or pseudorandom rotation) were abnormal in 77%, and the results of vestibulospinal function tests (computerized dynamic posturography, EquiTest) were abnormal in 57%, but there were no specific patterns of abnormality. Six had objective sensorineural hearing loss. Thirteen had an elevated summating/action potential (>0.40) on electrocochleography. All subjects except those with severe hearing loss (n = 3) had normal auditory brainstem response results. CONCLUSION: Patients with Waardenburg syndrome may experience primarily vestibular symptoms without hearing loss. Electrocochleography and vestibular function tests appear to be the most sensitive measures of otologic abnormalities in such patients.

  14. Hierarchical genetic clusters for phenotypic analysis

    Directory of Open Access Journals (Sweden)

    Luiza Barbosa da Matta

    2015-10-01

    Full Text Available Methods to obtain phenotypic information were evaluated to help breeders choosing the best methodology for analysis of genetic diversity in backcross populations. Phenotypes were simulated for 13 characteristics generated in 10 populations with 100 individuals each. Genotypic information was generated from 100 loci of which 20 were taken at random to determine the characteristics expressing two alleles. Dissimilarity measures were calculated, and genetic diversity was analyzed through hierarchical clustering and graphic projection of the distances. A backcross was performed from the two most divergent populations. A set of characteristics with variable heritability was taken into account. The environmental effect was simulated assuming . For hierarchical clusters, the following methods were used: Gower Method, average linkage within the cluster, average linkage among clusters, the furthest neighbor method, the nearest neighbor method, Ward’s method, and the median method. The environmental effect and heritability of the analyzed variables had an influence on the pattern of hierarchical clustering populations according to the backcrossed generations. The nearest neighbor method was the most efficient in reconstructing the system of backcrossing, and it presented the highest cophenetic correlation. The efficiency of the nearest neighbor method was the highest when the analysis involved characteristics of high heritability.

  15. GEE for GWAS using Longitudinal Phenotype Data

    Science.gov (United States)

    Sitlani, Colleen M.; Rice, Kenneth M.; Lumley, Thomas; McKnight, Barbara; Cupples, L. Adrienne; Avery, Christy L.; Noordam, Raymond; Stricker, Bruno H.C.; Whitsel, Eric A.; Psaty, Bruce M.

    2014-01-01

    Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here we discuss one such method – generalized estimating equations (GEE) – in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium – the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study (CHS), and the Rotterdam Study (RS). PMID:25297442

  16. Dynamic phenotypic clustering in noisy ecosystems.

    Directory of Open Access Journals (Sweden)

    Morten Ernebjerg

    2011-03-01

    Full Text Available In natural ecosystems, hundreds of species typically share the same environment and are connected by a dense network of interactions such as predation or competition for resources. Much is known about how fixed ecological niches can determine species abundances in such systems, but far less attention has been paid to patterns of abundances in randomly varying environments. Here, we study this question in a simple model of competition between many species in a patchy ecosystem with randomly fluctuating environmental conditions. Paradoxically, we find that introducing noise can actually induce ordered patterns of abundance-fluctuations, leading to a distinct periodic variation in the correlations between species as a function of the phenotypic distance between them; here, difference in growth rate. This is further accompanied by the formation of discrete, dynamic clusters of abundant species along this otherwise continuous phenotypic axis. These ordered patterns depend on the collective behavior of many species; they disappear when only individual or pairs of species are considered in isolation. We show that they arise from a balance between the tendency of shared environmental noise to synchronize species abundances and the tendency for competition among species to make them fluctuate out of step. Our results demonstrate that in highly interconnected ecosystems, noise can act as an ordering force, dynamically generating ecological patterns even in environments lacking explicit niches.

  17. Heliconia phenotypic diversity based on qualitative descriptors.

    Science.gov (United States)

    Guimarães, W N R; Martins, L S S; Castro, C E F; Carvalho Filho, J L S; Loges, V

    2014-01-01

    The aim of this study was to characterize Heliconia genotypes phenotypically using 26 qualitative descriptors. The evaluations were conducted in five flowering stems per clump in three replicates of 22 Heliconia genotypes. Data were subjected to multivariate analysis, the Mahalanobis dissimilarity measure was estimated, and the dendrogram was generated using the nearest neighbor method. From the values generated by the dissimilarity matrix and the clusters formed among the Heliconia genotypes studied, the phenotypic characterizations that best differentiated the genotypes were: pseudostem and wax green tone (light or dark green), leaf-wax petiole, the petiole hair, cleft margin at the base of the petiole, midrib underside shade of green, wax midrib underside, color sheet (light or dark green), unequal lamina base, torn limb, inflorescence-wax, position of inflorescence, bract leaf in apex, twisting of the rachis, and type of bloom. These results will be applied in the preparation of a catalog for Heliconia descriptors, in the selection of different genotypes with most promising characteristics for crosses, and for the characterization of new genotypes to be introduced in germplasm collections. PMID:24782170

  18. Nunukan Chicken: Genetic Characteristics, Phenotype and Utilization

    Directory of Open Access Journals (Sweden)

    Tike Sartika

    2006-12-01

    Full Text Available Nunukan chicken is a local chicken from East Kalimantan which spreads out in Tarakan and Nunukan Islands . The chicken has a specific buff color and Columbian type feather and also has very late feathering (VLF trait . The Nunukan cocks and hens have no wing and tail primary feather; the tail feathers are short and fragile . The VLF trait is known to have association with a K gene on the Z chromosome. The chicken is efficient in protein metabolism . Sulfur amino acids (cystine and methionine that needed for feather growth, could be utilized for meat and egg production . The egg production of Nunukan chicken was better than the Kampung chicken . The average of hen day, hen house and peak production of Nunukan chicken was 45 . 39.1 and 62%, respectively, while the Kampung chicken was 35 .9, 30 .9 and 48%, respectively . Based on genetic analysis, the external genotype characteristic of the Nunukan chicken is ii ce ss Idld pp. It means that the phenotype appearance of the Nunukan chicken was columbian and gold feathering type, yellow and white shank color and single comb type. This phenotype is similar to Merawang Chicken . The genetic introgression of the Nunukan chicken is affected by the Rhode Island Red with the genetic introgression value of 0.964 .

  19. Phenotypic variability of TRPV4 related neuropathies

    Science.gov (United States)

    Evangelista, Teresinha; Bansagi, Boglarka; Pyle, Angela; Griffin, Helen; Douroudis, Konstantinos; Polvikoski, Tuomo; Antoniadi, Thalia; Bushby, Kate; Straub, Volker; Chinnery, Patrick F.; Lochmüller, Hanns; Horvath, Rita

    2015-01-01

    Mutations in the transient receptor potential vanilloid 4 (TRPV4) gene have been associated with autosomal dominant skeletal dysplasias and peripheral nervous system syndromes (PNSS). PNSS include Charcot–Marie–Tooth disease (CMT) type 2C, congenital spinal muscular atrophy and arthrogryposis and scapuloperoneal spinal muscular atrophy. We report the clinical, electrophysiological and muscle biopsy findings in two unrelated patients with two novel heterozygous missense mutations in the TRPV4 gene. Whole exome sequencing was carried out on genomic DNA using Illumina TruseqTM 62Mb exome capture. Patient 1 harbours a de novo c.805C > T (p.Arg269Cys) mutation. Clinically, this patient shows signs of both scapuloperoneal spinal muscular atrophy and skeletal dysplasia. Patient 2 harbours a novel c.184G > A (p.Asp62Asn) mutation. While the clinical phenotype is compatible with CMT type 2C with the patient's muscle harbours basophilic inclusions. Mutations in the TRPV4 gene have a broad phenotypic variability and disease severity and may share a similar pathogenic mechanism with Heat Shock Protein related neuropathies. PMID:25900305

