35 results on '"Platko J"'
Search Results
2. PCN318 LESSONS LEARNT FROM A QUALITATIVE STUDY FOR BEST PRACTICE ECOA IMPLEMENTATION IN ONCOLOGY CLINICAL TRIALS
- Author
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Mowlem, F., primary, Sanderson, B., additional, Platko, J., additional, and Byrom, B., additional
- Published
- 2020
- Full Text
- View/download PDF
3. ASSOCIATION ANALYSIS OF DYSLEXIA IN AN AFRIKANER POPULATION
- Author
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Platko, J. V., OʼRourke, J., Birns, J., Purcell, S., Gericke, G., Pelser, I., Wood, F., and Pauls, D.
- Published
- 2009
4. ASSOCIATION ANALYSIS OF DYSLEXIA IN AN AFRIKANER POPULATION
- Author
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Platko, J. V., OʼRourke, J., Birns, J., Purcell, S., Gericke, G., Pelser, I., Wood, F., and Pauls, D.
- Published
- 2005
5. PNS201 MEASUREMENT COMPARABILITY OF ELECTRONIC AND PAPER ADMINISTERED VISUAL ANALOGUE SCALES: A REVIEW OF PUBLISHED STUDIES
- Author
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Byrom, B., primary, Eremenco, S., additional, Muehlhausen, W., additional, Howry, C., additional, Watson, C., additional, Bodart, S., additional, Platko, J., additional, and Elash, C., additional
- Published
- 2019
- Full Text
- View/download PDF
6. PNS1 CLINICIAN TRAINING REDUCES VARIABILITY IN CLINICIAN REPORTED OUTCOMES OF SKIN SURFACE SYMPTOMS IN A DERMATOLOGY STUDY
- Author
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Olt, J., primary, Khan, R., additional, Barbone, J.M., additional, Feaster, T., additional, Platko, J., additional, Sanderson, B., additional, Bodart, S., additional, Garner, K.S., additional, Solomon, T., additional, and Byrom, B., additional
- Published
- 2019
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- View/download PDF
7. Confirmation of dyslexia susceptibility loci on chromosomes 1p and 2p, but not 6p in a Dutch sib-pair collection
- Author
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Kovel, C.G.F. de, Franke, B., Hol, F.A., Lebrec, J.J., Maassen, B.A.M., Brunner, H.G., Padberg, G.W.A.M., Platko, J., and Pauls, D.
- Subjects
Genomic disorders and inherited multi-system disorders [IGMD 3] ,Genetics and epigenetic pathways of disease [NCMLS 6] ,Cognitive neurosciences [UMCN 3.2] ,Genetic defects of metabolism [UMCN 5.1] ,Perception and Action [DCN 1] ,Psychological determinants of chronic illness [NCEBP 8] ,Functional Neurogenomics [DCN 2] ,Neuromuscular development and genetic disorders [UMCN 3.1] ,Immunity, infection and tissue repair [NCMLS 1] - Abstract
Contains fulltext : 71322.pdf (Publisher’s version ) (Closed access) In this study, we attempted to confirm genetic linkage to developmental dyslexia and reading-related quantitative traits of loci that have been shown to be associated with dyslexia in previous studies. In our sample of 108 Dutch nuclear families, the categorical trait showed strongest linkage to 1p36 (NPL-LOD = 2.1). LOD scores for quantitative traits word-reading, non-word reading, and rapid naming peaked near the same location as the categorical trait, as well as on chromosome 2. Non-word repetition showed little phenotypic correlation with dyslexia or with the other quantitative traits, and this trait showed linkage peaks on 11p and 15q. No evidence for linkage to 6p22-23 was found for this set of families. Comparison of our results and literature data shows that loci link to different phenotypes in different samples. The mutual connections of these traits and their relation to developmental dyslexia remain elusive.
- Published
- 2008
8. A Genome-wide Scan for CHD Susceptibility in the Saguenay-Lac-Saint-Jean region of Quebec
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Engert, J.C., Vohl, M.-C., Lepage, P., Dor, C., Brewer, C., Frappier, D., Verner, A., Platko, J., Rioux, J., Gaudet, D., Morgan, K., and Hudson, T.J.
- Subjects
Human genetics -- Research ,Coronary heart disease -- Genetic aspects ,Biological sciences - Published
- 2000
9. The ilvIH operon of Escherichia coli
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ker, D. A., Ricca E., Platko J., Wang Q., J. M. Calvo, DE FELICE, MAURILIO, Z. Barak, D. M. Chipman, J. V. Schloss, Ker, D. A., Ricca, E., Platko, J., Wang, Q., DE FELICE, Maurilio, and J. M., Calvo
- Published
- 1990
10. PSY42 E-DIARY COMPLIANCE IN ACUTE PAIN STUDIES
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Marino, B, primary, Platko, J, additional, and Raymond, S, additional
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- 2008
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11. A single residue can modify target-binding affinity and activity of the functional domain of the Rho-subfamily GDP dissociation inhibitors.
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Platko, J V, primary, Leonard, D A, additional, Adra, C N, additional, Shaw, R J, additional, Cerione, R A, additional, and Lim, B, additional
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- 1995
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12. The amino acid sequence of Lrp is highly conserved in four enteric microorganisms
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Friedberg, D, primary, Platko, J V, additional, Tyler, B, additional, and Calvo, J M, additional
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- 1995
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13. Insect cell-expressed p180erbB3 possesses an impaired tyrosine kinase activity.
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Guy, P M, primary, Platko, J V, additional, Cantley, L C, additional, Cerione, R A, additional, and Carraway, K L, additional
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- 1994
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14. Mutations affecting the ability of Escherichia coli Lrp to bind DNA, activate transcription, or respond to leucine
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Platko, J V, primary and Calvo, J M, additional
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- 1993
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15. Leucine-responsive regulatory protein controls the expression of both the pap and fan pili operons in Escherichia coli.
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Braaten, B A, primary, Platko, J V, additional, van der Woude, M W, additional, Simons, B H, additional, de Graaf, F K, additional, Calvo, J M, additional, and Low, D A, additional
- Published
- 1992
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16. Lrp, a leucine-responsive protein, regulates branched-chain amino acid transport genes in Escherichia coli
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Haney, S A, primary, Platko, J V, additional, Oxender, D L, additional, and Calvo, J M, additional
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- 1992
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17. The ilvIH operon of Escherichia coli is positively regulated
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Platko, J V, primary, Willins, D A, additional, and Calvo, J M, additional
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- 1990
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18. Lack of association between SLITRK1var321 and Tourette syndrome in a large family-based sample.
- Author
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Scharf JM, Moorjani P, Fagerness J, Platko JV, Illmann C, Galloway B, Jenike E, Stewart SE, Pauls DL, Tourette Syndrome International Consortium for Genetics, Scharf, J M, Moorjani, P, Fagerness, J, Platko, J V, Illmann, C, Galloway, B, Jenike, E, Stewart, S E, and Pauls, D L
- Published
- 2008
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19. Meaningful change: Defining the interpretability of changes in endpoints derived from interactive and mHealth technologies in healthcare and clinical research.
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Byrom B, Breedon P, Tulkki-Wilke R, and Platko JV
- Abstract
Immersive, interactive and mHealth technologies are increasingly being used in clinical research, healthcare and rehabilitation solutions. Leveraging technology solutions to derive new and novel clinical outcome measures is important to the ongoing assessment of clinical interventions. While demonstrating statistically significant changes is an important element of intervention assessment, understanding whether changes detected reflect changes of a magnitude that are considered meaningful to patients is equally important. We describe methodologies used to determine meaningful change and recommend that these techniques are routinely included in the development and testing of clinical assessment and rehabilitation technology solutions., (© The Author(s) 2020.)
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- 2020
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20. Predicting Suicidal Behavior In Veterans And Active Military Personnel: Possibilities For Electronic Deployment To Discover A Predictive Assessment.
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Sage CC, Platko JV, and Nokela M
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- 2014
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21. The familial association of tourette's disorder and ADHD: the impact of OCD symptoms.
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O'Rourke JA, Scharf JM, Platko J, Stewart SE, Illmann C, Geller DA, King RA, Leckman JF, and Pauls DL
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- Age of Onset, Attention Deficit Disorder with Hyperactivity complications, Case-Control Studies, Comorbidity, Disease Susceptibility psychology, Humans, Interview, Psychological, Obsessive-Compulsive Disorder complications, Risk Factors, Tourette Syndrome complications, Attention Deficit Disorder with Hyperactivity psychology, Family psychology, Obsessive-Compulsive Disorder psychology, Psychiatric Status Rating Scales, Tourette Syndrome psychology
- Abstract
Tourette's disorder (TD) frequently co-occurs with attention-deficit/hyperactivity disorder (ADHD) and obsessive compulsive disorder (OCD). While the relationship between TD and OCD suggests that they share etiological factors, the exact relationship between TD and ADHD is less clear. The goal of the current analyses was to understand better the familial relationship between DSM-IV ADHD and TD. Direct interview diagnostic data from a case-control study of 692 relatives of 75 comorbid TD and ADHD (TD + ADHD), 74 TD without ADHD (TD Only), 41 ADHD without TD (ADHD Only), and 49 control probands were analyzed. Hierarchical loglinear modeling was used to explore association patterns between TD, ADHD, and OCD or sub-clinical OCD (OCD/OCDsub) diagnoses among the 190 affected probands and their 538 relatives. The presence of OCD or OCDsub diagnosis in a proband was associated with a significantly increased risk of comorbid TD + ADHD in his/her relatives. The finding of an association between TD, ADHD and a proband OCD/OCDsub diagnosis was unexpected. The current results suggest that TD, ADHD, and OCD symptoms have overlapping neurobiology when occurring in families of TD and/or ADHD probands., (Copyright © 2011 Wiley-Liss, Inc.)
- Published
- 2011
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22. Fine mapping and association studies of a high-density lipoprotein cholesterol linkage region on chromosome 16 in French-Canadian subjects.