  20. Al - BASED CAST COMPOSITES

    Directory of Open Access Journals (Sweden)

    Rakesh Kumar Yadav

    2011-08-01

    Full Text Available The economy is very important feature nowadays in themarket. The researches are playing an important role inengineering field to increase the life of machine parts /components and decrease the cost. The compositematerials have the potential to replace widely used steeland aluminium due to their good characteristics withbetter performance. The Al-based composites have foundextensive applications in automobile industries andaerospace industries due to their increased stiffness,strength, thermal conductivity and wear resistanceproperties. A number of particulate phases have beenemployed in the Al-alloy matrix. The cast aluminiumceramicparticulate composites are finding applications inpistons, connecting rods, cylinder liner, engine cylinderblock, electrical contacts etc.The present investigation isbased on study of the effect of particulate phase on theSEM study, micro-hardness, elastic modulus, tensilestrength and the wear behaviour of Al-5 % SiC-7 % Fe,Al-10 % SiC-6 % Fe and Al-15 % SiC-5 % Fe composites.

  1. A Neutrophil Phenotype Model for Extracorporeal Treatment of Sepsis.

    Directory of Open Access Journals (Sweden)

    Alexander D Malkin

    2015-10-01

    Full Text Available Neutrophils play a central role in eliminating bacterial pathogens, but may also contribute to end-organ damage in sepsis. Interleukin-8 (IL-8, a key modulator of neutrophil function, signals through neutrophil specific surface receptors CXCR-1 and CXCR-2. In this study a mechanistic computational model was used to evaluate and deploy an extracorporeal sepsis treatment which modulates CXCR-1/2 levels. First, a simplified mechanistic computational model of IL-8 mediated activation of CXCR-1/2 receptors was developed, containing 16 ODEs and 43 parameters. Receptor level dynamics and systemic parameters were coupled with multiple neutrophil phenotypes to generate dynamic populations of activated neutrophils which reduce pathogen load, and/or primed neutrophils which cause adverse tissue damage when misdirected. The mathematical model was calibrated using experimental data from baboons administered a two-hour infusion of E coli and followed for a maximum of 28 days. Ensembles of parameters were generated using a Bayesian parallel tempering approach to produce model fits that could recreate experimental outcomes. Stepwise logistic regression identified seven model parameters as key determinants of mortality. Sensitivity analysis showed that parameters controlling the level of killer cell neutrophils affected the overall systemic damage of individuals. To evaluate rescue strategies and provide probabilistic predictions of their impact on mortality, time of onset, duration, and capture efficacy of an extracorporeal device that modulated neutrophil phenotype were explored. Our findings suggest that interventions aiming to modulate phenotypic composition are time sensitive. When introduced between 3-6 hours of infection for a 72 hour duration, the survivor population increased from 31% to 40-80%. Treatment efficacy quickly diminishes if not introduced within 15 hours of infection. Significant harm is possible with treatment durations ranging from 5

  2. Is oxygen a key factor in the lipodystrophy phenotype?

    Directory of Open Access Journals (Sweden)

    Sonigo Pierre

    2006-10-01

    Full Text Available Abstract Background The lipodystrophic syndrome (LD is a disorder resulting from selective damage of adipose tissue by antiretroviral drugs included in therapy controlling human-immunodeficiency-virus-1. In the therapy cocktail the nucleoside reverse transcriptase inhibitors (NRTI contribute to the development of this syndrome. Cellular target of NRTI was identified as the mitochondrial polymerase-gamma and their toxicity described as a mitochondrial DNA (mtDNA depletion resulting in a mitochondrial cytopathy and involved in fat redistribution. No mechanisms offer explanation whatsoever for the lipo-atrophic and lipo-hypertrophic phenotype of LD. To understand the occurrence we proposed that the pO2 (oxygen partial pressure could be a key factor in the development of the LD. For the first time, we report here differential effects of NRTIs on human adipose cells depending on pO2 conditions. Results and discussion We showed that the hypoxia conditions could alter adipogenesis process by modifying expression of adipocyte makers as leptin and the peroxisome proliferator-activated receptor PPARgamma and inhibiting triglyceride (TG accumulation in adipocytes. Toxicity of NRTI followed on adipose cells in culture under normoxia versus hypoxia conditions showed, differential effects of drugs on mtDNA of these cells depending on pO2 conditions. Moreover, NRTI-treated adipocytes were refractory to the inhibition of adipogenesis under hypoxia. Finally, our hypothesis that variations of pO2 could exist between adipose tissue from anatomical origins was supported by staining of the hypoxic-induced angiopoietin ANGPTL4 depended on the location of fat. Conclusion Toxicity of NRTIs have been shown to be opposite on human adipose cells depending on the oxygen availability. These data suggest that the LD phenotype may be a differential consequence of NRTI effects, depending on the metabolic status of the targeted adipose tissues and provide new insights into the

  3. Academic Freedom in Al Al-Bayt University and the Level of Practicing It from the View Point of the Faculty Members Based on Some Variables

    Science.gov (United States)

    Al-Madi, Bayan

    2013-01-01

    The purpose of this study is to identify the level of practicing academic freedom by the faculty members of Al al-Bayt University. The study population included all the faculty members (297) of Al al-Bayt University, during the academic year, 2010/2011. The study sample was randomly selected and included 250 faculty members. To achieve the aims of…

  4. [Escherichia coli: diversity of biochemical phenotypes in aquatic environments (Santa, Fe, Argentina)].

    Science.gov (United States)

    Emiliani, F; Lajmanovich, R; González, S M

    2001-01-01

    During certain environmental conditions, the floating aquatic vegetation, mainly represented by Eichhornia crassipes (water hyacinth) invade and even cover water courses assigned to recreational activities or to the supply of drinkable water. The rhizosphere of these plants constitutes an unknown biotope of bacteria of sanitary interest, possibly different from waters without vegetation and of the sediment of the same aquatic system. To verify such possibility, 206 isolated strains in MacConkey Agar (Difco) were typified and identified (78 from water, 65 from sediment and 63 from rhizosphere) using the API 20 E system (v. 4.0) and Apilab plus software (v 3.3.3), both of bioMérieux (Marcy-l'Etoile, France, 1998). Nineteen different biochemical phenotypes from E. coli were found. The 79% of the population belonged to only 7 phenotypes; the 21% remaining, to the other 12 phenotypes. Twelve phenotypes did not share the biotopes, while only 4 were in the three. These results (and those obtained by other authors who used the API 20 E system in other biotopes) suggest that it would be possible to characterize the rhizosphere using those phenotypes that are found in smaller proportion. The greatest index of diversity (H) and evenness (E) were found in the rhizosphere (H = 2.903; E = 0.874). The dendrogram (average distances and UPGMA method) reaffirms the dissimilarity in biochemical phenotypes of E. coli populations of the rhizosphere with regard to the other biotopes. The most abundant bacterial species in the three biotopes were E. coli, Klebsiella terrigena and K. pneumoniae, corresponding to 75.2% of the community. The rhizosphere differed from Serratia odorifera and from Klebsiella spp. because of its higher rate of isolation. PMID:11494758