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Dastani Z, Pajukanta P, Marcil M, Rudzicz N, Ruel I, Bailey SD, Lee JC, Lemire M, Faith J, Platko J, Rioux J, Hudson TJ, Gaudet D, Engert JC, and Genest J
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- Canada, France, Gene Expression Regulation, Genome, Human, Humans, Lod Score, RNA, Messenger genetics, RNA, Messenger metabolism, Sequence Analysis, DNA, Cholesterol, HDL genetics, Chromosomes, Human, Pair 16 genetics, Genetic Linkage, Genetic Predisposition to Disease, Physical Chromosome Mapping
- Abstract
Low levels of high-density lipoprotein cholesterol (HDL-C) are an independent risk factor for cardiovascular disease. To identify novel genetic variants that contribute to HDL-C, we performed genome-wide scans and quantitative association studies in two study samples: a Quebec-wide study consisting of 11 multigenerational families and a study of 61 families from the Saguenay-Lac St-Jean (SLSJ) region of Quebec. The heritability of HDL-C in these study samples was 0.73 and 0.49, respectively. Variance components linkage methods identified a LOD score of 2.61 at 98 cM near the marker D16S515 in Quebec-wide families and an LOD score of 2.96 at 86 cM near the marker D16S2624 in SLSJ families. In the Quebec-wide sample, four families showed segregation over a 25.5-cM (18 Mb) region, which was further reduced to 6.6 Mb with additional markers. The coding regions of all genes within this region were sequenced. A missense variant in CHST6 segregated in four families and, with additional families, we observed a P value of 0.015 for this variant. However, an association study of this single-nucleotide polymorphism (SNP) in unrelated Quebec-wide samples was not significant. We also identified an SNP (rs11646677) in the same region, which was significantly associated with a low HDL-C (P=0.016) in the SLSJ study sample. In addition, RT-PCR results from cultured cells showed a significant difference in the expression of CHST6 and KIAA1576, another gene in the region. Our data constitute additional evidence for a locus on chromosome 16q23-24 that affects HDL-C levels in two independent French-Canadian studies.
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- 2010
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23. Confirmation of dyslexia susceptibility loci on chromosomes 1p and 2p, but not 6p in a Dutch sib-pair collection.
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de Kovel CG, Franke B, Hol FA, Lebrec JJ, Maassen B, Brunner H, Padberg GW, Platko J, and Pauls D
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- Adolescent, Chromosome Mapping, Genetic Linkage, Genotype, Humans, Netherlands, Phenotype, Siblings, Chromosomes, Human, Pair 1, Chromosomes, Human, Pair 2, Chromosomes, Human, Pair 7, Dyslexia genetics, Genetic Predisposition to Disease
- Abstract
In this study, we attempted to confirm genetic linkage to developmental dyslexia and reading-related quantitative traits of loci that have been shown to be associated with dyslexia in previous studies. In our sample of 108 Dutch nuclear families, the categorical trait showed strongest linkage to 1p36 (NPL-LOD = 2.1). LOD scores for quantitative traits word-reading, non-word reading, and rapid naming peaked near the same location as the categorical trait, as well as on chromosome 2. Non-word repetition showed little phenotypic correlation with dyslexia or with the other quantitative traits, and this trait showed linkage peaks on 11p and 15q. No evidence for linkage to 6p22-23 was found for this set of families. Comparison of our results and literature data shows that loci link to different phenotypes in different samples. The mutual connections of these traits and their relation to developmental dyslexia remain elusive., (Copyright 2007 Wiley-Liss, Inc.)
- Published
- 2008
- Full Text
- View/download PDF
24. Identification of a chromosome 8p locus for early-onset coronary heart disease in a French Canadian population.
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Engert JC, Lemire M, Faith J, Brisson D, Fujiwara TM, Roslin NM, Brewer CG, Montpetit A, Darmond-Zwaig C, Renaud Y, Doré C, Bailey SD, Verner A, Tremblay G, St-Pierre J, Bétard C, Platko J, Rioux JD, Morgan K, Hudson TJ, and Gaudet D
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- Adult, Age of Onset, Aged, Aged, 80 and over, Chromosome Mapping, Cohort Studies, DNA genetics, Female, Founder Effect, France ethnology, Genetic Markers, Genome, Human, Humans, Male, Microsatellite Repeats, Middle Aged, Polymorphism, Genetic, Quebec, Chromosomes, Human, Pair 8 genetics, Coronary Disease genetics
- Abstract
Susceptibility to coronary heart disease (CHD) has long been known to exhibit familial aggregation, with heritability estimated to be greater than 50%. The French Canadian population of the Saguenay-Lac Saint-Jean region of Quebec, Canada is descended from a founder population that settled this region 300-400 years ago and this may provide increased power to detect genes contributing to complex traits such as CHD. Probands with early-onset CHD, defined by angiographically determined coronary stenosis, and their relatives were recruited from this population (average sibship size of 6.4). Linkage analysis was performed following a genome-wide microsatellite marker scan on 42 families with 284 individuals. Nonparametric linkage (NPL) analysis provided suggestive evidence for a CHD susceptibility locus on chromosome 8 with an NPL score of 3.14 (P=0.001) at D8S1106. Linkage to this locus was verified by fine mapping in an enlarged sample of 50 families with 320 individuals. This analysis provided evidence of linkage at D8S552 (NPL score=3.53, P=0.0003), a marker that maps to the same location as D8S1106. Candidate genes in this region, including macrophage scavenger receptor 1, farnesyl-diphosphate farnesyltransferase 1, fibrinogen-like 1, and GATA-binding protein 4, were resequenced in all coding exons in both affected and unaffected individuals. Association studies with variants in these and five other genes did not identify a disease-associated mutation. In conclusion, a genome-wide scan and additional fine mapping provide evidence for a locus on chromosome 8 that contributes to CHD in a French Canadian population.
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- 2008
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25. Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder.
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Stewart SE, Fagerness JA, Platko J, Smoller JW, Scharf JM, Illmann C, Jenike E, Chabane N, Leboyer M, Delorme R, Jenike MA, and Pauls DL
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- Adolescent, Age Distribution, Age of Onset, Child, Chromosome Mapping, Female, Gene Frequency, Genetic Predisposition to Disease genetics, Genotype, Haplotypes genetics, Humans, Linkage Disequilibrium genetics, Male, Obsessive-Compulsive Disorder diagnosis, Sex Distribution, Excitatory Amino Acid Transporter 3 genetics, Obsessive-Compulsive Disorder genetics, Polymorphism, Single Nucleotide genetics
- Abstract
Context: Obsessive-Compulsive Disorder (OCD) is a debilitating illness with putative glutamatergic abnormalities. Two separate proximal haplotypes in the glutamate transporter gene, SLC1A1, were recently reported to be associated with OCD among males, but replication is required., Objectives: This study examines SLC1A1 as a candidate gene for OCD and explores gender influences. It was hypothesized that a significant association between SLC1A1 and OCD would be replicated in an independent sample of males but not females., Design: Family-based association candidate gene study., Setting: Participants were recruited from tertiary care OCD specialty clinics., Participants: OCD probands and their first degree relatives., Main Outcomes Measures: Association of OCD with genotypes of single nucleotide polymorphism (SNP) markers and related haplotypes., Results: Association between OCD and the three-marker haplotype rs12682807/ rs2072657/ rs301430, with overtransmission of A/T/T, was observed in both genders combined (global P = 0.0015) and in males (global P = 0.0031). Single-marker associations with OCD in the region (rs3780412 and rs2228622) demonstrated modest significance (permuted P = 0.045)., Conclusions: This study identifies a significant association between the SLC1A1 glutamate transporter gene and OCD in a haplotype overlapping with that recently reported., (2007 Wiley-Liss, Inc.)
- Published
- 2007
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26. A genetic family-based association study of OLIG2 in obsessive-compulsive disorder.
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Stewart SE, Platko J, Fagerness J, Birns J, Jenike E, Smoller JW, Perlis R, Leboyer M, Delorme R, Chabane N, Rauch SL, Jenike MA, and Pauls DL
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- Chromosome Mapping, Comorbidity, Gene Frequency, Genetic Markers, Genetic Predisposition to Disease, Haplotypes genetics, Humans, Linkage Disequilibrium, Obsessive-Compulsive Disorder diagnosis, Obsessive-Compulsive Disorder epidemiology, Oligodendrocyte Transcription Factor 2, Pedigree, Phenotype, Polymorphism, Single Nucleotide genetics, Tourette Syndrome epidemiology, Tourette Syndrome genetics, Basic Helix-Loop-Helix Transcription Factors genetics, Family, Nerve Tissue Proteins genetics, Obsessive-Compulsive Disorder genetics
- Abstract
Context: Obsessive-compulsive disorder (OCD) is a debilitating familial psychiatric illness with associated brain abnormalities in the white matter. The gene for oligodendrocyte lineage transcription factor 2 (OLIG2) is an essential regulator in the development of cells that produce white matter (myelin). The OLIG2 gene is also highly expressed in brain regions implicated in OCD., Objectives: To examine OLIG2 as a candidate gene for OCD susceptibility and to explore whether comorbidity subtypes of OCD have distinct associations with OLIG2 and the functionally related OLIG1 gene. It was hypothesized a priori that OLIG2 and OLIG1 were associated with OCD regardless of the presence of comorbid Tourette disorder (TD), but not with TD alone., Design: Family-based association candidate gene study., Setting: Participants and their family members were recruited from tertiary care OCD and TD specialty clinics., Participants: Families of 66 probands with OCD with and without TD and 31 probands with TD without OCD., Main Outcome Measures: Genotypes of single nucleotide polymorphism markers and related haplotypes., Results: The following 3 single nucleotide polymorphism markers on OLIG2 were associated with the OCD without TD phenotype: rs762178 (minor allele frequency, 35%; P<.001), rs1059004 (minor allele frequency, 44%; P = .005), and rs9653711 (minor allele frequency, 44%; P = .004). A 5-marker haplotype (A/C/T/T/G) constituting these single nucleotide polymorphisms and exonic single nucleotide polymorphisms rs6517137 and rs13046814 was undertransmitted (frequency, 32%; permuted P=.004), whereas the G/A/T/T/C haplotype (frequency, 22%; permuted P=.02) was overtransmitted to probands with OCD alone, with a significant global P value (permuted P=.008)., Conclusions: This is the first study reporting an association between OLIG2 and OCD, specifically when TD comorbidity is absent. The findings support a role for white matter abnormalities in the etiology of the disorder.