  5. Heterogeneous nucleation of solid Al from the melt by Al 3 Ti : Molecular dynamics simulations

    KAUST Repository

    Wang, Junsheng

    2010-10-27

    It has been known experimentally for some time that Al3 Ti is a powerful nucleant for the solidification of aluminum from the melt; however, a full microscopic understanding is still lacking. To develop this understanding, we have performed molecular dynamics simulations of the nucleation and early stages of growth using published embedded atom method potentials for Al-Ti, but modified by us to stabilize the D 022 structure. We discover that Al3 Ti can indeed be very effective in promoting the growth of solid Al but the manner in which growth takes place depends sensitively on the surface on which the Al nucleates. In particular, complete growth of solid Al from the liquid on the (001) and (110) surfaces of Al3 Ti occurs at a lower temperature than on the (112) surface. This anisotropy agrees with observations in previous experiments. We explain this observation in terms of interfacial energies. On the preferential (111) surface of Al the solid-liquid interfacial energy is highest while the solid-vacuum energy is lowest. Our simulations also show that the extent of ordering taking place in liquid Al close to the Al 3 Ti substrate above the melting point correlates well with the effectiveness of the substrate as a nucleant below the melting temperature: this could provide a computationally efficient scheme to identify good nucleants. © 2010 The American Physical Society.

  6. Rumen microbial communities influence metabolic phenotypes in lambs

    Directory of Open Access Journals (Sweden)

    Diego P. Morgavi

    2015-10-01

    Full Text Available The rumen microbiota is an essential part of ruminants forging their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted that differentially restricted the acquisition of microbes. Rumen microbiota, fermentation parameters, digestibility and growth were monitored for up to 31 weeks of age. Microbiota assembled in isolation from other ruminants lacked protozoa and had low bacterial and archaeal diversity whereas digestibility was not affected. Exposure to adult sheep microbiota increased bacterial and archaeal diversity independently of protozoa presence. For archaea, Methanomassiliicoccales displaced Methanosphaera. Notwithstanding, protozoa induced differences in functional traits such as digestibility and significantly shaped bacterial community structure, notably Ruminococcaceae and Lachnospiraceae lower up to 6 folds, Prevotellaceae lower by ~40%, and Clostridiaceae and Veillonellaceae higher up to 10 folds compared to microbiota without protozoa. An orthogonal partial least squares-discriminant analysis of urinary metabolome matched differences in microbiota structure. Discriminant metabolites were mainly involved in amino acids and protein metabolic pathways while a negative interaction was observed between methylotrophic methanogens Methanomassiliicoccales and trimethylamine N-oxide. These results stress the influence of gut microbes on animal phenotype and show the potential of metabolomics for monitoring rumen microbial functions.

  7. Cavin1; a regulator of lung function and macrophage phenotype.

    Directory of Open Access Journals (Sweden)

    Praveen Govender

    Full Text Available Caveolae are cell membrane invaginations that are highly abundant in adipose tissue, endothelial cells and the lung. The formation of caveolae is dependent on the expression of various structural proteins that serve as scaffolding for these membrane invaginations. Cavin1 is a newly identified structural protein whose deficiency in mice leads to loss of caveolae formation and to development of a lipodystrophic phenotype. In this study, we sought to investigate the functional role of Cavin1 in the lung. Cavin1 deficient mice possessed dramatically altered distal lung morphology and exhibited significant physiological alterations, notably, increased lung elastance. The changes in distal lung architecture were associated with hypercellularity and the accumulation of lung macrophages. The increases in lung macrophages occurred without changes to circulating numbers of mononuclear cells and without evidence for increased proliferation. However, the increases in lung macrophages were associated with higher levels of macrophage chemotactic factors CXCL2 and CCL2 in BAL fluid from Cavin1-/- mice suggesting a possible mechanism by which these cells accumulate. In addition, lung macrophages from Cavin1-/- mice were larger and displayed measurable differences in gene expression when compared to macrophages from wild-type mice. Interestingly, macrophages were also increased in adipose tissue but not in liver, kidney or skeletal muscle from Cavin1-/- mice, and similar tissue specificity for macrophage accumulation was observed in lungs and adipose tissue from Caveolin1-/- mice. In conclusion, this study demonstrates an important role for Cavin1 in lung homeostasis and suggests that caveolae structural proteins are necessary for regulating macrophage number and phenotype in the lung.

  8. Abscisic acid ameliorates the systemic sclerosis fibroblast phenotype in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Bruzzone, Santina, E-mail: santina.bruzzone@unige.it [Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova (Italy); Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova (Italy); Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genova (Italy); Battaglia, Florinda [Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova (Italy); Mannino, Elena [Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova (Italy); Parodi, Alessia [Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova (Italy); Fruscione, Floriana [Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova (Italy); Advanced Biotechnology Center, Largo Rosanna Benzi 10, 16132 Genova (Italy); Basile, Giovanna [Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova (Italy); Salis, Annalisa; Sturla, Laura [Department of Experimental Medicine, Section of Biochemistry, University of Genova, Viale Benedetto XV 1, 16132 Genova (Italy); Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova (Italy); Negrini, Simone; Kalli, Francesca; Stringara, Silvia [Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova (Italy); Filaci, Gilberto [Centre of Excellence for Biomedical Research, University of Genova, Viale Benedetto XV 9, 16132 Genova (Italy); Department of Internal Medicine, Viale Benedetto XV 6, 16132 Genova (Italy); and others

    2012-05-25

    Highlights: Black-Right-Pointing-Pointer ABA is an endogenous hormone in humans, regulating different cell responses. Black-Right-Pointing-Pointer ABA reverts some of the functions altered in SSc fibroblasts to a normal phenotype. Black-Right-Pointing-Pointer UV-B irradiation increases ABA content in SSc cultures. Black-Right-Pointing-Pointer SSc fibroblasts could benefit from exposure to ABA and/or to UV-B. -- Abstract: The phytohormone abscisic acid (ABA) has been recently identified as an endogenous hormone in humans, regulating different cell functions, including inflammatory processes, insulin release and glucose uptake. Systemic sclerosis (SSc) is a chronic inflammatory disease resulting in fibrosis of skin and internal organs. In this study, we investigated the effect of exogenous ABA on fibroblasts obtained from healthy subjects and from SSc patients. Migration of control fibroblasts induced by ABA was comparable to that induced by transforming growth factor-{beta} (TGF-{beta}). Conversely, migration toward ABA, but not toward TGF-{beta}, was impaired in SSc fibroblasts. In addition, ABA increased cell proliferation in fibroblasts from SSc patients, but not from healthy subjects. Most importantly, presence of ABA significantly decreased collagen deposition by SSc fibroblasts, at the same time increasing matrix metalloproteinase-1 activity and decreasing the expression level of tissue inhibitor of metalloproteinase (TIMP-1). Thus, exogenously added ABA appeared to revert some of the functions altered in SSc fibroblasts to a normal phenotype. Interestingly, ABA levels in plasma from SSc patients were found to be significantly lower than in healthy subjects. UV-B irradiation induced an almost 3-fold increase in ABA content in SSc cultures. Altogether, these results suggest that the fibrotic skin lesions in SSc patients could benefit from exposure to high(er) ABA levels.