- Published
- 2007
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27. Genomewide linkage analysis of stature in multiple populations reveals several regions with evidence of linkage to adult height.
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Hirschhorn JN, Lindgren CM, Daly MJ, Kirby A, Schaffner SF, Burtt NP, Altshuler D, Parker A, Rioux JD, Platko J, Gaudet D, Hudson TJ, Groop LC, and Lander ES
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- Chromosomes, Human, Pair 12 genetics, Chromosomes, Human, Pair 13 genetics, Chromosomes, Human, Pair 6 genetics, Chromosomes, Human, Pair 7 genetics, Environment, Female, Finland, Genotype, Humans, Lod Score, Male, Microsatellite Repeats genetics, Middle Aged, Quebec, Software, Sweden, Body Height genetics, Chromosome Mapping methods, Chromosome Mapping statistics & numerical data, Genetic Linkage genetics, Quantitative Trait, Heritable
- Abstract
Genomewide linkage analysis has been extremely successful at identification of the genetic variation underlying single-gene disorders. However, linkage analysis has been less successful for common human diseases and other complex traits in which multiple genetic and environmental factors interact to influence disease risk. We hypothesized that a highly heritable complex trait, in which the contribution of environmental factors was relatively limited, might be more amenable to linkage analysis. We therefore chose to study stature (adult height), for which heritability is approximately 75%-90% (Phillips and Matheny 1990; Carmichael and McGue 1995; Preece 1996; Silventoinen et al. 2000). We reanalyzed genomewide scans from four populations for which genotype and height data were available, using a variance-components method implemented in GENEHUNTER 2.0 (Pratt et al. 2000). The populations consisted of 408 individuals in 58 families from the Botnia region of Finland, 753 individuals in 183 families from other parts of Finland, 746 individuals in 179 families from Southern Sweden, and 420 individuals in 63 families from the Saguenay-Lac-St.-Jean region of Quebec. Four regions showed evidence of linkage to stature: 6q24-25, multipoint LOD score 3.85 at marker D6S1007 in Botnia (genomewide P<.06), 7q31.3-36 (LOD 3.40 at marker D7S2195 in Sweden, P<.02), 12p11.2-q14 (LOD 3.35 at markers D12S10990-D12S398 in Finland, P<.05) and 13q32-33 (LOD 3.56 at markers D13S779-D13S797 in Finland, P<.05). In a companion article (Perola et al. 2001 [in this issue]), strong supporting evidence is obtained for linkage to the region on chromosome 7. These studies suggest that highly heritable complex traits such as stature may be genetically tractable and provide insight into the genetic architecture of complex traits.
- Published
- 2001
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28. Polyoma middle T antigen in HL-60 cells accelerates hematopoietic myeloid and monocytic cell differentiation.
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Platko JD, Forbes ME, Varvayanis S, Williams MN, Brooks SC 3rd, Cherington V, and Yen A
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- Calcitriol pharmacology, Cell Adhesion Molecules biosynthesis, Cell Differentiation drug effects, Cell Division drug effects, Cytoskeletal Proteins biosynthesis, HL-60 Cells, Humans, Kinetics, Paxillin, Phosphoproteins biosynthesis, Recombinant Proteins biosynthesis, Time Factors, Transfection, Transglutaminases biosynthesis, Tretinoin pharmacology, Antigens, Polyomavirus Transforming biosynthesis, Cell Differentiation physiology, Granulocytes cytology, Monocytes cytology
- Abstract
Expression of the polyoma virus middle T antigen in HL-60 cells accelerates their differentiation in response to both monocytic and granulocytic differentiation-inducing agents. Middle T-expressing cells treated with the granulocytic inducer retinoic acid or the monocytic inducer 1,25-dihydroxy vitamin D3 differentiated 24 h earlier than parental, mock-electroporated, or vector control cell lines. The rapid onset of differentiation correlated with an increase in the cellular level of the middle T protein as well as two known retinoic-acid-inducible markers in HL-60 cells: the paxillin and transglutaminase gene products. The accelerated functional differentiation response and expression of retinoic-acid-inducible markers indicate that middle T played a causal role in differentiation. Thus, expression of the polyoma middle T antigen in HL-60 cells enhanced a variety of molecular changes associated with cellular differentiation.
- Published
- 1998
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29. Paxillin increases as retinoic acid or vitamin D3 induce HL-60 cell differentiation.
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Platko JD and Yen A
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- Cell Differentiation drug effects, Granulocytes cytology, Humans, Monocytes cytology, Paxillin, Cholecalciferol pharmacology, Cytoskeletal Proteins biosynthesis, HL-60 Cells cytology, Phosphoproteins biosynthesis, Tretinoin pharmacology
- Published
- 1997
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30. Expression of activated RAF accelerates cell differentiation and RB protein down-regulation but not hypophosphorylation.