  9. Design of Biomedical Robots for Phenotype Prediction Problems.

    Science.gov (United States)

    deAndrés-Galiana, Enrique J; Fernández-Martínez, Juan Luis; Sonis, Stephen T

    2016-08-01

    Genomics has been used with varying degrees of success in the context of drug discovery and in defining mechanisms of action for diseases like cancer and neurodegenerative and rare diseases in the quest for orphan drugs. To improve its utility, accuracy, and cost-effectiveness optimization of analytical methods, especially those that translate to clinically relevant outcomes, is critical. Here we define a novel tool for genomic analysis termed a biomedical robot in order to improve phenotype prediction, identifying disease pathogenesis and significantly defining therapeutic targets. Biomedical robot analytics differ from historical methods in that they are based on melding feature selection methods and ensemble learning techniques. The biomedical robot mathematically exploits the structure of the uncertainty space of any classification problem conceived as an ill-posed optimization problem. Given a classifier, there exist different equivalent small-scale genetic signatures that provide similar predictive accuracies. We perform the sensitivity analysis to noise of the biomedical robot concept using synthetic microarrays perturbed by different kinds of noises in expression and class assignment. Finally, we show the application of this concept to the analysis of different diseases, inferring the pathways and the correlation networks. The final aim of a biomedical robot is to improve knowledge discovery and provide decision systems to optimize diagnosis, treatment, and prognosis. This analysis shows that the biomedical robots are robust against different kinds of noises and particularly to a wrong class assignment of the samples. Assessing the uncertainty that is inherent to any phenotype prediction problem is the right way to address this kind of problem. PMID:27347715

  10. Rumen microbial communities influence metabolic phenotypes in lambs.

    Science.gov (United States)

    Morgavi, Diego P; Rathahao-Paris, Estelle; Popova, Milka; Boccard, Julien; Nielsen, Kristian F; Boudra, Hamid

    2015-01-01

    The rumen microbiota is an essential part of ruminants shaping their nutrition and health. Despite its importance, it is not fully understood how various groups of rumen microbes affect host-microbe relationships and functions. The aim of the study was to simultaneously explore the rumen microbiota and the metabolic phenotype of lambs for identifying host-microbe associations and potential biomarkers of digestive functions. Twin lambs, separated in two groups after birth were exposed to practices (isolation and gavage with rumen fluid with protozoa or protozoa-depleted) that differentially restricted the acquisition of microbes. Rumen microbiota, fermentation parameters, digestibility and growth were monitored for up to 31 weeks of age. Microbiota assembled in isolation from other ruminants lacked protozoa and had low bacterial and archaeal diversity whereas digestibility was not affected. Exposure to adult sheep microbiota increased bacterial and archaeal diversity independently of protozoa presence. For archaea, Methanomassiliicoccales displaced Methanosphaera. Notwithstanding, protozoa induced differences in functional traits such as digestibility and significantly shaped bacterial community structure, notably Ruminococcaceae and Lachnospiraceae lower up to 6 folds, Prevotellaceae lower by ~40%, and Clostridiaceae and Veillonellaceae higher up to 10 folds compared to microbiota without protozoa. An orthogonal partial least squares-discriminant analysis of urinary metabolome matched differences in microbiota structure. Discriminant metabolites were mainly involved in amino acids and protein metabolic pathways while a negative interaction was observed between methylotrophic methanogens Methanomassiliicoccales and trimethylamine N-oxide. These results stress the influence of gut microbes on animal phenotype and show the potential of metabolomics for monitoring rumen microbial functions. PMID:26528248

  11. Phenotypic detection of beta-lactamases production in enterobacteriaceae

    Directory of Open Access Journals (Sweden)

    Ćirković Ivana

    2014-01-01

    Full Text Available Introduction. Beta-lactam antibiotics are the most commonly used antibacterial drugs. However, many bacteria have developed resistance to these antibiotics, and the most common form of resistance is the production of beta-lactamase enzymes. Many members of the Enterobacteriaceae family produce different types of these enzymes. Objective. The aim of this study was to perform phenotypic detection of production and identification of beta-lactamase type in Enterobacteriaceae isolated from different clinical specimens from patients hospitalized in the Clinical Center of Serbia. Methods. The strains of Enterobacteriaceae were collected between November 2011 and January 2012 in the laboratory of the Clinical Center of Serbia. The isolates were identified according to the standard microbiology procedures and confirmed by the Vitek2 automated system. Antimicrobial susceptibility testing was performed by the disk diffusion method, and the phenotypic detection of production and identification of betalactamases was performed according to previously described methodologies. Results. In this study, a total of 172 Enterobacteriaceae strains were isolated. Further testing was performed on 54/145 (37.2% strains showing decreased susceptibility to beta-lactam antibiotics: 13/85 (15.3% Escherichia coli, 31/46 (67.4% Klebsiella pneumoniae and 10/14 (71.4% Proteus mirabilis. Among them, 40/145 (27.6% strains produced extended spectrum betalactamases (ESBLs, 9/145 (6.2% - AmpC, 1/145 (0.7% - K1 beta-lactamase and 4/145 (2.8% - carbapenemases. Carbapenemases were predominantly detected in K. pneumoniae (75%. Conclusion. Enterobacteriaceae produce different types of betalactamases, and the most common type in our study was ESBLs. Production of carbapenemases detected in Enterobacteriaceae is also an associated problem. [Projekat Ministarstva nauke Republike Srbije, br. ON 175039

  12. Abscisic acid ameliorates the systemic sclerosis fibroblast phenotype in vitro

    International Nuclear Information System (INIS)

    Highlights: ► ABA is an endogenous hormone in humans, regulating different cell responses. ► ABA reverts some of the functions altered in SSc fibroblasts to a normal phenotype. ► UV-B irradiation increases ABA content in SSc cultures. ► SSc fibroblasts could benefit from exposure to ABA and/or to UV-B. -- Abstract: The phytohormone abscisic acid (ABA) has been recently identified as an endogenous hormone in humans, regulating different cell functions, including inflammatory processes, insulin release and glucose uptake. Systemic sclerosis (SSc) is a chronic inflammatory disease resulting in fibrosis of skin and internal organs. In this study, we investigated the effect of exogenous ABA on fibroblasts obtained from healthy subjects and from SSc patients. Migration of control fibroblasts induced by ABA was comparable to that induced by transforming growth factor-β (TGF-β). Conversely, migration toward ABA, but not toward TGF-β, was impaired in SSc fibroblasts. In addition, ABA increased cell proliferation in fibroblasts from SSc patients, but not from healthy subjects. Most importantly, presence of ABA significantly decreased collagen deposition by SSc fibroblasts, at the same time increasing matrix metalloproteinase-1 activity and decreasing the expression level of tissue inhibitor of metalloproteinase (TIMP-1). Thus, exogenously added ABA appeared to revert some of the functions altered in SSc fibroblasts to a normal phenotype. Interestingly, ABA levels in plasma from SSc patients were found to be significantly lower than in healthy subjects. UV-B irradiation induced an almost 3-fold increase in ABA content in SSc cultures. Altogether, these results suggest that the fibrotic skin lesions in SSc patients could benefit from exposure to high(er) ABA levels.