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Yen A, Williams M, Platko JD, Der C, and Hisaka M
- Subjects
- Cell Differentiation genetics, Cell Division drug effects, Down-Regulation genetics, Humans, Phosphorylation, Time Factors, Transfection, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic drug effects, Macrophage Colony-Stimulating Factor pharmacology, Retinoblastoma Protein metabolism, Tretinoin pharmacology
- Abstract
Expression of an activated raf transgene accelerated the terminal myeloid differentiation of HL-60 human promyelocytic leukemia cells induced by retinoic acid. A similar result was obtained when 1,25-dihydroxyvitamin D3 was used to induce monocytic differentiation. The stable transfectants were derived by transfecting HL-60 cells with DNA encoding an N-terminal truncated raf-1 protein. In normal HL-60 cells retinoic acid is known to induce a colony-stimulating factor-1 (CSF-1)-dependent metabolic cascade culminating in G0 arrest and phenotypic conversion. Early in this cascade, expression of the RB tumor suppressor gene product is down-regulated. A progressive redistribution of the form of the protein from largely hyperphosphorylated protein to the hypophosphorylated form begins later with G0 arrest and differentiation. In the activated raf-transfected cells, RB down regulation occurred more rapidly, consistent with accelerated differentiation. But the conversion to the hypophosphorylated form was not accelerated and occurred after G0 arrest and phenotypic conversion to myeloid differentiated cells. Thus raf activation appears to be a component of the induced metabolic cascade culminating in terminal differentiation. In this cascade raf activation promotes RB down-regulation. The data are consistent with a model in which raf is an effector of the CSF-1-dependent metabolic cascade which culminates in terminal cell differentiation, and RB downregulation is one of the downstream consequences of RAF action. Furthermore, they indicate that RB down-regulation may be an essential component of the cellular processes causing G0 arrest and differentiation, but RB hypophosphorylation is more likely a consequence thereof and not a cause.
- Published
- 1994
31. The erbB3 gene product is a receptor for heregulin.
- Author
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Carraway KL 3rd, Sliwkowski MX, Akita R, Platko JV, Guy PM, Nuijens A, Diamonti AJ, Vandlen RL, Cantley LC, and Cerione RA
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- 3T3 Cells, Amino Acid Sequence, Animals, Baculoviridae genetics, Binding Sites, Cattle, Cells, Cultured, Cloning, Molecular, Escherichia coli genetics, Iodine Radioisotopes, Mice, Molecular Sequence Data, Moths, Phosphorylation, Receptor, ErbB-3, Transfection, Tyrosine metabolism, Carrier Proteins metabolism, ErbB Receptors metabolism, Glycoproteins metabolism, Neuregulin-1, Proto-Oncogene Proteins metabolism
- Abstract
ErbB3 is a member of the epidermal growth factor (EGF) receptor subfamily of receptor tyrosine kinases and is believed to be a receptor for an unknown ligand. We have tested the possibility that heregulin, a growth factor possessing an EGF-like domain, is a ligand for ErbB3. We have found that the iodinated recombinant EGF-like domain of heregulin-beta 1 (125I-rHRG beta 1(177-244) bound specifically to insect cell-expressed bovine ErbB3 with a dissociation constant of 0.85 nM. Moreover, 125I-rHRG beta 1(177-244) bound to NIH3T3 fibroblasts stably transfected with bovine erbB3 with a dissociation constant of 60 pM, but did not bind to parental cells. 125I-rHRG beta 1(177-244) could be chemically cross-linked to a 170-180 kDa protein in erbB3-transfected fibroblasts, and the cross-linked product could be immunoprecipitated with antibodies specific for ErbB3. Finally, rHRG beta 1 stimulated the tyrosine phosphorylation of both ErbB3 and endogenous p185erbB2/neu in transfectants but not in parental cells. We conclude that ErbB3 is a receptor for HRG and is capable of mediating HRG-stimulated tyrosine phosphorylation of itself and p185erbB2/neu in cells that express both receptors.
- Published
- 1994
32. C-FMS dependent HL-60 cell differentiation and regulation of RB gene expression.
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Yen A, Forbes ME, Varvayanis S, Tykocinski ML, Groger RK, and Platko JD
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- Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Antibody Specificity, Blotting, Western, Calcitriol pharmacology, Cell Transformation, Neoplastic genetics, DNA, Neoplasm analysis, DNA, Neoplasm genetics, Down-Regulation genetics, Gene Expression Regulation, Neoplastic physiology, Genes, Retinoblastoma physiology, Humans, Leukemia, Promyelocytic, Acute genetics, Leukemia, Promyelocytic, Acute metabolism, Macrophages chemistry, Macrophages pathology, Macrophages ultrastructure, Monocytes chemistry, Monocytes pathology, Monocytes ultrastructure, Receptor, Macrophage Colony-Stimulating Factor analysis, Receptor, Macrophage Colony-Stimulating Factor immunology, Time Factors, Transfection, Tretinoin pharmacology, Tumor Cells, Cultured, Cell Transformation, Neoplastic pathology, Gene Expression Regulation, Neoplastic genetics, Genes, Retinoblastoma genetics, Leukemia, Promyelocytic, Acute pathology, Receptor, Macrophage Colony-Stimulating Factor physiology
- Abstract
The dependence of induced myelomonocytic cell differentiation, and regulation of the RB tumor suppressor gene during this process, on the c-fms gene product, the CSF-1 lymphokine receptor, was determined in HL-60 promyelocytic leukemia cells. Adding a monoclonal antibody with specificity for the c-fms gene product to cells treated with various inducers of myelomonocytic or macrophage differentiation, including retinoic acid and 1,25-dihydroxy vitamin D3, inhibited the rate of differentiation. During the period of inducer treatment usually preceding onset of differentiation, longer periods of antibody exposure caused greater inhibition of differentiation. In a stable HL-60 transfectant overexpressing the CSF-1 receptor at the cell surface due to a constitutively driven c-fms trans gene, the rate of differentiation was enhanced compared to the wild type cell, consistent with a positive regulatory role for the CSF-1 receptor. The anti-fms antibody caused much less inhibition of differentiation in the transfectants than in wild type cells, consistent with a larger number of receptors causing reduced sensitivity. During the induced metabolic cascade leading to differentiation, the typical early down regulation of RB gene expression was inhibited by the antibody. The antibody itself caused an increase in RB expression per cell, which offset the decrease normally caused by differentiation inducers (1,25-dihydroxy vitamin D3 and retinoic acid). The changes in RB expression preceded changes in the RB protein to the hypophosphorylated state. Most of the RB protein in proliferating cells was phosphorylated and no significant accumulation of hypophosphorylated RB protein occurred until after onset of G0 arrest. Thus the metabolic cascade leading to myelomonocytic differentiation of HL-60 cells appears to be driven by a function of the c-fms protein. Inhibiting that process by attacking this receptor impedes differentiation and also compromises the early down regulation of RB tumor suppressor gene expression which normally precedes differentiation. These findings provide additional support for a potential role for down regulating RB expression in promoting cell differentiation, and suggest the possibility that RB may be either a target or intermediate mediator of CSF-1 actions.
- Published
- 1993
- Full Text
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33. 12-O-tetradecanoylphorbol-13-acetate and staurosporine induce increased retinoblastoma tumor suppressor gene expression with megakaryocytic differentiation of leukemic cells.
- Author
-
Yen A, Varvayanis S, and Platko JD
- Subjects
- Cell Cycle drug effects, Cell Differentiation, DNA, Neoplasm metabolism, Gene Expression Regulation, Leukemic drug effects, Gene Expression Regulation, Leukemic genetics, Genes, Retinoblastoma drug effects, Humans, Kinetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive metabolism, Megakaryocytes cytology, Phosphorylation, Protein Kinase C antagonists & inhibitors, Retinoblastoma Protein metabolism, Staurosporine, Tumor Cells, Cultured drug effects, Alkaloids pharmacology, Gene Expression drug effects, Genes, Retinoblastoma genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive pathology, Megakaryocytes physiology, Tetradecanoylphorbol Acetate pharmacology
- Abstract
The phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), induced increased expression of the retinoblastoma (RB) tumor suppressor gene product in the course of megakaryocytic differentiation of the K562 human leukemia cell line, a differentiatively multipotent hematopoietic precursor cell. The induced increase in RB protein per cell occurred early, by 8 h of treatment, preceding any significant phenotypic differentiation evidenced by cellular expression of the CD41 differentiation-specific megakaryocytic cell surface marker, but not inhibition of cell cycle transit, leading to a cell population arrested with 2 n, 4 n, and 8 n DNA content. The increase in RB protein per cell occurred for cells in all cell cycle phases. Staurosporine (STSP) was found to induce a similar course of cell cycle arrest and differentiation. Furthermore, STSP caused an up-regulation of RB expression similar to that caused by TPA. Almost all of the RB protein is phosphorylated in untreated cells, but TPA and STSP both caused the late appearance of hypophosphorylated RB protein following cell cycle arrest. The STSP-caused hypophosphorylation was much later than the TPA effect. Hypophosphorylation of RB is, thus, not necessarily a prerequisite for cell cycle arrest but may be a consequence of G0. Given that TPA can be an activator and STSP an inhibitor of protein kinase C, it appears that the induced processes of tumor suppressor gene regulation and growth and differentiation control are not necessarily protein kinase C dependent in K562 cells. Furthermore, the findings that these two presumably divergent inducing agents caused a similar increase in RB gene expression suggests that the up-regulation of RB associated with differentiation is not a coincidence of just one specific inducer but may be a common essential feature of the induced differentiation. The amount of RB protein per cell increased within hours of exposure to TPA or STSP and may have a role in the induced metabolic cascade producing the new phenotype.