  13. Computational investigation of epithelial cell dynamic phenotype in vitro

    Directory of Open Access Journals (Sweden)

    Debnath Jayanta

    2009-05-01

    Full Text Available Abstract Background When grown in three-dimensional (3D cultures, epithelial cells typically form cystic organoids that recapitulate cardinal features of in vivo epithelial structures. Characterizing essential cell actions and their roles, which constitute the system's dynamic phenotype, is critical to gaining deeper insight into the cystogenesis phenomena. Methods Starting with an earlier in silico epithelial analogue (ISEA1 that validated for several Madin-Darby canine kidney (MDCK epithelial cell culture attributes, we built a revised analogue (ISEA2 to increase overlap between analogue and cell culture traits. Both analogues used agent-based, discrete event methods. A set of axioms determined ISEA behaviors; together, they specified the analogue's operating principles. A new experimentation framework enabled tracking relative axiom use and roles during simulated cystogenesis along with establishment of the consequences of their disruption. Results ISEA2 consistently produced convex cystic structures in a simulated embedded culture. Axiom use measures provided detailed descriptions of the analogue's dynamic phenotype. Dysregulating key cell death and division axioms led to disorganized structures. Adhering to either axiom less than 80% of the time caused ISEA1 to form easily identified morphological changes. ISEA2 was more robust to identical dysregulation. Both dysregulated analogues exhibited characteristics that resembled those associated with an in vitro model of early glandular epithelial cancer. Conclusion We documented the causal chains of events, and their relative roles, responsible for simulated cystogenesis. The results stand as an early hypothesis–a theory–of how individual MDCK cell actions give rise to consistently roundish, cystic organoids.

  14. Digital Identifier Systems: Comparative Evaluation

    Directory of Open Access Journals (Sweden)

    Hamid Reza Khedmatgozar

    2015-02-01

    Full Text Available Identifier is one of the main elements in identifying an object in digital environment. Digital identifier systems were developed followed by a lot of problems such as violation of persistency and uniqueness of physical identifiers and URL in digital environment. These identifiers try to guarantee uniqueness and persistency of hostnames by using indirect names for Domain Name System (DNS. The main objective of this research is to identify qualified digital identifier system among other systems. To achieve the research objective, researchers have considered two major steps: first, identifying main criteria for distinguishing digital identifier based on literature review and focus group interview; and second, performing a comparative evaluation on common identifier systems in the world. Findings of first step demonstrated seven main criteria in three domains for distinguishing digital identifier systems: identifier uniqueness and persistency in the identifier features domain, digital identification, digital uniqueness, digital persistency and digital actionability in the digital coverage domain, and globality in the comprehensiveness of scope domain. In the second step, results of the comparative evaluation on common identifier systems indicated that six identifier systems, included, DOI, Handle, UCI, URN, ARK and PURL, are appropriate choices for using as a digital identifier system. Also, according to these results, three identification systems Including NBN, MARIAM and ISNI were identified as suitable choices for digital identification in certain specialized fields. According to many benefits of using these identifiers in important applied fields, such as, digital content chains and networks integration, digital right management, cross referencing, digital libraries and citation analysis, results of this study can help digital environment experts to diagnose digital identifier and their effective use in applied fields.

  15. The AMPA receptor antagonist perampanel robustly rescues amyotrophic lateral sclerosis (ALS) pathology in sporadic ALS model mice.

    Science.gov (United States)

    Akamatsu, Megumi; Yamashita, Takenari; Hirose, Naoki; Teramoto, Sayaka; Kwak, Shin

    2016-01-01

    Both TDP-43 pathology and failure of RNA editing of AMPA receptor subunit GluA2, are etiology-linked molecular abnormalities that concomitantly occur in the motor neurons of the majority of patients with amyotrophic lateral sclerosis (ALS). AR2 mice, in which an RNA editing enzyme adenosine deaminase acting on RNA 2 (ADAR2) is conditionally knocked out in the motor neurons, exhibit a progressive ALS phenotype with TDP-43 pathology in the motor neurons through a Ca(2+)-permeable AMPA receptor-mediated mechanism. Therefore, amelioration of the increased Ca(2+) influx by AMPA receptor antagonists may be a potential ALS therapy. Here, we showed that orally administered perampanel, a selective, non-competitive AMPA receptor antagonist significantly prevented the progression of the ALS phenotype and normalized the TDP-43 pathology-associated death of motor neurons in the AR2 mice. Given that perampanel is an approved anti-epileptic drug, perampanel is a potential candidate ALS drug worthy of a clinical trial. PMID:27350567

  16. Elusive identities and overlapping phenotypes of proangiogenic myeloid cells in tumors.

    Science.gov (United States)

    Coffelt, Seth B; Lewis, Claire E; Naldini, Luigi; Brown, J Martin; Ferrara, Napoleone; De Palma, Michele

    2010-04-01

    It is now established that bone marrow-derived myeloid cells regulate tumor angiogenesis. This was originally inferred from studies of human tumor biopsies in which a positive correlation was seen between the number of tumor-infiltrating myeloid cells, such as macrophages and neutrophils, and tumor microvessel density. However, unequivocal evidence was only provided once mouse models were used to examine the effects on tumor angiogenesis by genetically or pharmacologically targeting myeloid cells. Since then, identifying the exact myeloid cell types involved in this process has proved challenging because of myeloid cell heterogeneity and the expression of overlapping phenotypic markers in tumors. As a result, investigators often simply refer to them now as "bone marrow-derived myeloid cells." Here we review the findings of various attempts to phenotype the myeloid cells involved and discuss the therapeutic implications of correctly identifying-and thus being able to target-this proangiogenic force in tumors. PMID:20167863

  17. Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

    DEFF Research Database (Denmark)

    Pant, Sameer Dinkar; Karlskov-Mortensen, Peter; Jacobsen, Mette Juul;

    2015-01-01

    The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological...... features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits in...... analyses were performed to identify the extent of overlap between previously identified QTLs in both humans and pigs. The combined analysis of a large number of obesity phenotypes has provided insight in the genetic architecture of the molecular mechanisms underlying these traits indicating that QTLs...

  18. The kinetochore protein, CENPF, is mutated in human ciliopathy and microcephaly phenotypes

    DEFF Research Database (Denmark)

    Waters, Aoife M; Asfahani, Rowan; Carroll, Paula; Bicknell, Louise; Lescai, Francesco; Bright, Alison; Chanudet, Estelle; Brooks, Anthony; Christou-Savina, Sonja; Osman, Guled; Walsh, Patrick; Bacchelli, Chiara; Chapgier, Ariane; Vernay, Bertrand; Bader, David M; Deshpande, Charu; O' Sullivan, Mary; Ocaka, Louise; Stanescu, Horia; Stewart, Helen S; Hildebrandt, Friedhelm; Otto, Edgar; Johnson, Colin A; Szymanska, Katarzyna; Katsanis, Nicholas; Davis, Erica; Kleta, Robert; Hubank, Mike; Doxsey, Stephen; Jackson, Andrew; Stupka, Elia; Winey, Mark; Beales, Philip L

    2015-01-01

    BACKGROUND: Mutations in microtubule-regulating genes are associated with disorders of neuronal migration and microcephaly. Regulation of centriole length has been shown to underlie the pathogenesis of certain ciliopathy phenotypes. Using a next-generation sequencing approach, we identified...... mutations in a novel centriolar disease gene in a kindred with an embryonic lethal ciliopathy phenotype and in a patient with primary microcephaly. METHODS AND RESULTS: Whole exome sequencing data from a non-consanguineous Caucasian kindred exhibiting mid-gestation lethality and ciliopathic malformations...... microcephaly, we identified two CENPF mutations [c.1744G>T, p.E582X; c.8692 C>T, p.R2898X] by whole exome sequencing. We found that CENP-F colocalised with Ninein at the subdistal appendages of the mother centriole in mouse inner medullary collecting duct cells. Intraflagellar transport protein-88 (IFT-88...

  19. Survival of Phenotypic Information during Cellular Growth Transitions.

    Science.gov (United States)

    Ray, J Christian J

    2016-08-19

    Phenotypic memory can predispose cells to physiological outcomes, contribute to heterogeneity in cellular populations, and allow computation of environmental features, such as nutrient gradients. In bacteria and synthetic circuits in general, memory can often be set by protein concentrations: because of the relative stability of proteins, the degradation rate is often dominated by the growth rate, and inheritance is a significant factor. Cells can then be primed to respond to events that recur with frequencies faster than the time to eliminate proteins. Protein memory can be extended if cells reach extremely low growth rates or no growth. Here we characterize the necessary time scales for different quantities of protein memory, measured as relative entropy (Kullback-Leibler divergence), for a variety of cellular growth arrest transition dynamics. We identify a critical manifold in relative protein degradation/growth arrest time scales where information is, in principle, preserved indefinitely because proteins are trapped at a concentration determined by the competing time scales as long as nongrowth-mediated protein degradation is negligible. We next asked what characteristics of growth arrest dynamics and initial protein distributions best preserve or eliminate information about previous environments. We identified that sharp growth arrest transitions with skewed initial protein distributions optimize flexibility, with information preservation and minimal cost of residual protein. As a result, a nearly memoryless regime, corresponding to a form of bet-hedging, may be an optimal strategy for storage of information by protein concentrations in growth-arrested cells. PMID:26910476

  20. Kabuki syndrome: expanding the phenotype to include microphthalmia and anophthalmia.

    Science.gov (United States)

    McVeigh, Terri P; Banka, Siddharth; Reardon, William

    2015-10-01

    Kabuki syndrome is a rare genetic malformation syndrome that is characterized by distinct facies, structural defects and intellectual disability. Kabuki syndrome may be caused by mutations in one of two histone methyltransferase genes: KMT2D and KDM6A. We describe a male child of nonconsanguineous Irish parents presenting with multiple malformations, including bilateral extreme microphthalmia; cleft palate; congenital diaphragmatic hernia; duplex kidney; as well as facial features of Kabuki syndrome, including interrupted eyebrows and lower lid ectropion. A de-novo germline mutation in KMT2D was identified. Whole-exome sequencing failed to reveal mutations in any of the known microphthalmia/anopthalmia genes. We also identified four other patients with Kabuki syndrome and microphthalmia. We postulate that Kabuki syndrome may produce this type of ocular phenotype as a result of extensive interaction between KMT2D, WAR complex proteins and PAXIP1. Children presenting with microphthalmia/anophthalmia should be examined closely for other signs of Kabuki syndrome, especially at an age where the facial gestalt might be less readily appreciable. PMID:26049589

  1. Systems Biology for Mapping Genotype-Phenotype Relations in Yeast

    KAUST Repository

    Nielsen, Jens

    2016-01-25

    The yeast Saccharomyces cerevisiae is widely used for production of fuels, chemicals, pharmaceuticals and materials. Through metabolic engineering of this yeast a number of novel new industrial processes have been developed over the last 10 years. Besides its wide industrial use, S. cerevisiae serves as an eukaryal model organism, and many systems biology tools have therefore been developed for this organism. Among these genome-scale metabolic models have shown to be most successful as they easy integrate with omics data and at the same time have been shown to have excellent predictive power. Despite our extensive knowledge of yeast metabolism and its regulation we are still facing challenges when we want to engineer complex traits, such as improved tolerance to toxic metabolites like butanol and elevated temperatures or when we want to engineer the highly complex protein secretory pathway. In this presentation it will be demonstrated how we can combine directed evolution with systems biology analysis to identify novel targets for rational design-build-test of yeast strains that have improved phenotypic properties. In this lecture an overview of systems biology of yeast will be presented together with examples of how genome-scale metabolic modeling can be used for prediction of cellular growth at different conditions. Examples will also be given on how adaptive laboratory evolution can be used for identifying targets for improving tolerance towards butanol, increased temperature and low pH and for improving secretion of heterologous proteins.

  2. Is it all the X: familial learning dysfunction and the impact of behavioral aspects of the phenotypic presentation of XXY?

    Science.gov (United States)

    Samango-Sprouse, Carole A; Stapleton, Emily; Sadeghin, Teresa; Gropman, Andrea L

    2013-02-15

    The behavioral phenotype of children with XXY has not been extensively studied until recently and this research has been confounded by insufficient study populations and ascertainment biases. The aim of the study was to expand the behavioral aspect of the XXY phenotype as well as investigate the role of existing familial learning disabilities (FLD) on behavioral problems. Behavioral phenotype of XXY includes social anxiety, ADHD, social communication, and atypical peer interactions. The Child Behavior Checklist (CBCL), Social Responsiveness Scale (SRS), and Gilliam Autism Rating Scale (GARS) were completed by the parents of 54 boys with XXY who had not received hormonal replacement prior to participation. Our findings suggest fewer behavioral deficits and lower severity in the general 47,XXY population than previously published and found significant differences between the groups with a positive FLD on the behavioral assessments. Findings demonstrate that boys with FLD exhibit an increased incidence and severity of behavioral problems. Our study expands on the findings of Samango-Sprouse et al. [Samango-Sprouse et al. (2012b) J Intellect Disabil Res] and the significant influence that FLD has on not only neurodevelopment, but also behavioral deficits. Our study suggests that part of the XXY phenotypic profile may be modulated by FLD. Further study is underway to examine the interaction between the many salient factors effecting behavioral and neurodevelopmental progression in XXY and variant forms. © 2013 Wiley Periodicals, Inc. PMID:23359595

  3. Prediction of disease and phenotype associations from genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Stephanie N Lewis

    Full Text Available BACKGROUND: Genome wide association studies (GWAS have proven useful as a method for identifying genetic variations associated with diseases. In this study, we analyzed GWAS data for 61 diseases and phenotypes to elucidate common associations based on single nucleotide polymorphisms (SNP. The study was an expansion on a previous study on identifying disease associations via data from a single GWAS on seven diseases. METHODOLOGY/PRINCIPAL FINDINGS: Adjustments to the originally reported study included expansion of the SNP dataset using Linkage Disequilibrium (LD and refinement of the four levels of analysis to encompass SNP, SNP block, gene, and pathway level comparisons. A pair-wise comparison between diseases and phenotypes was performed at each level and the Jaccard similarity index was used to measure the degree of association between two diseases/phenotypes. Disease relatedness networks (DRNs were used to visualize our results. We saw predominant relatedness between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis for the first three levels of analysis. Expected relatedness was also seen between lipid- and blood-related traits. CONCLUSIONS/SIGNIFICANCE: The predominant associations between Multiple Sclerosis, type 1 diabetes, and rheumatoid arthritis can be validated by clinical studies. The diseases have been proposed to share a systemic inflammation phenotype that can result in progression of additional diseases in patients with one of these three diseases. We also noticed unexpected relationships between metabolic and neurological diseases at the pathway comparison level. The less significant relationships found between diseases require a more detailed literature review to determine validity of the predictions. The results from this study serve as a first step towards a better understanding of seemingly unrelated diseases and phenotypes with similar symptoms or modes of treatment.