- Published
- 1993
34. The identification and characterization of a GDP-dissociation inhibitor (GDI) for the CDC42Hs protein.
- Author
-
Leonard D, Hart MJ, Platko JV, Eva A, Henzel W, Evans T, and Cerione RA
- Subjects
- Amino Acid Sequence, Animals, Brain metabolism, Cattle, Cell Line, Cell Membrane metabolism, Chromatography, Ion Exchange, Cloning, Molecular, Cytosol metabolism, Escherichia coli genetics, GTP-Binding Proteins genetics, GTP-Binding Proteins isolation & purification, Humans, Kinetics, Molecular Sequence Data, Moths, Recombinant Proteins isolation & purification, Recombinant Proteins metabolism, Recombinant Proteins pharmacology, Sequence Homology, Amino Acid, Transfection, cdc42 GTP-Binding Protein, rho-Specific Guanine Nucleotide Dissociation Inhibitors, Blood Platelets metabolism, GTP-Binding Proteins metabolism, Guanine Nucleotide Dissociation Inhibitors, Guanosine Diphosphate metabolism
- Abstract
The ras-related protein, CDC42Hs, is a 22-kDa GTP-binding protein which is the human homolog of a Saccharomyces cerevisiae yeast-cell-division cycle protein. In attempting to isolate and biochemically characterize mammalian proteins capable of regulating various activities of CDC42Hs, we have identified an activity in bovine brain cytosol which effectively inhibits the dissociation of [3H]GDP from the platelet- or the Spodoptera frugiperda-expressed CDC42Hs protein. The purification of this activity was achieved by a series of steps which included ammonium sulfate fractionation, DEAE-Sephacel, Mono-Q, and Mono-S chromatographies. The purified CDC42Hs regulatory protein has an apparent molecular weight of 28,000, and cyanogen bromide-generated peptide sequences of this protein were identical to sequences from the carboxyl-terminal portion of rho-GDP-dissociation inhibitor (rho-GDI) (Fukumoto, Y., Kaibuchi, K., Hori, Y., Fujioka, H., Araki, S., Ueda, T., Kikuchi, A., and Takai, Y. (1990) Oncogene 5, 1321-1328). In addition, an Escherichia coli-expressed, glutathione S-transferase-rho-GDI fusion protein fully substitutes for the GDI which we have purified from bovine brain in its ability to inhibit GDP dissociation from CDC42Hs. These findings suggest either that a common regulatory protein (GDI) is capable of inhibiting GDP dissociation from the rho and CDC42Hs proteins or that these two GTP-binding proteins interact with GDI proteins of very similar structure. The purified brain GDI protein shows little ability to inhibit GDP dissociation from the E. coli-expressed CDC42Hs and is capable of only a very weak inhibition of the dissociation of [35S]guanosine 5'-3-O-(thio)triphosphate (GTP gamma S) from the Spodoptera frugiperda-expressed CDC42. However, brain GDI very effectively inhibits the ability of the human dbl oncogene product to catalyze GDP dissociation from CDC42Hs. In addition to influencing guanine nucleotide association with CDC42Hs, the purified brain GDI protein also appears to catalyze the dissociation of CDC42Hs from the plasma membranes of human placenta and human epidermoid carcinoma (A431) cells. This effect by the GDI protein is observed whether the membrane-associated CDC42Hs is preincubated with GDP, GTP gamma S, or no guanine nucleotides, and occurs over a similar concentration range as that necessary for the inhibition of the intrinsic GDP dissociation.
- Published
- 1992
35. Characterization of Lrp, and Escherichia coli regulatory protein that mediates a global response to leucine.
- Author
-
Willins DA, Ryan CW, Platko JV, and Calvo JM
- Subjects
- Amino Acid Sequence, Bacterial Proteins isolation & purification, Bacterial Proteins metabolism, Base Sequence, Blotting, Western, Chromatography, Affinity, Chromatography, Gel, Chromatography, Ion Exchange, Cloning, Molecular, DNA-Binding Proteins isolation & purification, DNA-Binding Proteins metabolism, Electrophoresis, Polyacrylamide Gel, Escherichia coli drug effects, Escherichia coli metabolism, Escherichia coli Proteins, Genes, Bacterial, Leucine-Responsive Regulatory Protein, Molecular Sequence Data, Oligonucleotide Probes, Polymerase Chain Reaction, Sequence Homology, Nucleic Acid, Bacterial Proteins genetics, DNA-Binding Proteins genetics, Escherichia coli genetics, Leucine pharmacology, Operon drug effects, Transcription Factors
- Abstract
Exogenous leucine affects the expression of a number of different operons in Escherichia coli. For at least some of these operons, the leucine-related effect is mediated by a protein called Lrp (Leucine-responsive regulatory protein). The purification of Lrp to near homogeneity is described. Lrp is a moderately abundant, basic protein composed of two subunits of molecular mass 18.8 kDa each. In addition, the corresponding protein was purified from a strain having a mutation within the gene that encodes Lrp (lrp). This mutation (lrp-1) causes high constitutive expression of ilvIH, one of the operons controlled by Lrp (Platko, J. V., Willins, D.A., and Calvo, J.M. (1990) J. Bacteriol. 172, 4563-4570). The Lrp-1 and Lrp proteins have similar physical properties, but they show some differences in the characteristics with which they bind DNA upstream of the ilvIH promoter. The nucleotide sequences of the lrp and lrp-1 genes differ by only a single nucleotide, a C to G change that would substitute a Glu for an Asp at amino acid 114. Lrp has some amino acid sequence similarity to AsnC, a protein that regulates asnA expression (Kolling, R., and Lother, H. (1985) J. Bacteriol. 164, 310-315).
- Published
- 1991
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