  4. Phenotypic convergence in genetically distinct lineages of a Rhinolophus species complex (Mammalia, Chiroptera.

    Directory of Open Access Journals (Sweden)

    David S Jacobs

    Full Text Available Phenotypes of distantly related species may converge through adaptation to similar habitats and/or because they share biological constraints that limit the phenotypic variants produced. A common theme in bats is the sympatric occurrence of cryptic species that are convergent in morphology but divergent in echolocation frequency, suggesting that echolocation may facilitate niche partitioning, reducing competition. If so, allopatric populations freed from competition, could converge in both morphology and echolocation provided they occupy similar niches or share biological constraints. We investigated the evolutionary history of a widely distributed African horseshoe bat, Rhinolophus darlingi, in the context of phenotypic convergence. We used phylogenetic inference to identify and date lineage divergence together with phenotypic comparisons and ecological niche modelling to identify morphological and geographical correlates of those lineages. Our results indicate that R. darlingi is paraphyletic, the eastern and western parts of its distribution forming two distinct non-sister lineages that diverged ~9.7 Mya. We retain R. darlingi for the eastern lineage and argue that the western lineage, currently the sub-species R. d. damarensis, should be elevated to full species status. R. damarensis comprises two lineages that diverged ~5 Mya. Our findings concur with patterns of divergence of other co-distributed taxa which are associated with increased regional aridification between 7-5 Mya suggesting possible vicariant evolution. The morphology and echolocation calls of R. darlingi and R. damarensis are convergent despite occupying different biomes. This suggests that adaptation to similar habitats is not responsible for the convergence. Furthermore, R. darlingi forms part of a clade comprising species that are bigger and echolocate at lower frequencies than R. darlingi, suggesting that biological constraints are unlikely to have influenced the

  5. Novel Meta-Analysis-Derived Type 2 Diabetes Risk Loci Do Not Determine Prediabetic Phenotypes

    OpenAIRE

    Staiger, Harald; Machicao, Fausto; Kantartzis, Konstantinos; Schäfer, Silke A.; Kirchhoff, Kerstin; Guthoff, Martina; Silbernagel, Günther; Stefan, Norbert; Fritsche, Andreas; Häring, Hans-Ulrich

    2008-01-01

    Background Genome-wide association (GWA) studies identified a series of novel type 2 diabetes risk loci. Most of them were subsequently demonstrated to affect insulin secretion of pancreatic β-cells. Very recently, a meta-analysis of GWA data revealed nine additional risk loci with still undefined roles in the pathogenesis of type 2 diabetes. Using our thoroughly phenotyped cohort of subjects at an increased risk for type 2 diabetes, we assessed the association of the nine latest genetic vari...

  6. The Heritability of Hedonic Capacity and Perceived Stress: A Twin Study Evaluation of Candidate Depressive Phenotypes

    OpenAIRE

    Bogdan, Ryan; Pizzagalli, Diego

    2008-01-01

    Background. Anhedonia and stress sensitivity have been identified as promising depressive phenotypes. Research suggests that stress-induced anhedonia is a possible mechanism underlying the association between stress and depression. The present proof-of-concept study assessed whether hedonic capacity and stress perception are heritable and whether their genetic and environmental contributions are shared. Method. Twenty monozygotic (MZ) and 15 dizygotic (DZ) twin pairs completed a probabilistic...

  7. Identification of a Dopaminergic Enhancer Indicates Complexity in Vertebrate Dopamine Neuron Phenotype Specification

    OpenAIRE

    Fujimoto, Esther; Stevenson, Tamara J.; Chien, Chi-Bin; Bonkowsky, Joshua L.

    2011-01-01

    The dopaminergic neurons of the basal ganglia play critical roles in CNS function and human disease, but specification of dopamine neuron phenotype is poorly understood in vertebrates. We performed an in vivo screen in zebrafish to identify dopaminergic neuron enhancers, in order to facilitate studies on the specification of neuronal identity, connectivity, and function in the basal ganglia. Based primarily on identification of conserved non-coding elements, we tested 54 DNA elements from fou...

  8. Visual Phenotype Matching: Cues to Paternity Are Present in Rhesus Macaque Faces

    OpenAIRE

    Kazem, A.; Widdig, A.

    2013-01-01

    The ability to recognize kin and thus behaviourally discriminate between conspecifics based on genetic relatedness is of importance both in acquiring inclusive fitness benefits and to enable optimal inbreeding. In primates, mechanisms allowing recognition of paternal relatives are of particular interest, given that in these mating systems patrilineal information is unlikely to be available via social familiarity. Humans use visual phenotype matching based on facial features to identify their ...

  9. Improving persistence in red clover: Insights from QTL analysis and comparative phenotypic evaluation

    DEFF Research Database (Denmark)

    Herrmann, Dorris; Boller, Beat; Studer, Bruno; Widmer, Franco; Kölliker, Roland

    2008-01-01

    Cultivars of red clover (Trifolium pratense L.) often suffer from low persistence, leading to insufficient legume proportions in pluriannual forage stands. Persistence is a complex trait often negatively correlated with other important traits and its phenotyping is laborious. Consequently....... Moreover, length of stem may present a candidate character for indirect selection of these two traits. The QTLs and the indirect selection criteria identified in this study may substantially assist future breeding efforts for the improvement of persistence in red clover...

  10. Efficacy of Vigabatrin Intervention in a Mild Phenotypic Expression of Succinic Semialdehyde Dehydrogenase Deficiency

    OpenAIRE

    Casarano, M.; Alessandrì, M G.; Salomons, G.S.; E. Moretti; Jakobs, C.; Gibson, K. M.; G. Cioni; Battini, R.

    2011-01-01

    We report a patient with succinic semialdehyde dehydrogenase deficiency who presented a mild phenotype including developmental language delay, in association with the typical elevations of 4-hydroxybutyric acid (GHB) in biological fluids and MRI alterations. Two pathogenic mutations were identified one transversion (c.278 G>T) in exon 1 and another (c.1557 T>G) in exon 10. Both parents are carriers of one of the mutations, confirming compound-heterozygosity in their affected child. To reduce ...

  11. The ecology and evolution of animal medication : genetically fixed response versus phenotypic plasticity

    OpenAIRE

    Choisy, Marc; de Roode, J. C.

    2014-01-01

    Animal medication against parasites can occur either as a genetically fixed (constitutive) or phenotypically plastic (induced) behavior. Taking the tritrophic interaction between the monarch butterfly Danaus plexippus, its protozoan parasite Ophryocystis elektroscirrha, and its food plant Asclepias spp. as a test case, we develop a game-theory model to identify the epidemiological (parasite prevalence and virulence) and environmental (plant toxicity and abundance) conditions that predict the ...

  12. Novel Phenotypic Fluorescent Three-Dimensional Platforms for High-throughput Drug Screening and Personalized Chemotherapy

    OpenAIRE

    Fang, Changge; Avis, Ingalill; Salomon, David; Cuttitta, Frank

    2013-01-01

    We have developed novel phenotypic fluorescent three-dimensional co-culture platforms that efficiently and economically screen anti-angiogenic/anti-metastatic drugs on a high-throughput scale. Individual cell populations can be identified and isolated for protein/gene expression profiling studies and cellular movement/interactions can be tracked by time-lapse cinematography. More importantly, these platforms closely parallel the in vivo angiogenic and metastatic outcomes of a given tumor xeno...

  13. The Interaction of Obesity Related Genotypes, Phenotypes, and Economics: An Experimental Economics Approach with Mice

    OpenAIRE

    Davis, George C.; Jacob, Jacy; Good, Deborah J.

    2011-01-01

    Food intake is greatly influenced by economic factors. Consequently, neuroeconomics has been identified as a new and important area for understanding the interaction between genotypes and phenotypes related to food intake. A foundational element of economics is choice between alternatives. Changing food choices are a central element in the explanation of the increasing obesity rates in human populations. The purpose of this research is to incorporate the key element of choice into the investi...

  14. Penalized likelihood phenotyping: unifying voxelwise analyses and multi-voxel pattern analyses in neuroimaging: penalized likelihood phenotyping.

    Science.gov (United States)

    Adluru, Nagesh; Hanlon, Bret M; Lutz, Antoine; Lainhart, Janet E; Alexander, Andrew L; Davidson, Richard J

    2013-04-01

    Neuroimage phenotyping for psychiatric and neurological disorders is performed using voxelwise analyses also known as voxel based analyses or morphometry (VBM). A typical voxelwise analysis treats measurements at each voxel (e.g., fractional anisotropy, gray matter probability) as outcome measures to study the effects of possible explanatory variables (e.g., age, group) in a linear regression setting. Furthermore, each voxel is treated independently until the stage of correction for multiple comparisons. Recently, multi-voxel pattern analyses (MVPA), such as classification, have arisen as an alternative to VBM. The main advantage of MVPA over VBM is that the former employ multivariate methods which can account for interactions among voxels in identifying significant patterns. They also provide ways for computer-aided diagnosis and prognosis at individual subject level. However, compared to VBM, the results of MVPA are often more difficult to interpret and prone to arbitrary conclusions. In this paper, first we use penalized likelihood modeling to provide a unified framework for understanding both VBM and MVPA. We then utilize statistical learning theory to provide practical methods for interpreting the results of MVPA beyond commonly used performance metrics, such as leave-one-out-cross validation accuracy and area under the receiver operating characteristic (ROC) curve. Additionally, we demonstrate that there are challenges in MVPA when trying to obtain image phenotyping information in the form of statistical parametric maps (SPMs), which are commonly obtained from VBM, and provide a bootstrap strategy as a potential solution for generating SPMs using MVPA. This technique also allows us to maximize the use of available training data. We illustrate the empirical performance of the proposed framework using two different neuroimaging studies that pose different levels of challenge for classification using MVPA. PMID:23397550

  15. Partial 1q Duplications and Associated Phenotype

    Science.gov (United States)

    Morris, Marcos L.M.; Baroneza, José E.; Teixeira, Patricia; Medina, Cristina T.N.; Cordoba, Mara S.; Versiani, Beatriz R.; Roese, Liege L.; Freitas, Erika L.; Fonseca, Ana C.S.; dos Santos, Maria C.G.; Pic-Taylor, Aline; Rosenberg, Carla; Oliveira, Silviene F.; Ferrari, Iris; Mazzeu, Juliana F.

    2016-01-01

    Duplications of the long arm of chromosome 1 are rare. Distal duplications are the most common and have been reported as either pure trisomy or unbalanced translocations. The paucity of cases with pure distal 1q duplications has made it difficult to delineate a partial distal trisomy 1q syndrome. Here, we report 2 patients with overlapping 1q duplications detected by G-banding. Array CGH and FISH were performed to characterize the duplicated segments, exclude the involvement of other chromosomes and determine the orientation of the duplication. Patient 1 presents with a mild phenotype and carries a 22.5-Mb 1q41q43 duplication. Patient 2 presents with a pure 1q42.13qter inverted duplication of 21.5 Mb, one of the smallest distal 1q duplications ever described and one of the few cases characterized by array CGH, thus contributing to a better characterization of distal 1q duplication syndrome. PMID:27022331

  16. Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype.

    Science.gov (United States)

    Phoenix, Timothy N; Patmore, Deanna M; Boop, Scott; Boulos, Nidal; Jacus, Megan O; Patel, Yogesh T; Roussel, Martine F; Finkelstein, David; Goumnerova, Liliana; Perreault, Sebastien; Wadhwa, Elizabeth; Cho, Yoon-Jae; Stewart, Clinton F; Gilbertson, Richard J

    2016-04-11

    The childhood brain tumor, medulloblastoma, includes four subtypes with very different prognoses. Here, we show that paracrine signals driven by mutant β-catenin in WNT-medulloblastoma, an essentially curable form of the disease, induce an aberrant fenestrated vasculature that permits the accumulation of high levels of intra-tumoral chemotherapy and a robust therapeutic response. In contrast, SHH-medulloblastoma, a less curable disease subtype, contains an intact blood brain barrier, rendering this tumor impermeable and resistant to chemotherapy. The medulloblastoma-endothelial cell paracrine axis can be manipulated in vivo, altering chemotherapy permeability and clinical response. Thus, medulloblastoma genotype dictates tumor vessel phenotype, explaining in part the disparate prognoses among medulloblastoma subtypes and suggesting an approach to enhance the chemoresponsiveness of other brain tumors. PMID:27050100

  17. The Social Phenotype of Williams Syndrome

    Science.gov (United States)

    Järvinen, Anna; Korenberg, Julie R.; Bellugi, Ursula

    2014-01-01

    Williams syndrome (WS) offers an exciting model for social neuroscience because its genetic basis is well-defined, and the unique phenotype reflects dimensions of prosocial behaviors. WS is associated with a strong drive to approach strangers, a gregarious personality, heightened social engagement yet difficult peer interactions, high non-social anxiety, unusual bias toward positive affect, and diminished sensitivity to fear. New neurobiological evidence points toward alterations in structure, function, and connectivity of the social brain (amygdala, fusiform face area, orbital-frontal regions). Recent genetic studies implicate gene networks in the WS region with the dysregulation of prosocial neuropeptides. The study of WS has implications for understanding human social development, and may provide insight for translating genetic and neuroendocrine evidence into treatments for disorders of social behavior. PMID:23332975

  18. A Review of Imaging Techniques for Plant Phenotyping

    OpenAIRE

    Lei Li; Qin Zhang; Danfeng Huang

    2014-01-01

    Given the rapid development of plant genomic technologies, a lack of access to plant phenotyping capabilities limits our ability to dissect the genetics of quantitative traits. Effective, high-throughput phenotyping platforms have recently been developed to solve this problem. In high-throughput phenotyping platforms, a variety of imaging methodologies are being used to collect data for quantitative studies of complex traits related to the growth, yield and adaptation to biotic or abiotic st...

  19. Genotype–phenotype mapping in a post-GWAS world

    OpenAIRE

    Nuzhdin, Sergey V.; Friesen, Maren L.; McIntyre, Lauren M.

    2012-01-01

    Understanding how metabolic reactions, cell signaling, and developmental pathways translate the genome of an organism into its phenotype is a grand challenge in biology. Genome-wide association studies (GWAS) statistically connect genotypes to phenotypes, without any recourse to known molecular interactions, whereas a molecular biology approach directly ties gene function to phenotype through gene regulatory networks (GRNs). Using natural variation in allele-specific expression, GWAS and GRN ...

  20. On-time clinical phenotype prediction based on narrative reports

    OpenAIRE

    Bejan, Cosmin A.; Vanderwende, Lucy; Evans, Heather L.; Wurfel, Mark M.; Yetisgen-Yildiz, Meliha

    2013-01-01

    In this paper we describe a natural language processing system which is able to predict whether or not a patient exhibits a specific phenotype using the information extracted from the narrative reports associated with the patient. Furthermore, the phenotypic annotations from our report dataset were performed at the report level which allows us to perform the prediction of the clinical phenotype at any point in time during the patient hospitalization period. Our experiments indicate that an im...